Universal antifungal therapy is not needed in persistent febrile neutropenia: a tailored diagnostic and therapeutic approach

PubMed Central

Aguilar-Guisado, Manuela; Martín-Peña, Almudena; Espigado, Ildefonso; Ruiz Pérez de Pipaon, Maite; Falantes, José; de la Cruz, Fátima; Cisneros, José M.

2012-01-01

Background Giving antifungal therapy exclusively to selected patients with persistent febrile neutropenia may avoid over-treatment without increasing mortality. The aim of this study was to validate an innovative diagnostic and therapeutic approach based on assessing patients’ risk profile and clinical criteria in order to select those patients requiring antifungal therapy. The efficacy of this approach was compared to that of universal empirical antifungal therapy. Design and Methods This was a prospective study which included all consecutive adult hematology patients with neutropenia and fever refractory to 5 days of empirical antibacterial therapy admitted to a teaching hospital in Spain over a 2-year period. A diagnostic and therapeutic approach based on clinical criteria and risk profile was applied in order to select patients for antifungal therapy. The sensitivity, specificity and negative predictive value of this approach and also the overall success rate, according to the same criteria of efficacy described in classical clinical trials, were analyzed. Results Eighty-five episodes were included, 35 of them (41.2%) in patients at high risk of invasive fungal infections. Antifungal therapy was not indicated in 33 episodes (38.8%). The overall incidence of proven and probable invasive fungal infections was 14.1%, all of which occurred in patients who had received empirical antifungal therapy. The 30-day crude mortality rate was 15.3% and the invasive fungal infection-related mortality rate was 2.8% (2/72). The overall success rate following the diagnostic and therapeutic approach was 36.5% compared with 33.9% and 33.7% obtained in the trial by Walsh et al. The sensitivity, specificity and negative predictive value of the study approach were 100%, 52.4% and 100%, respectively. Conclusions Based on the high negative predictive value of this diagnostic and therapeutic approach in persistent febrile neutropenia patients with hematologic malignancies or patients

Antifungal therapies for allergic bronchopulmonary aspergillosis in people with cystic fibrosis.

PubMed

Elphick, Heather E; Southern, Kevin W

2014-11-28

Allergic bronchopulmonary aspergillosis (ABPA) is an allergic reaction to colonisation of the lungs with the fungus Aspergillus fumigatus and affects around 10% of people with cystic fibrosis. ABPA is associated with an accelerated decline in lung function. High doses of corticosteroids are the main treatment for ABPA; although the long-term benefits are not clear, their many side effects are well-documented. A group of compounds, the azoles, have activity against Aspergillus fumigatus and have been proposed as an alternative treatment for ABPA. Of this group, itraconazole is the most active. A separate antifungal compound, amphotericin B, has been employed in aerosolised form to treat invasive infection with Aspergillus fumigatus, and may have potential for the treatment of ABPA. Antifungal therapy for ABPA in cystic fibrosis needs to be evaluated. The review aimed to test the hypotheses that antifungal interventions for the treatment of ABPA in cystic fibrosis:1. improve clinical status compared to placebo or standard therapy (no placebo);2. do not have unacceptable adverse effects.If benefit was demonstrated, we aimed to assess the optimal type, duration and dose of antifungal therapy. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings.In addition, pharmaceutical companies were approached.Date of the most recent search of the Group's Trials Register: 17 March 2014. Published or unpublished randomised controlled trials, where antifungal treatments have been compared to either placebo or no treatment, or where different doses of the same treatment have been used in the treatment of ABPA in people with cystic fibrosis. Four trials were identified by the searches; none of which was judged eligible for inclusion in the review. No completed randomised controlled trials

Antifungal therapies for allergic bronchopulmonary aspergillosis in people with cystic fibrosis.

PubMed

Elphick, Heather E; Southern, Kevin W

2016-11-08

Allergic bronchopulmonary aspergillosis (ABPA) is an allergic reaction to colonisation of the lungs with the fungus Aspergillus fumigatus and affects around 10% of people with cystic fibrosis. ABPA is associated with an accelerated decline in lung function. High doses of corticosteroids are the main treatment for ABPA; although the long-term benefits are not clear, their many side effects are well-documented. A group of compounds, the azoles, have activity against Aspergillus fumigatus and have been proposed as an alternative treatment for ABPA. Of this group, itraconazole is the most active. A separate antifungal compound, amphotericin B, has been employed in aerosolised form to treat invasive infection with Aspergillus fumigatus, and may have potential for the treatment of ABPA. Antifungal therapy for ABPA in cystic fibrosis needs to be evaluated. This is an update of a previously published review. The review aimed to test the hypotheses that antifungal interventions for the treatment of ABPA in cystic fibrosis:1. improve clinical status compared to placebo or standard therapy (no placebo);2. do not have unacceptable adverse effects.If benefit was demonstrated, we aimed to assess the optimal type, duration and dose of antifungal therapy. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings.In addition, pharmaceutical companies were approached.Date of the most recent search of the Group's Trials Register: 29 September 2016. Published or unpublished randomised controlled trials, where antifungal treatments have been compared to either placebo or no treatment, or where different doses of the same treatment have been used in the treatment of ABPA in people with cystic fibrosis. Four trials were identified by the searches; none of which was judged eligible for inclusion in

The antifungal pipeline: a reality check

PubMed Central

Perfect, John R.

2017-01-01

Invasive fungal infections continue to appear in record numbers as the immunocompromised population of the world increases, owing partially to the increased number of individuals who are infected with HIV and partially to the successful treatment of serious underlying diseases. The effectiveness of current antifungal therapies — polyenes, flucytosine, azoles and echinocandins (as monotherapies or in combinations for prophylaxis, or as empiric, pre-emptive or specific therapies) — in the management of these infections has plateaued. Although these drugs are clinically useful, they have several limitations, such as off-target toxicity, and drug-resistant fungi are now emerging. New antifungals are therefore needed. In this Review, I discuss the robust and dynamic antifungal pipeline, including results from preclinical academic efforts through to pharmaceutical industry products, and describe the targets, strategies, compounds and potential outcomes. PMID:28496146

Antifungal resistance in mucorales.

PubMed

Dannaoui, E

2017-11-01

The order Mucorales, which includes the agents of mucormycosis, comprises a large number of species. These fungi are characterised by high-level resistance to most currently available antifungal drugs. Standardised antifungal susceptibility testing methods are now available, allowing a better understanding of the in vitro activity of antifungal drugs against members of Mucorales. Such tests have made apparent that antifungal susceptibility within this group may be species-specific. Experimental animal models of mucormycosis have also been developed and are of great importance in bridging the gap between in vitro results and clinical trials. Amphotericin B, posaconazole and isavuconazole are currently the most active agents against Mucorales; however, their activity remains suboptimal and new therapeutic strategies are needed. Combination therapy could be a promising approach to overcome resistance, but further studies are required to confirm its benefits and safety for patients. Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Possible mechanisms of the antifungal activity of fluconazole in combination with terbinafine against Candida albicans.

PubMed

Khodavandi, Alireza; Alizadeh, Fahimeh; Vanda, Nasim Aghai; Karimi, Golgis; Chong, Pei Pei

2014-12-01

Candidiasis is a term describing infections by yeasts from the genus Candida, the majority Candida albicans. Treatment of such infections often requires antifungals such as the azoles, but increased use of these drugs has led to selection of yeasts with increased resistance to these drugs. Combination therapy would be one of the best strategies for the treatment of candidiasis due to increased resistance to azoles. The antifungal activities of fluconazole and terbinafine were evaluated in vitro alone and in combination using broth microdilution test and time kill study. Eventually the expression level of selected genes involved in ergosterol biosynthesis of Candida was evaluated using semi-quantitative RT-PCR. The obtained results showed the significant MICs ranging from 0.25 to 8 µg/mL followed by FICs ranged from 0.37 to 1 in combination with fluconazole/terbinafine. Our findings have demonstrated that the combination of fluconazole and terbinafine could also significantly reduce the expression of ERG1, 3, and 11 in the cell membrane of Candida in all concentrations tested ranging from 1.73- to 6.99-fold. This study was undertaken with the ultimate goal of finding the probable targets of fluconazole/terbinafine in C. albicans by looking at its effects on cell membrane synthesis.

Antifungal activity of geldanamycin alone or in combination with fluconazole against Candida species.

PubMed

Zhang, Jinqing; Liu, Wei; Tan, Jingwen; Sun, Yi; Wan, Zhe; Li, Ruoyu

2013-04-01

A standardized broth microdilution method was used to test the antifungal activity of geldanamycin (GA), an inhibitor of heat shock protein 90 (Hsp90), alone or in combination with the antifungal agent fluconazole (FLC) against 32 clinical isolates of Candida spp. In addition, a disk diffusion test was also used to evaluate the antifungal effect of these two drugs against Candida spp. by measuring the inhibition zone diameters. We found that the range of minimal inhibitory concentrations (MICs) for GA alone against Candida spp. was 3.2-12.8 mg/L and the geometric mean of MICs was 6.54 mg/L. In addition, the combination of GA with FLC showed synergistic effects in vitro against 2 FLC-susceptible and 6 FLC-resistant isolates of C. albicans. As for the other isolates, indifference but no antagonism was observed. In the disk diffusion assay, the diameter of inhibition zones for FLC combined with GA against FLC-resistant C. albicans isolates was 30 mm, while no inhibition was observed with FLC alone. These results demonstrate that GA possesses antifungal activity against Candida spp., and the combination of GA with FLC shows in vitro synergistic activity against some C. albicans isolates, especially those resistant to FLC.

Antifungal Resistance, Metabolic Routes as Drug Targets, and New Antifungal Agents: An Overview about Endemic Dimorphic Fungi

PubMed Central

Parente-Rocha, Juliana Alves; Bailão, Alexandre Melo; Amaral, André Correa; Paccez, Juliano Domiraci; Borges, Clayton Luiz

2017-01-01

Diseases caused by fungi can occur in healthy people, but immunocompromised patients are the major risk group for invasive fungal infections. Cases of fungal resistance and the difficulty of treatment make fungal infections a public health problem. This review explores mechanisms used by fungi to promote fungal resistance, such as the mutation or overexpression of drug targets, efflux and degradation systems, and pleiotropic drug responses. Alternative novel drug targets have been investigated; these include metabolic routes used by fungi during infection, such as trehalose and amino acid metabolism and mitochondrial proteins. An overview of new antifungal agents, including nanostructured antifungals, as well as of repositioning approaches is discussed. Studies focusing on the development of vaccines against antifungal diseases have increased in recent years, as these strategies can be applied in combination with antifungal therapy to prevent posttreatment sequelae. Studies focused on the development of a pan-fungal vaccine and antifungal drugs can improve the treatment of immunocompromised patients and reduce treatment costs. PMID:28694566

Concepts and Principles of Photodynamic Therapy as an Alternative Antifungal Discovery Platform

PubMed Central

Dai, Tianhong; Fuchs, Beth B.; Coleman, Jeffrey J.; Prates, Renato A.; Astrakas, Christos; St. Denis, Tyler G.; Ribeiro, Martha S.; Mylonakis, Eleftherios; Hamblin, Michael R.; Tegos, George P.

2012-01-01

Opportunistic fungal pathogens may cause superficial or serious invasive infections, especially in immunocompromised and debilitated patients. Invasive mycoses represent an exponentially growing threat for human health due to a combination of slow diagnosis and the existence of relatively few classes of available and effective antifungal drugs. Therefore systemic fungal infections result in high attributable mortality. There is an urgent need to pursue and deploy novel and effective alternative antifungal countermeasures. Photodynamic therapy (PDT) was established as a successful modality for malignancies and age-related macular degeneration but photodynamic inactivation has only recently been intensively investigated as an alternative antimicrobial discovery and development platform. The concept of photodynamic inactivation requires microbial exposure to either exogenous or endogenous photosensitizer molecules, followed by visible light energy, typically wavelengths in the red/near infrared region that cause the excitation of the photosensitizers resulting in the production of singlet oxygen and other reactive oxygen species that react with intracellular components, and consequently produce cell inactivation and death. Antifungal PDT is an area of increasing interest, as research is advancing (i) to identify the photochemical and photophysical mechanisms involved in photoinactivation; (ii) to develop potent and clinically compatible photosensitizers; (iii) to understand how photoinactivation is affected by key microbial phenotypic elements multidrug resistance and efflux, virulence and pathogenesis determinants, and formation of biofilms; (iv) to explore novel photosensitizer delivery platforms; and (v) to identify photoinactivation applications beyond the clinical setting such as environmental disinfectants. PMID:22514547

In Vitro Activities of 35 Double Combinations of Antifungal Agents against Scedosporium apiospermum and Scedosporium prolificans▿

PubMed Central

Cuenca-Estrella, Manuel; Alastruey-Izquierdo, Ana; Alcazar-Fuoli, Laura; Bernal-Martinez, Leticia; Gomez-Lopez, Alicia; Buitrago, Maria J.; Mellado, Emilia; Rodriguez-Tudela, Juan L.

2008-01-01

Activities of 35 combinations of antifungal agents against Scedosporium spp. were analyzed by a checkerboard microdilution design and the summation of fractional concentration index. An average indifferent effect was detected apart from combinations of azole agents and echinocandins against Scedosporium apiospermum. Antagonism was absent for all antifungal combinations against both species. PMID:18195067

Granulocyte Colony-Stimulating Factor and Azole Antifungal Therapy in Murine Aspergillosis: Role of Immune Suppression

PubMed Central

Graybill, John R.; Bocanegra, Rosie; Najvar, Laura K.; Loebenberg, David; Luther, Mike F.

1998-01-01

Outbred ICR mice were immune suppressed either with hydrocortisone or with 5-fluorouracil and were infected intranasally with Aspergillus fumigatus. Beginning 3 days before infection some groups of mice were given recombinant human granulocyte colony-stimulating factor (G-CSF), SCH56592 (an antifungal triazole), or both. Corticosteroid-pretreated mice responded to SCH56592 and had reduced counts in lung tissue and prolonged survival. In these mice, G-CSF strongly antagonized the antifungal activity of SCH56592. Animals treated with both agents developed large lung abscesses with polymorphonuclear leukocytes and large amounts of Aspergillus. In contrast, mice made neutropenic with 5-fluorouracil and then infected with A. fumigatus conidia benefited from either G-CSF or triazoles, and the effect of the combination was additive rather than antagonistic. Host predisposing factors contribute in different ways to the outcome of growth factor therapy in aspergillosis. PMID:9756743

Tinea of vellus hair: an indication for systemic antifungal therapy.

PubMed

Gómez-Moyano, E; Crespo-Erchiga, V

2010-09-01

Topical antifungal treatment is indicated in tinea of glabrous skin, except in cases of extensive, multiple or recurrent lesions, or immunocompromised patients. However, in daily practice there are cases resistant to topical treatment despite these indications. Parasitism of the hair could be the cause behind the majority of isolated lesions of ringworm of hairless skin with a poor outcome with topical antifungal treatment. To present a prospective observational study of 13 cases of tinea of glabrous skin with topical antifungal resistance during the period 2007-2009. Cases were analysed from a clinical, mycological and therapeutic standpoint. The mean age was 7 years. Eight (62%) patients reported prior contact with an animal and 10 (77%) patients had received topical corticosteroids before visiting the dermatologist. Excoriation was observed in eight (62%) patients, and follicular micropustules were seen in 11 (85%). In all patients, some short thin hairs fell easily on to the slide during the skin scraping. In all patients all the few vellus hairs identified in direct examination were affected. All identified species were zoophilic or geophilic. All cases resolved after oral antifungal treatment. In tinea of glabrous skin with low response to topical antifungal treatment we must rule out tinea of the vellus hair. Infection by nonanthropophilic dermatophytes, previous corticosteroid therapy and excoriation might be predisposing factors. Parasitism of the vellus hair, observed by direct microscopy, should be another criterion for establishing systemic treatment from the onset, as is the case in tinea capitis. © 2010 The Authors. Journal Compilation © 2010 British Association of Dermatologists.

P&T Committee review of fluconazole: an effective alternative to antifungal therapy.

PubMed

Neu, H C; Bennett, J E; Bodey, G P; Rubin, R H; Schentag, J J; Sugar, A M

1990-03-01

Fluconazole is a new antifungal agent available in both oral and parenteral formulations. According to the experts in this roundtable discussion, fluconazole represents a major clinical advance in the treatment of candidiasis and cryptococcosis in cancer patients, patients with AIDS, organ transplant recipients, and other patients at risk for opportunistic mycoses. The pharmacokinetic profile for fluconazole permits infrequent dosing and also makes it ideal for tissue site infections. Fluconazole's low toxicity gives it an advantage over currently available antifungal therapy and will permit prompt presumptive treatment of selected infections.

Success rate and risk factors for failure of empirical antifungal therapy with itraconazole in patients with hematological malignancies: a multicenter, prospective, open-label, observational study in Korea.

PubMed

Kim, Soo-Jeong; Cheong, June-Won; Min, Yoo Hong; Choi, Young Jin; Lee, Dong-Gun; Lee, Je-Hwan; Yang, Deok-Hwan; Lee, Sang Min; Kim, Sung-Hyun; Kim, Yang Soo; Kwak, Jae-Yong; Park, Jinny; Kim, Jin Young; Kim, Hoon-Gu; Kim, Byung Soo; Ryoo, Hun-Mo; Jang, Jun Ho; Kim, Min Kyoung; Kang, Hye Jin; Cho, In Sung; Mun, Yeung Chul; Jo, Deog-Yeon; Kim, Ho Young; Park, Byeong-Bae; Kim, Jin Seok

2014-01-01

We assessed the success rate of empirical antifungal therapy with itraconazole and evaluated risk factors for predicting the failure of empirical antifungal therapy. A multicenter, prospective, observational study was performed in patients with hematological malignancies who had neutropenic fever and received empirical antifungal therapy with itraconazole at 22 centers. A total of 391 patients who had abnormal findings on chest imaging tests (31.0%) or a positive result of enzyme immunoassay for serum galactomannan (17.6%) showed a 56.5% overall success rate. Positive galactomannan tests before the initiation of the empirical antifungal therapy (P=0.026, hazard ratio [HR], 2.28; 95% confidence interval [CI], 1.10-4.69) and abnormal findings on the chest imaging tests before initiation of the empirical antifungal therapy (P=0.022, HR, 2.03; 95% CI, 1.11-3.71) were significantly associated with poor outcomes for the empirical antifungal therapy. Eight patients (2.0%) had premature discontinuation of itraconazole therapy due to toxicity. It is suggested that positive galactomannan tests and abnormal findings on the chest imaging tests at the time of initiation of the empirical antifungal therapy are risk factors for predicting the failure of the empirical antifungal therapy with itraconazole. (Clinical Trial Registration on National Cancer Institute website, NCT01060462).

Systemic antifungals to treat onychomycosis in children: a systematic review.

PubMed

Gupta, Aditya K; Paquet, Maryse

2013-01-01

Because of the low prevalence of onychomycosis in children, little is known about the efficacy and safety of systemic antifungals in this population. PubMed and Embase databases and the references of related publications were searched in March 2012 for clinical trials (CTs), retrospective analyses (RAs), and case reports (CRs) on the use of systemic antifungals for onychomycosis in children (<18 years). Twenty-six studies (5 CTs, 3 RAs, and 18 CRs) were published between 1976 and 2011. Most of these studies reported the use of systemic terbinafine and itraconazole for the treatment of onychomycosis in children. Therapy with systemic antifungals alone in children ages 1 to 17 years resulted in a complete cure rate of 70.8% (n = 151), whereas combined systemic and topical antifungal therapy in one infant and 19 children age 8 and older resulted in a complete cure rate of 80.0% (n = 20). The efficacy and safety profiles of terbinafine, itraconazole, griseofulvin, and fluconazole in children were similar to those previously reported for adults. In conclusion, based on the little information available on onychomycosis in children, systemic antifungal therapies in children are safe and cure rates are similar to the rates achieved in adults. © 2012 Wiley Periodicals, Inc.

ArtinM offers new perspectives in the development of antifungal therapy

PubMed Central

Ruas, Luciana P.; Carvalho, Fernanda C.; Roque-Barreira, Maria-Cristina

2012-01-01

The thermally dimorphic fungus Paracoccidioides brasiliensis is the causative agent of paracoccidioidomycosis (PCM), the most frequent systemic mycosis that affects the rural populations in Latin America. Despite significant developments in antifungal chemotherapy, its efficacy remains limited since drug therapy is prolonged and associated with toxic side effects and relapses. In response to these challenges, it is now recognized that several aspects of antifungal immunity can be modulated to better deal with fungal infections. A common idea for halting fungal infections has been the need to activate a cell-based, pro-inflammatory Th1 immune response to improve the fungal elimination. ArtinM, a D-mannose binding lectin from Artocarpus heterophyllus, has the property of modulating immunity against several intracellular pathogens. Here, we review the immunomodulatory activity of ArtinM during experimental PCM in mice. Both prophylactic and therapeutic protocols of ArtinM administration promotes a Th1 immune response balanced by IL-10, which outstandingly reduces the fungal load in organs of the treated mice while maintaining a controlled inflammation at the site of infection. A carbohydrate recognition-based interaction of ArtinM with Toll-like receptor 2 (TLR2) accounts for initiating the immunomodulatory effect of the lectin. The precise identification of the TLR2 N-glycan(s) targeted by ArtinM may support novel basis for the development of antifungal therapy. PMID:22715337

Combination of fluconazole with non-antifungal agents: a promising approach to cope with resistant Candida albicans infections and insight into new antifungal agent discovery.

PubMed

Liu, Shuyuan; Hou, Yinglong; Chen, Xu; Gao, Yuan; Li, Hui; Sun, Shujuan

2014-05-01

The past decades have witnessed a dramatic increase in invasive fungal infections, especially candidiasis. Despite the development of more effective new antifungal agents, fluconazole (FLC) is still widely used in the clinic because of its efficacy and low toxicity. However, as the number of patients treated with FLC has increased, FLC-resistant Candida albicans isolates emerge more frequently. In addition, biofilm-associated infections are commonly encountered and their resistance poses a great challenge to antifungal treatment. Various approaches have been proposed to increase the susceptibility of C. albicans to FLC in order to cope with treatment failures, among which is the combination of FLC with different classes of non-antifungal agents such as antibacterials, calcineurin inhibitors, heat shock protein 90 inhibitors, calcium homeostasis regulators and traditional Chinese medicine drugs. Interestingly, many of these combinations showed synergistic effects against C. albicans, especially resistant strains. The main mechanisms of these synergistic effects appear to be increasing the permeability of the membrane, reducing the efflux of antifungal drugs, interfering with intracellular ion homeostasis, inhibiting the activity of proteins and enzymes required for fungal survival, and inhibiting biofilm formation. These modes of action and the antifungal mechanisms of various compounds referenced in this paper highlight the idea that the reversal of fungal resistance can be achieved through various mechanisms. Studies examining drug interactions will hopefully provide new approaches against antifungal drug resistance as well as insight into antifungal agent discovery. Copyright © 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Searching new antifungals: The use of in vitro and in vivo methods for evaluation of natural compounds.

PubMed

Scorzoni, Liliana; Sangalli-Leite, Fernanda; de Lacorte Singulani, Junya; de Paula E Silva, Ana Carolina Alves; Costa-Orlandi, Caroline Barcelos; Fusco-Almeida, Ana Marisa; Mendes-Giannini, Maria José Soares

2016-04-01

In the last decades, the increased number of immunocompromised patients has led to the emergence of many forms of fungal infections. Furthermore, there are a restricted arsenal of antifungals available and an increase in the development of resistance to antifungal drugs. Because of these disadvantages, the search for new antifungal agents in natural sources has increased. The development of these new antifungal drugs involves various steps and methodologies. The evaluation of the in vitro antifungal activity and cytotoxicity are the first steps in the screening. There is also the possibility of antifungal combinations to improve the therapy and reduce toxicity. Despite that, the application of the new antifungal candidate could be used in association with photodynamic therapy or using nanotechnology as an ally. In vivo tests can be performed to evaluate the efficacy and toxicity using conventional and alternative animal models. In this work, we review the methods available for the evaluation of the antifungal activity and safety of natural products, as well as the recent advances of new technology in the application of natural products for antifungal therapy. Copyright © 2016 Elsevier B.V. All rights reserved.

Oral Candida in Patients with Fixed Orthodontic Appliance: In Vitro Combination Therapy.

PubMed

Alhamadi, Wisam; Al-Saigh, Rafal J; Al-Dabagh, Nebras N; Al-Humadi, Hussam W

2017-01-01

Fixed orthodontic appliance (FOA) increases the cariogenic microorganisms of mouth including candida. The aim was to evaluate the pharmacodynamic effects of some antibacterial drugs in combination with most applicable antifungal agents on candida isolated from patients with FOA. Three antifungal agents (amphotericin B (AMB), ketoconazole (KET), and itraconazole (ITZ)) and three antibacterial drugs (ciprofloxacin (CIP), doxycycline (DOX), and metronidazole (MET)) with serial concentrations have been used and microdilution broth method has been done for single and combination therapy, then fungal growth was assessed spectrophotometrically, and the combinations were evaluated by bliss independent analysis. According to bliss independent interaction, the synergistic interactions depended on Δ E values that showed the best for CIP was with AMB (Δ E = 55.14) followed with KET (Δ E = 41.23) and lastly ITR (Δ E = 39.67) at CIP = 150 mg/L. DOX was optimal with KET (Δ E = 42.11) followed with AMB (Δ E = 40.77) and the lowest with ITR (Δ E = 9.12) at DOX = 75 mg/L. MET is the best with AMB (Δ E = 40.95) and then with ITR (Δ E = 35.45) and finally KET (Δ E = 15.15) at MET 200 mg/L. Moreover, usage of higher concentrations of antibacterial agents revealed inhibitory effects. This study uncovers the optimum antibiotic combination therapy against cariogenic candida with FOA by usage of low therapeutic concentrations.

Ibuprofen Potentiates the In Vivo Antifungal Activity of Fluconazole against Candida albicans Murine Infection

PubMed Central

Miranda, Isabel M.; Silva-Dias, Ana; Silva, Ana P.; Rodrigues, Acácio G.; Pina-Vaz, Cidália

2015-01-01

Candida albicans is the most prevalent cause of fungemia worldwide. Its ability to develop resistance in patients receiving azole antifungal therapy is well documented. In a murine model of systemic infection, we show that ibuprofen potentiates fluconazole antifungal activity against a fluconazole-resistant strain, drastically reducing the fungal burden and morbidity. The therapeutic combination of fluconazole with ibuprofen may constitute a new approach for the management of antifungal therapeutics to reverse the resistance conferred by efflux pump overexpression. PMID:25845879

Targeting efflux pumps to overcome antifungal drug resistance

PubMed Central

Holmes, Ann R; Cardno, Tony S; Strouse, J Jacob; Ivnitski-Steele, Irena; Keniya, Mikhail V; Lackovic, Kurt; Monk, Brian C; Sklar, Larry A; Cannon, Richard D

2016-01-01

Resistance to antifungal drugs is an increasingly significant clinical problem. The most common antifungal resistance encountered is efflux pump-mediated resistance of Candida species to azole drugs. One approach to overcome this resistance is to inhibit the pumps and chemosensitize resistant strains to azole drugs. Drug discovery targeting fungal efflux pumps could thus result in the development of azole-enhancing combination therapy. Heterologous expression of fungal efflux pumps in Saccharomyces cerevisiae provides a versatile system for screening for pump inhibitors. Fungal efflux pumps transport a range of xenobiotics including fluorescent compounds. This enables the use of fluorescence-based detection, as well as growth inhibition assays, in screens to discover compounds targeting efflux-mediated antifungal drug resistance. A variety of medium- and high-throughput screens have been used to identify a number of chemical entities that inhibit fungal efflux pumps. PMID:27463566

Chemosensitization as a Means to Augment Commercial Antifungal Agents

PubMed Central

Campbell, Bruce C.; Chan, Kathleen L.; Kim, Jong H.

2012-01-01

Antimycotic chemosensitization and its mode of action are of growing interest. Currently, use of antifungal agents in agriculture and medicine has a number of obstacles. Foremost of these is development of resistance or cross-resistance to one or more antifungal agents. The generally high expense and negative impact, or side effects, associated with antifungal agents are two further issues of concern. Collectively, these problems are exacerbated by efforts to control resistant strains, which can evolve into a treadmill of higher dosages for longer periods. This cycle in turn, inflates cost of treatment, dramatically. A further problem is stagnation in development of new and effective antifungal agents, especially for treatment of human mycoses. Efforts to overcome some of these issues have involved using combinations of available antimycotics (e.g., combination therapy for invasive mycoses). However, this approach has had inconsistent success and is often associated with a marked increase in negative side effects. Chemosensitization by natural compounds to increase effectiveness of commercial antimycotics is a somewhat new approach to dealing with the aforementioned problems. The potential for safe natural products to improve antifungal activity has been observed for over three decades. Chemosensitizing agents possess antifungal activity, but at insufficient levels to serve as antimycotics, alone. Their main function is to disrupt fungal stress response, destabilize the structural integrity of cellular and vacuolar membranes or stimulate production of reactive oxygen species, augmenting oxidative stress and apoptosis. Use of safe chemosensitizing agents has potential benefit to both agriculture and medicine. When co-applied with a commercial antifungal agent, an additive or synergistic interaction may occur, augmenting antifungal efficacy. This augmentation, in turn, lowers effective dosages, costs, negative side effects and, in some cases, countermands resistance

Effect of 2-Phenylethanol as Antifungal Agent and Common Antifungals (Amphotericin B, Fluconazole, and Itraconazole) on Candida Species Isolated from Chronic and Recurrent Cases of Candidal Vulvovaginitis.

PubMed

Majdabadi, Niloufar; Falahati, Mehraban; Heidarie-Kohan, Fariba; Farahyar, Shirin; Rahimi-Moghaddam, Parvaneh; Ashrafi-Khozani, Mahtab; Razavi, Tandis; Mohammadnejad, Sina

2018-04-01

The antifungal effects of 2-phenylethanol are clearly visible through its intervention in Candida morphogenesis. Chronic and recurrent vulvovaginitis, however, does not respond to this standard experimental therapy; therefore, the study presented in this article investigated the effect of common antifungal drugs (amphotericin B [AMB], fluconazole [FLU], and itraconazole [ITC]), in combination with 2-phenylethanol, on the Candida species isolated from cases of chronic and recurrent vulvovaginitis, thereby allowing the recommendation of a more appropriate treatment option. Forty isolates from patients with chronic and recurrent vaginal candidiasis were investigated in this experimental study. The specimens were examined by direct microscopy, culturing, and PCR to identify the species. The antifungal effects of 2-phenylethanol and conventional drugs, both alone and in combination, were determined in duplicate. Finally, the findings were analyzed. In this study, 40 strains of Candida species were identified, whose agents were Candida albicans (95%) and Candida africana (5%). After 48 h, the minimum inhibitory concentration (MIC) range of the 2-phenylethanol was 800-3,200 μg/mL. Also, in the final study on the MIC levels of common antifungal drugs, AMB (0.42 μg/mL) had the lowest MIC, FLU (40.51 μg/mL) had the highest MIC, and the combination of ITC and 2-phenylethanol had the lowest fractional inhibitory concentration index (FICI) of any of the combinations (FICI range, 0.26-1.03). Combining FLU and ITC with 2-phenylethanol can effectively increase their antifungal effect.

Combination of different antifungal agents in oil-in-water emulsions to control strawberry jam spoilage.

PubMed

Ribes, Susana; Fuentes, Ana; Talens, Pau; Barat, Jose Manuel

2018-01-15

The combination of antifungal agents (cinnamon bark oil, zinc gluconate and trans-ferulic acid) in oil-in-water emulsions to control the fungal spoilage of strawberry jams, minimising essential oil's sensory impact, was evaluated in this work. The in vitro assays of free antifungal agents were performed against five fungal strains; meanwhile, the emulsions assays were conducted against Aspergillus niger given its strong resistance and its relevance in strawberry products. The emulsion formulated with 0.08mg/g of essential oil was able to inhibit mould growth after the incubation period. The incorporation of zinc gluconate or trans-ferulic acid, independently of the concentration used, allowed to reduce a 25% the amount of essential oil needed to inhibit the microbial growth. The combination of antifungal agents in the emulsions has demonstrated to be an effective alternative to reduce the amount of essential oil employed, maintaining the hygienic quality and sensory profile of the strawberry jam. Copyright © 2017 Elsevier Ltd. All rights reserved.

Antifungal activity of silver nanoparticles in combination with nystatin and chlorhexidine digluconate against Candida albicans and Candida glabrata biofilms.

PubMed

Monteiro, Douglas R; Silva, Sónia; Negri, Melyssa; Gorup, Luiz F; de Camargo, Emerson R; Oliveira, Rosário; Barbosa, Debora B; Henriques, Mariana

2013-11-01

Although silver nanoparticles (SN) have been investigated as an alternative to conventional antifungal drugs in the control of Candida-associated denture stomatitis, the antifungal activity of SN in combination with antifungal drugs against Candida biofilms remains unknown. Therefore, the aim of this study was to evaluate the antifungal efficacy of SN in combination with nystatin (NYT) or chlorhexidine digluconate (CHG) against Candida albicans and Candida glabrata biofilms. The drugs alone or combined with SN were applied on mature Candida biofilms (48 h), and after 24 h of treatment their antibiofilm activities were assessed by total biomass quantification (by crystal violet staining) and colony forming units enumeration. The structure of Candida biofilms was analysed by scanning electron microscopy (SEM) images. The data indicated that SN combined with either NYT or CHG demonstrated synergistic antibiofilm activity, and this activity was dependent on the species and on the drug concentrations used. SEM images showed that some drug combinations were able to disrupt Candida biofilms. The results of this study suggest that the combination of SN with NYT or CHG may have clinical implications in the treatment of denture stomatitis. However, further studies are needed before recommending the use of these drugs safely in clinical situations. © 2013 Blackwell Verlag GmbH.

Effects of antifungal agents alone and in combination against Candida glabrata strains susceptible or resistant to fluconazole.

PubMed

Alves, Izabel Almeida; Bandeira, Laíssa Arévalo; Mario, Débora Alves Nunes; Denardi, Laura Bedin; Neves, Louise Vignoles; Santurio, Janio Morais; Alves, Sydney Hartz

2012-09-01

The rise of Candida spp. resistant to classic triazole antifungal agents has led to a search for new therapeutic options. Here, we evaluated combinations of antifungals in a checkerboard assay against two groups of Candida glabrata strains: one containing fluconazole-susceptible clinical isolates (FS) and another containing fluconazole-resistant laboratory derivative (FR). The most synergistic combination observed was amphotericin B + flucytosine (synergistic for 61.77 % of FS strains and 76.47 % of FR strains). The most antagonistic combination observed was ketoconazole + flucytosine (FS 61.77 % and FR 55.88 %). Surprisingly, most combinations evidenced indifferent interactions, and the best synergism appeared when amphotericin B and flucytosine were combined against both groups of isolates.

Combined antifungal therapy against systemic murine infections by rare Cryptococcus species.

PubMed

Thomson, Pamela; Mayayo, Emilio; López-Fernández, Loida; Guarro, Josep; Capilla, Javier

2017-02-01

Cryptococcus albidus and Cryptococcus laurentii are uncommon species of this genus that in recent decades have increasingly caused opportunistic infections in humans, mainly in immunocompromised patients; the best therapy for such infection being unknown. Using a murine model of systemic infection by these fungi, we have evaluated the efficacy of amphotericin B (AMB) at 0.8 mg/kg, administered intravenously, fluconazole (FLC) or voriconazole (VRC), both administered orally, at 25 mg/kg and the combination of AMB plus VRC against three C. albidus and two C. laurentii strains. All the treatments significantly reduced the fungal burden in all the organs studied. The combination showed a synergistic effect in the reduction in fungal load, working better than both monotherapies. The histopathological study confirmed the efficacy of the treatments. © 2016 Blackwell Verlag GmbH.

Antifungal activity of Rubus chingii extract combined with fluconazole against fluconazole-resistant Candida albicans.

PubMed

Han, Bing; Chen, Jia; Yu, Yi-qun; Cao, Yong-bing; Jiang, Yuan-ying

2016-02-01

This study aimed to investigate the antifungal activity of Rubus chingii extract in combination with fluconazole (FLC) against FLC-resistant Candida albicans 100 in vitro. A R. chingii extract and FLC-resistant C. albicans fungus suspension were prepared. The minimum inhibitory concentration and fractional inhibitory concentration index of R. chingii extract combined with FLC against C. albicans were determined, after which growth curves for C. albicans treated with R. chingii extract, FLC alone and a combination of these preparations were constructed. Additionally, the mechanisms of drug combination against C. albicans were explored by flow cytometry, gas chromatographic mass spectrometry and drug efflux pump function detection. R. chingii extract combined with FLC showed significant synergy. Flow cytometry suggested that C. albicans cells mainly arrest in G1 and S phases when they have been treated with the drug combination. The drug combination resulted in a marked decrease in the ergosterol content of the cell membrane. Additionally, efflux of Rhodamine 6G decreased with increasing concentrations of R. chingii extract. R. chingii extract combined with FLC has antifungal activity against FLC-resistant C. albicans. © 2016 The Societies and John Wiley & Sons Australia, Ltd.

Update on antifungal therapy with terbinafine.

PubMed

Gianni, C

2010-06-01

Terbinafine, a synthetic antifungal of allylamine class, has fungicidal activity against dermatophytes, moulds and certain dimorphic fungi and fungistatic activity against Candida albicans. Following oral administration the terbinafine is absorbed rapidly (>70%) and reaches within 2 hours the peak plasma concentration. The drug is highly lipophilic and keratophilic and is highly bound to plasma protein (>90%) with a bioavailability of 70% to 80%. The drug is rapidly delivered and it is present in the stratum corneum, sebum, nails and hair for months after stopping the medication. The drug has been proven to be the choice treatment in the therapy of onychomycosis as it is very effective, well tolerated and has a relatively low potential for drug interactions. The pharmacologic and pharmacokinetic properties of terbinafine give strong support to the possibility that the pulse therapy may be equally effective in onychomycoses, possibly reducing medication costs and drug exposure. Several therapeutic patterns have been proposed: weekly intermittent terbinafine (500 mg/d for 1 week each month for 4 months), or single-dose terbinafine (1000 mg per month for 4 months). Use of topical terbinafine 1% may be practical where the tinea involvement is not extensive or chronic. Recently, the terbinafine is available in a novel topical solution (film-forming solution--FFS) effective in the treatment of tinea pedis (athlete's foot).

Treatment of murine invasive candidiasis with amphotericin B and cilofungin: evidence for enhanced activity with combination therapy.

PubMed Central

Sugar, A M; Goldani, L Z; Picard, M

1991-01-01

The in vivo interactions of cilofungin, an echinocandin antifungal agent, and amphotericin B, a polyene derivative, in a murine model of disseminated candidiasis have been investigated. While single therapy with either drug alone prolonged survival of infected mice, kidney colony counts were not appreciably reduced. In contrast, combination therapy, especially at higher doses of both drugs, resulted in significant prolongation of survival and suppression of growth of yeast cells in the kidneys. Combination therapy of experimental candidiasis with cilofungin and amphotericin B did not result in antagonism; rather, additive or synergistic effects were seen. Future preclinical work with other echinocandin and polyene derivatives should include studies evaluating the in vivo interactions of both classes of compounds. PMID:1759836

Efficacy of T2 Magnetic Resonance Assay in Monitoring Candidemia after Initiation of Antifungal Therapy: the Serial Therapeutic and Antifungal Monitoring Protocol (STAMP) Trial

PubMed Central

2018-01-01

ABSTRACT The performance of blood culture for monitoring candidemia clearance is hampered by its low sensitivity, especially during antifungal therapy. The T2 magnetic resonance (T2MR) assay combines magnetic resonance with nanotechnology to identify whole Candida species cells. A multicenter clinical trial studied the performance of T2MR in monitoring candidemia clearance compared to blood culture. Adults with a blood culture positive for yeast were enrolled and had blood cultures and T2MR testing performed on prespecified days. Thirty-one patients completed the trial. Thirteen of the 31 patients (41.9%) had at least one positive surveillance T2MR and/or blood culture result. All positive blood cultures (7/7 [100%]) had an accompanying positive T2MR result with concordance in the identified Candida sp., while only 7/23 (30.4%) T2MR results had an accompanying positive blood culture. There was one case of discordance in species identification between T2MR and the preenrollment blood culture with evidence to support deep-seated infection by the Candida spp. detected by the T2MR assay. Based on the log rank test, there was a statistically significant improvement in posttreatment surveillance using the T2MR assay compared to blood culture (P = 0.004). Limitations of the study include the small sample size and lack of outcome data. In conclusion, the T2MR assay significantly outperformed blood cultures for monitoring the clearance of candidemia in patients receiving antifungal therapy and may be useful in determining adequate source control, timing for deescalation, and optimal duration of treatment. However, further studies are needed to determine the viability of Candida species cells detected by the T2MR assay and correlate the results with patient outcomes. (This study is registered at ClinicalTrials.gov under registration number NCT02163889.) PMID:29367293

Efficacy of T2 Magnetic Resonance Assay in Monitoring Candidemia after Initiation of Antifungal Therapy: the Serial Therapeutic and Antifungal Monitoring Protocol (STAMP) Trial.

PubMed

Mylonakis, Eleftherios; Zacharioudakis, Ioannis M; Clancy, Cornelius J; Nguyen, M Hong; Pappas, Peter G

2018-04-01

The performance of blood culture for monitoring candidemia clearance is hampered by its low sensitivity, especially during antifungal therapy. The T2 magnetic resonance (T2MR) assay combines magnetic resonance with nanotechnology to identify whole Candida species cells. A multicenter clinical trial studied the performance of T2MR in monitoring candidemia clearance compared to blood culture. Adults with a blood culture positive for yeast were enrolled and had blood cultures and T2MR testing performed on prespecified days. Thirty-one patients completed the trial. Thirteen of the 31 patients (41.9%) had at least one positive surveillance T2MR and/or blood culture result. All positive blood cultures (7/7 [100%]) had an accompanying positive T2MR result with concordance in the identified Candida sp., while only 7/23 (30.4%) T2MR results had an accompanying positive blood culture. There was one case of discordance in species identification between T2MR and the preenrollment blood culture with evidence to support deep-seated infection by the Candida spp. detected by the T2MR assay. Based on the log rank test, there was a statistically significant improvement in posttreatment surveillance using the T2MR assay compared to blood culture ( P = 0.004). Limitations of the study include the small sample size and lack of outcome data. In conclusion, the T2MR assay significantly outperformed blood cultures for monitoring the clearance of candidemia in patients receiving antifungal therapy and may be useful in determining adequate source control, timing for deescalation, and optimal duration of treatment. However, further studies are needed to determine the viability of Candida species cells detected by the T2MR assay and correlate the results with patient outcomes. (This study is registered at ClinicalTrials.gov under registration number NCT02163889.). Copyright © 2018 Mylonakis et al.

Defining the frontiers between antifungal resistance, tolerance and the concept of persistence.

PubMed

Delarze, Eric; Sanglard, Dominique

2015-11-01

A restricted number of antifungal agents are available for the therapy of fungal diseases. With the introduction of epidemiological cut-off values for each agent in important fungal pathogens based on the distribution of minimal inhibitory concentration (MIC), the distinction between wild type and drug-resistant populations has been facilitated. Antifungal resistance has been described for all currently available antifungal agents in several pathogens and most of the associated resistance mechanisms have been deciphered at the molecular level. Clinical breakpoints for some agents have been proposed and can have predictive value for the success or failure of therapy. Tolerance to antifungals has been a much more ignored area. By definition, tolerance operates at antifungal concentrations above individual intrinsic inhibitory values. Important is that tolerance to antifungal agents favours the emergence of persister cells, which are able to survive antifungal therapy and can cause relapses. Here we will review the current knowledge on antifungal tolerance, its potential mechanisms and also evaluate the role of antifungal tolerance in the efficacy of drug treatments. Copyright © 2015 Elsevier Ltd. All rights reserved.

Genetic and Genomic Architecture of the Evolution of Resistance to Antifungal Drug Combinations

PubMed Central

Hill, Jessica A.; Ammar, Ron; Torti, Dax; Nislow, Corey; Cowen, Leah E.

2013-01-01

The evolution of drug resistance in fungal pathogens compromises the efficacy of the limited number of antifungal drugs. Drug combinations have emerged as a powerful strategy to enhance antifungal efficacy and abrogate drug resistance, but the impact on the evolution of drug resistance remains largely unexplored. Targeting the molecular chaperone Hsp90 or its downstream effector, the protein phosphatase calcineurin, abrogates resistance to the most widely deployed antifungals, the azoles, which inhibit ergosterol biosynthesis. Here, we evolved experimental populations of the model yeast Saccharomyces cerevisiae and the leading human fungal pathogen Candida albicans with azole and an inhibitor of Hsp90, geldanamycin, or calcineurin, FK506. To recapitulate a clinical context where Hsp90 or calcineurin inhibitors could be utilized in combination with azoles to render resistant pathogens responsive to treatment, the evolution experiment was initiated with strains that are resistant to azoles in a manner that depends on Hsp90 and calcineurin. Of the 290 lineages initiated, most went extinct, yet 14 evolved resistance to the drug combination. Drug target mutations that conferred resistance to geldanamycin or FK506 were identified and validated in five evolved lineages. Whole-genome sequencing identified mutations in a gene encoding a transcriptional activator of drug efflux pumps, PDR1, and a gene encoding a transcriptional repressor of ergosterol biosynthesis genes, MOT3, that transformed azole resistance of two lineages from dependent on calcineurin to independent of this regulator. Resistance also arose by mutation that truncated the catalytic subunit of calcineurin, and by mutation in LCB1, encoding a sphingolipid biosynthetic enzyme. Genome analysis revealed extensive aneuploidy in four of the C. albicans lineages. Thus, we identify molecular determinants of the transition of azole resistance from calcineurin dependence to independence and establish multiple

Nosocomial Candidiasis: Antifungal Stewardship and the Importance of Rapid Diagnosis.

PubMed

Pfaller, Michael A; Castanheira, Mariana

2016-01-01

Candidemia and other forms of candidiasis are associated with considerable excess mortality and costs. Despite the addition of several new antifungal agents with improved spectrum and potency, the frequency of Candida infection and associated mortality have not decreased in the past two decades. The lack of rapid and sensitive diagnostic tests has led to considerable overuse of antifungal agents resulting in increased costs, selection pressure for resistance, unnecessary drug toxicity, and adverse drug interactions. Both the lack of timely diagnostic tests and emergence of antifungal resistance pose considerable problems for antifungal stewardship. Whereas antifungal stewardship with a focus on nosocomial candidiasis should be able to improve the administration of antifungal therapy in terms of drug selection, proper dose and duration, source control and de-escalation therapy, an important parameter, timeliness of antifungal therapy, remains a victim of slow and insensitive diagnostic tests. Fortunately, new proteomic and molecular diagnostic tools are improving the time to species identification and detection. In this review we will describe the potential impact that rapid diagnostic testing and antifungal stewardship can have on the management of nosocomial candidiasis. © The Author 2015. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Synthesis, antifungal activity of caffeic acid derivative esters, and their synergism with fluconazole and nystatin against Candida spp.

PubMed

Sardi, Janaína de Cássia Orlandi; Gullo, Fernanda Patrícia; Freires, Irlan Almeida; Pitangui, Nayla de Souza; Segalla, Maicon Petrônio; Fusco-Almeida, Ana Marisa; Rosalen, Pedro Luiz; Regasini, Luís Octávio; Mendes-Giannini, Maria José Soares

2016-12-01

We tested the antifungal potential of caffeic acid and 8 of its derivative esters against Candidaalbicans ATCC 90028 and 9 clinical isolatesand carried out a synergism assay with fluconazole and nystatin. Propyl caffeate (C3) showed the best antifungal activity against the tested strains. When in combination, C3 markedly reduced the MIC of fluconazole and nystatin with synergistic effect up to 64-fold. Finally, C3 showed a high IC 50 value and selective indexagainst oral keratinocytes, demonstrating low toxicity against this cell type and selectivity for yeast cells. Further research should confirm its antifungal potential for development of combined therapy to treat C. albicans infections. Copyright © 2016 Elsevier Inc. All rights reserved.

Antifungal therapy did not improve outcomes including 30-day all-cause mortality in patients suffering community-acquired perforated peptic ulcer-associated peritonitis with Candida species isolated from their peritoneal fluid.

PubMed

Li, Wei-Sin; Lee, Chen-Hsiang; Liu, Jien-Wei

2017-06-01

Although patients suffering community-acquired perforated peptic ulcer (PPU)-associated peritonitis with Candida species isolated from their peritoneal fluid have higher chances of mortality and experiencing a complicated postoperative clinical course, universal antifungal therapy for these patients remains controversial. This is a retrospective analysis of the impacts of antifungal therapy on outcomes of patients suffering community-acquired PPU-associated peritonitis with Candida species isolated from their ascites at a medical center in Taiwan. All included patients received source control and antibiotic treatment, with or without additional postoperative antifungal therapy with fluconazole or an echinocandin for at least 3 days. Among the 133 included patients, 76 did not receive (Group 1) and 57 did receive (Group 2) antifungal therapy. Sixteen (12%) of the overall included patients died within 30 days. Shock [odds ratio (OR), 5.6; 95% confidence interval (CI), 1.9-16.5; p = 0.002] and higher Acute Physiology and Chronic Health Evaluation II score (>20; OR, 9.5; 95% CI, 1.1-80.7; p = 0.04) were independently associated with 30-day mortality. Among the 80 matched patients from Groups 1 and 2 (1:1 matched) with the closest propensity score, no significant difference was found in 30-day all-cause mortality, time to mortality, the need for reoperation/abscess formation/anastomotic leakage, prolonged intensive care unit stay, and prolonged mechanical ventilator dependence between patients with and without antifungal therapy. Our study provides solid evidence supporting the notions that antifungal therapies do not benefit patients suffering PPU peritonitis with Candida species isolated from their ascites in general, and antifungal therapy could be reserved for patients who are critically ill and/or severely immunocompromised. Copyright © 2015. Published by Elsevier B.V.

Synergistic and antagonistic effects of immunomodulatory drugs on the action of antifungals against Candida glabrata and Saccharomyces cerevisiae.

PubMed

Tome, Miha; Zupan, Jure; Tomičić, Zorica; Matos, Tadeja; Raspor, Peter

2018-01-01

Candidemia and other forms of invasive fungal infections caused by Candida glabrata and to a lesser extent Saccharomyces cerevisiae are a serious health problem, especially if their steadily rising resistance to the limited range of antifungal drugs is taken into consideration. Various drug combinations are an attractive solution to the resistance problem, and some drug combinations are already common in the clinical environment due to the nature of diseases or therapies. We tested a few of the common antifungal-immunomodulatory drug combinations and evaluated their effect on selected strains of C. glabrata and S. cerevisiae . The combinations were performed using the checkerboard microdilution assay and interpreted using the Loewe additivity model and a model based on the Bliss independence criterion. A synergistic interaction was confirmed between calcineurin inhibitors (Fk506 and cyclosporine A) and antifungals (fluconazole, itraconazole, and amphotericin B). A new antagonistic interaction between mycophenolic acid (MPA) and azole antifungals was discovered in non-resistant strains. A possible mechanism that explains this is induction of the Cdr1 efflux pump by MPA in C. glabrata ATCC 2001. The Pdr1 regulatory cascade plays a role in overall resistance to fluconazole, but it is not essential for the antagonistic interaction. This was confirmed by the Cg pdr1 Δ mutant still displaying the antagonistic interaction between the drugs, although at lower concentrations of fluconazole. This antagonism calls into question the use of simultaneous therapy with MPA and azoles in the clinical environment.

Antifungal Therapy in Birds: Old Drugs in a New Jacket.

PubMed

Antonissen, Gunther; Martel, An

2018-05-01

The use of antifungals in birds is characterized by interspecies and interindividual variability in the pharmacokinetics, affecting drug safety and efficacy. Oral antifungal drug absorption is a complex process affected by drug formulation characteristics, gastrointestinal anatomy, and physiology. New antifungal drug delivery systems can enhance drug stability, reduce off-target side effects, prolong residence time in the blood, and improve efficacy. Topical administration of antifungals through nebulization shows promising results. However, therapeutic output is highly influenced by drug formulation and type of nebulizer, indicating these factors should be taken into account when selecting this medication route. Copyright © 2018 Elsevier Inc. All rights reserved.

[Evaluation of PNA-FISH method for direct identification of Candida species in blood culture samples and its potential impact on guidance of antifungal therapy].

PubMed

Doğan, Özlem; İnkaya, Ahmet Çağkan; Gülmez, Dolunay; Uzun, Ömrüm; Akova, Murat; Arıkan Akdağlı, Sevtap

2016-10-01

identified by conventional methods in 23 specimens. Results of PNA-FISH and conventional methods were in full agreement in 19 of the 23 specimens (82.6%). Two specimens were negative by PNA-FISH and yielded S.capitata and C.neoformans which were not included in the test panel. In three specimens that were infected with multiple species, PNA-FISH detected only one of the species. On the other hand and in one specimen, PNA-FISH detected a second species (C.glabrata or C.krusei) that could not be isolated and identified conventionally. Species identification were obtained 72 hours (mean) earlier with PNA-FISH. PNA-FISH provided accurate species identification that were consistent with conventional methods. However and expectedly, it failed to detect species that were not included in the test panel. During the study period, 13 of the 23 patients have passed away. Apart from six patients died prior to blood culture positivity and the one that could not get any antifungal therapy during hospital stay, 16 patients received antifungal treatment. Of sixteen patients who received antifungal therapy, initial antifungal treatment was fluconazole for five and echinocandin for 10 patients. Fluconazole and amphotericin B combination was preferred for one patient. In this study, PNA-FISH result had an influence on the modification of the antifungal treatment of only for one patient in accordance with the clinical findings. We conclude that the utility of PNA-FISH method appeared to be limited in our center since the assay cannot differentiate C.albicans and C.parapsilosis, the two commonly isolated species among our candidemia isolates. However, advantages of the assay might be more pronounced for the centers where C.glabrata is a relatively more frequent species.

Antifungal activities of diphenyl diselenide and ebselen alone and in combination with antifungal agents against Fusarium spp.

PubMed

Venturini, Tarcieli Pozzebon; Chassot, Francieli; Loreto, Érico Silva; Keller, Jéssica Tairine; Azevedo, Maria Izabel; Zeni, Gilson; Santurio, Janio Morais; Alves, Sydney Hartz

2016-07-01

Herein, we describe the in vitro activity of a combination of the organoselenium compounds diphenyl diselenide and ebselen alone and in combination with amphotericin B, caspofungin, itraconazole, and voriconazole against 25 clinical isolates of Fusarium spp. For this analysis, we used the broth microdilution method based on the M38-A2 technique and checkerboard microdilution method. Diphenyl diselenide (MIC range = 4-32 μg/ml) and ebselen (MIC range = 2-8 μg/ml) showed in vitro activity against the isolates tested. The most effective combinations were (synergism rates): ebselen + amphotericin B (88%), ebselen + voriconazole (80%), diphenyl diselenide + amphotericin B (72%), and diphenyl diselenide + voriconazole (64%). Combination with caspofungin resulted in low rates of synergism: ebselen + caspofungin, 36%, and diphenyl diselenide + caspofungin, 28%; combination with itraconazole demonstrated indifferent interactions. Antagonistic effects were not observed for any of the combinations tested. Our findings suggest that the antifungal potential of diphenyl diselenide and ebselen deserves further investigation in in vivo experimental models, especially in combination with amphotericin B and voriconazole. © The Author 2016. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Invasive Fungal Infections in Patients with Hematological Malignancies: Emergence of Resistant Pathogens and New Antifungal Therapies

PubMed Central

Gamaletsou, Maria N.; Walsh, Thomas J.; Sipsas, Nikolaos V.

2018-01-01

Invasive fungal infections caused by drug-resistant organisms are an emerging threat to heavily immunosuppressed patients with hematological malignancies. Modern early antifungal treatment strategies, such as prophylaxis and empirical and preemptive therapy, result in long-term exposure to antifungal agents, which is a major driving force for the development of resistance. The extended use of central venous catheters, the nonlinear pharmacokinetics of certain antifungal agents, neutropenia, other forms of intense immunosuppression, and drug toxicities are other contributing factors. The widespread use of agricultural and industrial fungicides with similar chemical structures and mechanisms of action has resulted in the development of environmental reservoirs for some drug-resistant fungi, especially azole-resistant Aspergillus species, which have been reported from four continents. The majority of resistant strains have the mutation TR34/L98H, a finding suggesting that the source of resistance is the environment. The global emergence of new fungal pathogens with inherent resistance, such as Candida auris, is a new public health threat. The most common mechanism of antifungal drug resistance is the induction of efflux pumps, which decrease intracellular drug concentrations. Overexpression, depletion, and alteration of the drug target are other mechanisms of resistance. Mutations in the ERG11 gene alter the protein structure of C-demethylase, reducing the efficacy of antifungal triazoles. Candida species become echinocandin-resistant by mutations in FKS genes. A shift in the epidemiology of Candida towards resistant non-albicans Candida spp. has emerged among patients with hematological malignancies. There is no definite association between antifungal resistance, as defined by elevated minimum inhibitory concentrations, and clinical outcomes in this population. Detection of genes or mutations conferring resistance with the use of molecular methods may offer better

The relationship between the success rate of empirical antifungal therapy with intravenous itraconazole and clinical parameters, including plasma levels of itraconazole, in immunocompromised patients receiving itraconazole oral solution as prophylaxis: a multicenter, prospective, open-label, observational study in Korea.

PubMed

Kim, Jin Seok; Cheong, June-Won; Kim, Yeo-Kyeoung; Park, Jinny; Mun, Yeung-Chul; Kang, Hye Jin; Yi, Hyeon Gyu; Lee, Je-Hwan; Kim, Yang Soo; Ryoo, Hun-Mo; Kim, Sung-Hyun; Kim, Ho Young; Kim, Jin Young; Lee, Dong-Gun; Kim, Hoon-Gu; Kim, Hawk; Joo, Young-Don; Min, Yoo Hong

2014-01-01

To identify the role of therapeutic drug monitoring of itraconazole (ITZ) in the setting of empirical antifungal therapy with intravenous (IV) ITZ, we performed a multicenter, prospective study in patients with hematological malignancies who had received antifungal prophylaxis with ITZ oral solution (OS). We evaluated the plasma levels of ITZ and hydroxy (OH) ITZ both before initiation of IV ITZ and on days 5-7 of IV ITZ. A total of 181 patients showed an overall success rate of 68.0 %. Prolonged baseline neutropenia and accompanying cardiovascular comorbidity were significantly associated with poor outcomes of the empirical antifungal therapy (P = 0.005 and P = 0.001, respectively). A significantly higher trough plasma level of OH ITZ per body weight was found in the patients who achieved success with empirical antifungal therapy (P = 0.036). There were no significant correlations between plasma concentrations of ITZ/OH ITZ (baseline or trough levels) and toxicities. Seven patients had a discontinuation of ITZ therapy due to toxicity. This study demonstrated that IV ITZ as empirical antifungal therapy was effective and therapeutic drug monitoring was helpful to estimate the outcome of empirical antifungal therapy in patients receiving antifungal prophylaxis with ITZ OS. To predict the outcome of empirical antifungal therapy with IV ITZ, we should evaluate baseline clinical characteristics and also perform the therapeutic drug monitoring of both ITZ and OH ITZ.

Invasive fungal infections and antifungal therapies in solid organ transplant recipients.

PubMed

Gabardi, Steven; Kubiak, David W; Chandraker, Anil K; Tullius, Stefan G

2007-12-01

This manuscript will review the risk factors, prevalence, clinical presentation, and management of invasive fungal infections (IFIs) in solid organ transplant (SOT) recipients. Primary literature was obtained via MEDLINE (1966-April 2007) and EMBASE. Abstracts were obtained from scientific meetings or pharmaceutical manufacturers and included in the analysis. All studies and abstracts evaluating IFIs and/or antifungal therapies, with a primary focus on solid organ transplantation, were considered for inclusion. English-language literature was selected for inclusion, but was limited to those consisting of human subjects. Infectious complications following SOT are common. IFIs are associated with high morbidity and mortality rates in this patient population. Determining the best course of therapy is difficult due to the limited availability of data in SOT recipients. Well-designed clinical studies are infrequent and much of the available information is often based on case-reports or retrospective analyses. Transplant practitioners must remain aware of their therapeutic options and the advantages and disadvantages associated with the available treatment alternatives.

Inappropriate empiric antifungal therapy for candidemia in the ICU and hospital resource utilization: a retrospective cohort study

PubMed Central

2010-01-01

Background Candida represents the most common cause of invasive fungal disease, and candidal blood stream infections (CBSI) are prevalent in the ICU. Inappropriate antifungal therapy (IAT) is known to increase a patient's risk for death. We hypothesized that in an ICU cohort it would also adversely affect resource utilization. Methods We retrospectively identified all patients with candidemia on or before hospital day 14 and requiring an ICU stay at Barnes-Jewish Hospital between 2004 and 2007. Hospital length of stay following culture-proven onset of CBSI (post-CBSI HLOS) was primary and hospital costs secondary endpoints. IAT was defined as treatment delay of ≥24 hours from candidemia onset or inadequate dose of antifungal agent active against the pathogen. We developed generalized linear models (GLM) to assess independent impact of inappropriate therapy on LOS and costs. Results Ninety patients met inclusion criteria. IAT was frequent (88.9%). In the IAT group antifungal delay ≥24 hours occurred in 95.0% and inappropriate dosage in 26.3%. Unadjusted hospital mortality was greater among IAT (28.8%) than non-IAT (0%) patients, p = 0.059. Both crude post-CBSI HLOS (18.4 ± 17.0 vs. 10.7 ± 9.4, p = 0.062) and total costs ($66,584 ± $49,120 vs. $33,526 ± $27,244, p = 0.006) were higher in IAT than in non-IAT. In GLMs adjusting for confounders IAT-attributable excess post-CBSI HLOS was 7.7 days (95% CI 0.6-13.5) and attributable total costs were $13,398 (95% CI $1,060-$26,736). Conclusions IAT of CBSI, such as delays and incorrect dosing, occurs commonly. In addition to its adverse impact on clinical outcomes, IAT results in substantial prolongation of hospital LOS and increase in hospital costs. Efforts to enhance rates of appropriate therapy for candidemia may improve resource use. PMID:20525301

Addition of DNase Improves the In Vitro Activity of Antifungal Drugs against Candida albicans Biofilms

PubMed Central

Martins, Margarida; Henriques, Mariana; Lopez-Ribot, José L.; Oliveira, Rosário

2011-01-01

SUMMARY Background Cells within Candida albicans biofilms display decreased susceptibility to most clinically used antifungal agents. We recently demonstrated that extracellular DNA (eDNA) plays an important role in biofilm integrity, as a component of the biofilm matrix. Objective To gain insight into the contributions of eDNA to C. albicans biofilms antifungal susceptibility by the investigation of the impact of the combined use of deoxyribonuclease I (DNase) and antifungals to treat biofilms. Methods C. albicans biofilms were formed using a simple and reproducible 96-well plate-based method. The activity of the combined use of 0.13 mg l−1 DNase and antifungals was estimated by the 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide (XTT) reduction assay, and total viable counts. Results and Conclusions Here we report the improved efficacy of amphotericin B when in combination with DNase against C. albicans biofilms, as assessed by XTT readings and viable counts. Furthermore, although DNase increased the efficacy of caspofungin in the reduction of mitochondrial activity, no changes were observed in terms of culturable cells. DNase did not affect biofilm cells susceptibility to fluconazole. This work suggests that agents that target processes affecting the biofilm structural integrity may have potential use as adjuvants of a catheter–lock therapy. PMID:21668524

Training should be the first step toward an antifungal stewardship program.

PubMed

Valerio, Maricela; Muñoz, Patricia; Rodríguez-González, Carmen; Sanjurjo, María; Guinea, Jesús; Bouza, Emilio

2015-04-01

The frequency of use of systemic antifungal agents has increased significantly in most tertiary centers. However, antifungal stewardship has received very little attention. The objective of this article was to assess the knowledge of prescribing physicians in our institution as a first step in the development of an antifungal stewardship program. Attending physicians from the departments that prescribe most antifungals were invited to complete a questionnaire based on current guidelines on diagnosis and therapy of invasive candidiasis and invasive aspergillosis (IA). The survey was completed by 60.8% (200/329) of the physicians who were invited to participate. The physicians belonged to the following departments: medical (60%), pediatric (19%), intensive care (15.5%), and surgical (5.5%). The mean (±SD) score of correct responses was 5.16±1.73. In the case of candidiasis, only 55% of the physicians clearly distinguished between colonization and infection, and 17.5% knew the local rate of fluconazole resistance. Thirty-three percent knew the accepted indications for antifungal prophylaxis, and 23% the indications for empirical therapy. However, most physicians knew which antifungals to choose when starting empirical therapy (73.5%). As for aspergillosis, most physicians (67%) could differentiate between colonization and infection, and 34.5% knew the diagnostic value of galactomannan. The radiological features of IA were well recognized by 64%, but only 31.5% were aware of the first line of treatment for IA, and 36% of the recommended duration of therapy. The usefulness of antifungal levels was known by 67%. This simple, easily completed questionnaire enabled us to identify which areas of our training strategy could be improved. Copyright © 2013 Elsevier España, S.L.U. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

Photodynamic Therapy Combined with Terbinafine Against Chromoblastomycosis and the Effect of PDT on Fonsecaea monophora In Vitro

PubMed Central

Hu, Yongxuan; Huang, Xiaowen; Lu, Sha; Hamblin, Michael R.; Mylonakis, Eleftherios; Zhang, Junmin

2014-01-01

Chromoblastomycosis, a chronic fungal infection of skin and subcutaneous tissue caused by dematiaceous fungi, is associated with low cure and high relapse rates. Among all factors affecting clinical outcome, etiological agents have an important position. In southern China, Fonsecaea pedrosoi and Fonsecaea monophora are main causative agents causing Chromoblastomycosis. We treated one case of chromoblastomycosis by photodynamic therapy (PDT) of 5-aminolevulinic acid (ALA) irradiation combined with terbinafine 250 mg a day. The lesions were improved after two sessions of ALA-PDT treatment, each including nine times, at an interval of 1 week, combined with terbinafine 250 mg/day oral, and clinical improvement could be observed. In the following study, based on the clinical treatment, the effect of PDT and antifungal drugs on this isolate was detected in vitro. It showed sensitivity to terbinafine, itraconazole or voriconazole, and PDT inhibited the growth. Both the clinic and experiments in vitro confirm the good outcome of ALA-PDT applied in the inhibition of F. monophora. It demonstrated that combination of antifungal drugs with ALA-PDT arises as a promising alternative method for the treatment of these refractory cases of chromoblastomycosis. PMID:25366276

Antifungal activity of multifunctional Fe 3O 4-Ag nanocolloids

NASA Astrophysics Data System (ADS)

Chudasama, Bhupendra; Vala, Anjana K.; Andhariya, Nidhi; Upadhyay, R. V.; Mehta, R. V.

2011-05-01

In recent years, rapid increase has been observed in the population of microbes that are resistant to conventionally used antibiotics. Antifungal drug therapy is no exception and now resistance to many of the antifungal agents in use has emerged. Therefore, there is an inevitable and urgent medical need for antibiotics with novel antimicrobial mechanisms. Aspergillus glaucus is the potential cause of fatal brain infections and hypersensitivity pneumonitis in immunocompromised patients and leads to death despite aggressive multidrug antifungal therapy. In the present article, we describe the antifungal activity of multifunctional core-shell Fe 3O 4-Ag nanocolloids against A. glaucus isolates. Controlled experiments are also carried out with Ag nanocolloids in order to understand the role of core (Fe 3O 4) in the antifungal action. The minimum inhibitory concentration (MIC) of nanocolloids is determined by the micro-dilution method. MIC of A. glaucus is 2000 μg/mL. The result is quite promising and requires further investigations in order to develop a treatment methodology against this death causing fungus in immunocompromised patients.

Antifungal treatment in haematological and oncological patients: Need for quality assessment in routine care.

PubMed

Lachenmayr, Sarah J; Berking, Sophie; Horns, Heidi; Strobach, Dorothea; Ostermann, Helmut; Berger, Karin

2018-03-25

Invasive fungal infections in haematological and oncological patients have a major impact on morbidity, mortality and treatment costs. Therefore, rational use of antifungal agents is important for optimal patient care and resource use. The study's objective was to analyse antifungal usage in a German tertiary teaching hospital, department of haematology and oncology, to evaluate quality of antifungal treatment and to assess the need for an antifungal stewardship programme. This retrospective observational study included patients ≥18 years receiving systemic antifungals for prophylaxis or therapy of invasive fungal infection between January and June 2016. Appropriateness of antifungal prescriptions was evaluated in accordance with guidelines of the German Society of Haematology and Oncology (DGHO) and drug labelling. In total, 104/1278 (8.1%) patients received antifungals. One hundred seventy-one antifungals were prescribed: 48 for prophylaxis, 104 for empirical and 19 for targeted therapy. In 127 (74.3%) prescriptions, indication was appropriate, and in 132 (77.2%), choice of drug. Antifungals were correctly dosed in 131 prescriptions (76.6%). Thirty-four antifungals (20.0%) were co-administrated with interacting drugs (5 mild to moderate, 29 severe interactions). Results of this analysis demonstrate that use of systemic antifungals in routine care differs in a substantial number of patients from guideline and labelling recommendations. To optimise antifungal use, the implementation of antifungal stewardship programmes seems to be justified. © 2018 Blackwell Verlag GmbH.

Improved efficacy in onychomycosis therapy.

PubMed

Gupta, Aditya K; Paquet, Maryse

2013-01-01

The success rate of onychomycosis treatment is limited by several factors, including the access of the therapeutic agent to the fungal mass, the presence of conidia, and the susceptibility of the different infectious agents to the antifungals. Different strategies used to improve efficacy of the currently available antifungal treatments, their rationale, and the published evidence of their beneficial effects are reviewed. An improved efficacy was demonstrated for some of these strategies, such as combined oral and topical antifungal therapies, whereas most of them lack clear and direct evidence of an increase in therapeutic success. © 2013 Elsevier Inc. All rights reserved.

Comparison of two in vitro antifungal sensitivity tests and monitoring during therapy of Sporothrix schenckii sensu stricto in Malaysian cats.

PubMed

Han, Hock Siew; Kano, Rui; Chen, Charles; Noli, Chiara

2017-02-01

Feline sporotrichosis is common in Malaysia. Thermosensitivity and effects of azole treatment on fungal susceptibility are unknown. To evaluate thermotolerance and antifungal susceptibility of feline Malaysian Sporothrix isolates, compare microdilution (MD) and E-test results, and investigate changes in susceptibility during azole therapy. Sporothrix schenckii sensu stricto was isolated from 44 cats. Thermotolerance was determined via culture at 37°C for 7 days. Susceptibility to itraconazole (ITZ), ketoconazole (KTZ) and terbinafine (TRB) was assessed in 40 isolates by MD; to amphotericin B (AMB), KTZ, ITZ, fluconazole (FLC) and posaconazole (POS) by E-test. Results were statistically compared by Pearson's Product Moment. In eight ketoconazole treated cats, susceptibility testing to itraconazole and ketoconazole was repeated every two months for six months. Thermotolerance was observed in 36 of 44 (82%) isolates. Assuming that isolates growing at antifungal concentrations ≥4 mg/mL were resistant, all were resistant on E-test to FLC and AMB, 11 (28%) to POS, 6 (15%) to ITZ and 1 (3%) to KTZ. On MD, 27 of 40 (68%) were resistant to TRB, 2 (5%) to ITZ and 3 (8%) to KTZ. There was no correlation between E-test and MD results (KTZ r = 0.10, P = 0.54, and ITZ r = 0.11, P = 0.48). MD values for ITZ and KTZ did not exceed 4 mg/L during KTZ therapy. The majority of feline isolates in Malaysia are thermosensitive. Lack of correlation between E-test and MD suggests that the E-test is unreliable to test antifungal susceptibility for Sporothrix spp. compared to MD. KTZ was the antifungal drug with the lowest MIC. Prolonged KTZ administration may not induce changes in antifungal susceptibility. © 2017 ESVD and ACVD.

(1→3)-β-D-Glucan Assay in Monitoring Response to Anti-Fungal Therapy in Fungal Endocarditis.

PubMed

Slim, Jihad; Saling, Christopher; Szabela, Maria; Brown, Melinda; Johnson, Tamara; Goldfarb, Irvin

2017-03-01

A case is reported of Candida glabrata infective endocarditis (IE) treated without surgical intervention. The study aim was to: (i) briefly discuss the outcomes of other documented cases of fungal IE managed medically with fluconazole; (ii) discuss the (1→3)-β-D-glucan assay and its previously studied role in the diagnosis of invasive fungal infections; and (iii) examine a possible application of the (1→3)-β-D-glucan assay to monitor response to antifungal treatment in patients with Candida endocarditis. The serum Fungitell assay was used to trend (1→3)-β-D-glucan in a patient with Candida endocarditis to determine treatment effectiveness with fluconazole, to provide an appropriate end date for antifungal therapy, and to survey infection suppression while off treatment. The (1→03)-β-D-glucan assay began trending downwards at 197 days into treatment with oral fluconazole. After 16 months of therapy, fluconazole was stopped due to transaminitis. (1→3)-β-Dglucan levels were checked six weeks after the discontinuation of treatment and were negative. The patient has now been off therapy for 21 weeks with no signs of clinical disease, and values remain negative. The present case indicates that a trending (1→3)-β-D-glucan assay may have valuable application in monitoring treatment response and infection suppression for Candida endocarditis.

Pathogenesis and host defence against Mucorales: the role of cytokines and interaction with antifungal drugs.

PubMed

Roilides, Emmanuel; Antachopoulos, Charalampos; Simitsopoulou, Maria

2014-12-01

Innate immune response, including macrophages, neutrophils and dendritic cells and their respective receptors, plays an important role in host defences against Mucorales with differential activity against specific fungal species, while adaptive immunity is not the first line of defence. A number of endogenous and exogenous factors, such as cytokines and growth factors as well as certain antifungal agents have been found that they influence innate immune response to these organisms. Used alone or especially in combination have been shown to exert antifungal effects against Mucorales species. These findings suggest novel ways of adjunctive therapy for patients with invasive mucormycosis. © 2014 Blackwell Verlag GmbH.

Posaconazole exhibits in vitro and in vivo synergistic antifungal activity with caspofungin or FK506 against Candida albicans.

PubMed

Chen, Ying-Lien; Lehman, Virginia N; Averette, Anna F; Perfect, John R; Heitman, Joseph

2013-01-01

The object of this study was to test whether posaconazole, a broad-spectrum antifungal agent inhibiting ergosterol biosynthesis, exhibits synergy with the β-1,3 glucan synthase inhibitor caspofungin or the calcineurin inhibitor FK506 against the human fungal pathogen Candida albicans. Although current drug treatments for Candida infection are often efficacious, the available antifungal armamentarium may not be keeping pace with the increasing incidence of drug resistant strains. The development of drug combinations or novel antifungal drugs to address emerging drug resistance is therefore of general importance. Combination drug therapies are employed to treat patients with HIV, cancer, or tuberculosis, and has considerable promise in the treatment of fungal infections like cryptococcal meningitis and C. albicans infections. Our studies reported here demonstrate that posaconazole exhibits in vitro synergy with caspofungin or FK506 against drug susceptible or resistant C. albicans strains. Furthermore, these combinations also show in vivo synergy against C. albicans strain SC5314 and its derived echinocandin-resistant mutants, which harbor an S645Y mutation in the CaFks1 β-1,3 glucan synthase drug target, suggesting potential therapeutic applicability for these combinations in the future.

In vitro susceptibility of Scedosporium isolates to N-acetyl-L-cysteine alone and in combination with conventional antifungal agents.

PubMed

Homa, Mónika; Galgóczy, László; Tóth, Eszter; Virágh, Máté; Chandrasekaran, Muthusamy; Vágvölgyi, Csaba; Papp, Tamás

2016-10-01

In recent years, Scedosporium species have been more commonly recognized from severe, difficult-to-treat human infections, such as upper respiratory tract and pulmonary infections. To select an appropriate therapeutic approach for these infections is challenging, because of the commonly observed resistance of the causative agents to several antifungal drugs. Therefore, to find a novel strategy for the treatment of pulmonary Scedosporium infections the in vitro antifungal effect of a mucolytic agent, N-acetyl-L-cysteine and its in vitro combinations with conventional antifungals were investigated. Synergistic and indifferent interactions were registered in 23 and 13 cases, respectively. Antagonism was not revealed between the compounds. © The Author 2016. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

[Antifungal effects of three medicinal crops on Phytophthora nicotianae].

PubMed

He, Da-Min; Chen, Yang; Yang, Shui-Ping; Zhang, Xue; Zhao, Jian; Mo, Jing-Jing; Zhang, Dong-Yan; Zhao, Xin-Mei; Chen, Da-Xia; Ding, Wei

2017-09-01

Tobacco black shank is one of the most harmful soil-borne diseases infected by Phytophthora parasitica. In order to probe the control method to this disease, in this study, the mycelial growth rate method was employed to investigate the antifungal effects of extracts from stem-leaf and root, root exudates, and their combination of Scrophularia ningpoensis, Chuanmingshen violaceum and Pinellia ternata The results showed that: ①Stem-leaf and root extracts of S. ningpoensis, C. violaceum and P. ternata exhibited different antifungal activities, and the inhibition increased with the increase of extract concentration. The antifungal effect of S. ningpoensis extracts at 0.5 g•mL⁻¹ was the strongest than other medicinal plants, the inhibition rate of steam-leaf and root extracts reached 74.88%, 69.27%, respectively. The inhibitory effect of C. violaceum and P. ternata was relatively lower, however, there is a significant gain effect after combination of steam-leaf and root extracts of C. violaceum. ②The root exudates of S. ningpoensis, C. violaceum and P. ternata showed fungistasis to Phytophthora nicotianae, and fungistasis was enhanced with the increase of root exudate concentration. The antifungal effect in the order of C. violaceum > S. ningpoensis > P. ternata. ③The antifungal activity of combination of extract and root exudate from S. ningpoensis was similar with the effect of C. violaceum, they were both stronger than P. ternata, and the antifungal activity for three combination were located between the antifungal activity of their extracts and root exudates. S. ningpoensis and C. violaceum can be potentially applied to prevent and control the tobacco black shank. Copyright© by the Chinese Pharmaceutical Association.

Meta-Analysis and Cost Comparison of Empirical versus Pre-Emptive Antifungal Strategies in Hematologic Malignancy Patients with High-Risk Febrile Neutropenia.

PubMed

Fung, Monica; Kim, Jane; Marty, Francisco M; Schwarzinger, Michaël; Koo, Sophia

2015-01-01

Invasive fungal disease (IFD) causes significant morbidity and mortality in hematologic malignancy patients with high-risk febrile neutropenia (FN). These patients therefore often receive empirical antifungal therapy. Diagnostic test-guided pre-emptive antifungal therapy has been evaluated as an alternative treatment strategy in these patients. We conducted an electronic search for literature comparing empirical versus pre-emptive antifungal strategies in FN among adult hematologic malignancy patients. We systematically reviewed 9 studies, including randomized-controlled trials, cohort studies, and feasibility studies. Random and fixed-effect models were used to generate pooled relative risk estimates of IFD detection, IFD-related mortality, overall mortality, and rates and duration of antifungal therapy. Heterogeneity was measured via Cochran's Q test, I2 statistic, and between study τ2. Incorporating these parameters and direct costs of drugs and diagnostic testing, we constructed a comparative costing model for the two strategies. We conducted probabilistic sensitivity analysis on pooled estimates and one-way sensitivity analyses on other key parameters with uncertain estimates. Nine published studies met inclusion criteria. Compared to empirical antifungal therapy, pre-emptive strategies were associated with significantly lower antifungal exposure (RR 0.48, 95% CI 0.27-0.85) and duration without an increase in IFD-related mortality (RR 0.82, 95% CI 0.36-1.87) or overall mortality (RR 0.95, 95% CI 0.46-1.99). The pre-emptive strategy cost $324 less (95% credible interval -$291.88 to $418.65 pre-emptive compared to empirical) than the empirical approach per FN episode. However, the cost difference was influenced by relatively small changes in costs of antifungal therapy and diagnostic testing. Compared to empirical antifungal therapy, pre-emptive antifungal therapy in patients with high-risk FN may decrease antifungal use without increasing mortality. We

In vitro antifungal susceptibility testing of Scopulariopsis brevicaulis strains using agar diffusion method.

PubMed

Skóra, Magdalena; Macura, Anna B

2011-01-01

The genus Scopulariopsis is a common soil saprotroph and has been isolated from air, organic waste and also from plant, animal and human tissues. Scopulariopsis has mainly been associated in humans with superficial mycoses, but it has also been described as the cause of subcutaneous and invasive infections. The most common aetiological agent of infections in humans is Scopulariopsis brevicaulis. This species has been reported to be resistant in vitro to broad-spectrum antifungal agents available today. The aim of the study was to establish in vitro antifungal susceptibility of 35 S. brevicaulis strains against amphotericin B (AMB), flucytosine (FC), caspofungin (CAS), terbinafine (TER), ciclopirox (CIC), voriconazole (VOR), clotrimazole (CTR), miconazole (MCZ), econazole (ECO), ketoconazole (KET), itraconazole (ITR), and fluconazole (FLU). Antifungal susceptibility tests were evaluated by an agar diffusion method (Neo-Sensitabs, Rosco, Denmark). AMB, FC, CAS, ITR and FLU showed no antifungal activity against S. brevicaulis. TER, CIC, CTR, KET, VOR, ECO, and MCZ revealed inhibitory activity for S. brevicaulis, but it varied for each of the drugs. The best antifungal effect was observed for TER and CIC. All isolates had large inhibition zones for TER and CIC. CTR was also inhibitory for all tested S. brevicaulis isolates, but the diameters of inhibition zones were smaller than for TER and CIC. Nearly 89% isolates showed inhibition zones for KET and the mean diameter of the inhibition zone was comparable to CTR. The least antifungal activity exhibited VQR, ECO and MCZ. Because of the multiresistance of S. brevicaulis, infections due to this species may not respond to particular antifungal treatment and other therapeutic approaches should be considered, e.g., combined therapy and/or surgery.

The epidemiology of mycotic vulvovaginitis and the use of antifungal agents in suspected mycotic vulvovaginitis and its implications for clinical practice.

PubMed

Jackson, S T; Mullings, A M; Rainford, L; Miller, A

2005-06-01

Data in the Caribbean documenting the speciation of yeast associated with vulvovaginitis are lacking. The widespread use of antibiotics and increased availability of antimycotic agents, both prescribed and over-the-counter, predisposes both to a change in the epidemiologic patterns and the possible development of secondary resistance among previously susceptible yeast. This study was conducted to evaluate the aetiologic agents associated with mycotic vulvovaginitis and to review the appropriateness of prescribed antifungal therapy. Of 134 positive isolates, the most frequent yeast isolate was C. albicans accounting for 78%, C. tropicalis 10%, Prototheca wickerhamii (P. wickerhamii) 5%, C. glabrata 4%, Cryptococcus albidus (C. albidus) 2% and C. lusitaniae (1%) were also isolated. Of the positive cases, 75% were treated with antifungals, 17% with antibiotics and 8% were not treated. The azole group was the most frequently prescribed antifungal (71%). Of cases with negative yeast cultures, 83% were treated with antifungals. The presence of non-albicans Candida species and other opportunistic fungi is an important finding and combined with the pattern of therapy, represents a major challenge for future empirical therapeutic and prophylactic strategies in the treatment of mycotic vulvovaginitis.

Antifungal activity of medicinal plant extracts; preliminary screening studies.

PubMed

Webster, Duncan; Taschereau, Pierre; Belland, René J; Sand, Crystal; Rennie, Robert P

2008-01-04

In the setting of HIV and organ transplantation, opportunistic fungal infections have become a common cause of morbidity and mortality. Thus antifungal therapy is playing a greater role in health care. Traditional plants are a valuable source of novel antifungals. To assess in vitro antifungal activity of aqueous plant extracts. The minimum inhibitory concentrations were determined for each extract in the setting of human pathogenic fungal isolates. Plants were harvested and identification verified. Aqueous extracts were obtained and antifungal susceptibilities determined using serial dilutional extracts with a standardized microdilution broth methodology. Twenty-three fungal isolates were cultured and exposed to the plant extracts. Five known antifungals were used as positive controls. Results were read at 48 and 72 h. Of the 14 plants analyzed, Fragaria virginiana Duchesne, Epilobium angustifolium L. and Potentilla simplex Michx. demonstrated strong antifungal potential overall. Fragaria virginiana had some degree of activity against all of the fungal pathogens. Alnus viridis DC., Betula alleghaniensis Britt. and Solidago gigantea Ait. also demonstrated a significant degree of activity against many of the yeast isolates. Fragaria virginiana, Epilobium angustifolium and Potentilla simplex demonstrate promising antifungal potential.

Management of symptomatic erosive-ulcerative lesions of oral lichen planus in an adult Egyptian population using Selenium-ACE combined with topical corticosteroids plus antifungal agent

PubMed Central

Belal, Mahmoud Helmy

2015-01-01

Aim: Oral lichen planus (OLP) is a chronic mucocutaneous disease with an immunological etiology. This study was conducted to evaluate the effect of selenium combined with Vitamins A, C & E (Selenium-ACE) in the treatment of erosive-ulcerative OLP as an adjunctive to topical corticosteroids plus antifungal agent. Subjects and Methods: Thirty patients with a confirmed clinical and histopathologic diagnosis of OLP participated in this clinical trial. Patients were randomly allocated into one of three groups and treated as follows: (I) Topical corticosteroids, (II) topical corticosteroids plus antifungal, and (III) SE-ACE combined with topical corticosteroids plus antifungal. The patients were followed for 6 weeks. The pain and severity of the lesions were recorded at the initial and follow-up visits. All recorded data were analyzed using paired t-test and ANOVA test. A P ≤ 0.05 was considered significant. Results: The experimental groups showed a marked reduction in pain sensation and size of lesions, particularly in the final follow-up period, but there was no significant difference between the first two Groups I and II. However, healing of lesions and improvement of pain sensation was effective in Group III since a significant difference was found favoring Group III over both Groups I and II. Conclusion: No significant difference was found in treating erosive-ulcerative lesions of OLP by topical corticosteroids alone or combined with antifungal. However, when using SE-ACE in combination with topical corticosteroids plus antifungal, this approach may be effective in managing ulcerative lesions of OLP; but more research with a larger sample size and a longer evaluation period may be recommended. PMID:26681847

Betamethasone augments the antifungal effect of menadione--towards a novel anti-Candida albicans combination therapy.

PubMed

Jakab, Ágnes; Emri, Tamás; Sipos, Lilla; Kiss, Ágnes; Kovács, Renátó; Dombrádi, Viktor; Kemény-Beke, Ádám; Balla, József; Majoros, László; Pócsi, István

2015-08-01

The fluorinated glucocorticoid betamethasone stimulated both the extracellular phospholipase production and hypha formation of the opportunistic human pathogen Candida albicans and also decreased the efficiency of the polyene antimycotics amphotericin B and nystatin against C. albicans in a dose-dependent manner. Importantly, betamethasone increased synergistically the anti-Candida activity of the oxidative stress generating agent menadione, which may be exploited in future combination therapies to prevent or cure C. albicans infections, in the field of dermatology. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Pharmacological considerations for azole antifungal drug management in cystic fibrosis lung transplant patients.

PubMed

Billaud, Eliane M; Guillemain, Romain; Berge, Maud; Amrein, Catherine; Lefeuvre, Sandrine; Louët, Agnès Lillo-Le; Boussaud, Véronique; Chevalier, Patrick

2010-11-01

This paper aims to present our experience in the pharmacological approach of the management of azole antifungal drugs in cystic fibrosis lung transplant patients. Cystic fibrosis (CF) lung transplantation is associated with multi-factorial care management, because of immunosuppressive requirements, risk of infections, frequency of gastro-oesophageal reflux disease, hepatic alterations and CF pharmacokinetics (PK) specificities that result in important PK variability. CF is associated with frequent colonization of the airways by filamentous fungi, especially by Aspergillus species. Today the antifungal therapeutic arsenal offers several possibilities for long-term oral therapy including azole drugs (itraconazole, voriconazole and posaconazole). Therefore, nephrotoxic amphotericin B should be avoided. The liver is important in the pharmacological profile of azole drugs, due to metabolic elimination, hepatotoxicity and PK drug-drug interaction (DDI) involving CYP3A4 metabolic inhibition. Targets for such DDI are numerous, but immunosuppressive drugs are of major concern, justifying combined therapeutic drug monitoring (TDM) of both azoles (inhibitors) and immunosuppressants (targets) on an individualized patient basis to adjust the coprescription quantitatively. The risk of long under-dosed periods, frequently addressed in this population, could justify, on a PK basis, the need for combination with an exclusive parenteral antifungal while waiting for azole relevant drug level. High PK variability, the risk of low exposure, therapeutic issues and DDI management in this complex underlying disease justify close monitoring with systematic combined TDM of azole and immunosuppressants, in case of coprescription.

D-Cateslytin: a new antifungal agent for the treatment of oral Candida albicans associated infections.

PubMed

Dartevelle, Pauline; Ehlinger, Claire; Zaet, Abdurraouf; Boehler, Christian; Rabineau, Morgane; Westermann, Benoit; Strub, Jean-Marc; Cianferani, Sarah; Haïkel, Youssef; Metz-Boutigue, Marie-Hélène; Marban, Céline

2018-06-18

The excessive use of antifungal agents, compounded by the shortage of new drugs being introduced into the market, is causing the accumulation of multi-resistance phenotypes in many fungal strains. Consequently, new alternative molecules to conventional antifungal agents are urgently needed to prevent the emergence of fungal resistance. In this context, Cateslytin (Ctl), a natural peptide derived from the processing of Chromogranin A, has already been described as an effective antimicrobial agent against several pathogens including Candida albicans. In the present study, we compared the antimicrobial activity of two conformations of Ctl, L-Ctl and D-Ctl against Candida albicans. Our results show that both D-Ctl and L-Ctl were potent and safe antifungal agents. However, in contrast to L-Ctl, D-Ctl was not degraded by proteases secreted by Candida albicans and was also stable in saliva. Using video microscopy, we also demonstrated that D-Ctl can rapidly enter C. albicans, but is unable to spread within a yeast colony unless from a mother cell to a daughter cell during cellular division. Besides, we revealed that the antifungal activity of D-Ctl could be synergized by voriconazole, an antifungal of reference in the treatment of Candida albicans related infections. In conclusion, D-Ctl can be considered as an effective, safe and stable antifungal and could be used alone or in a combination therapy with voriconazole to treat Candida albicans related diseases including oral candidosis.

Microemulsion and Microemulsion-Based Gels for Topical Antifungal Therapy with Phytochemicals.

PubMed

Boonme, Prapaporn; Kaewbanjong, Jarika; Amnuaikit, Thanaporn; Andreani, Tatiana; Silva, Amélia M; Souto, Eliana B

2016-01-01

Skin fungal infections are regular injuries suffered by people living in tropical areas. Most common pathogens are Trichophyton, Microsporum and Epidermophyton which can cause skin lesions in many parts of body. Topical antifungal phytochemicals are commonly used to avoid systemic adverse events and are more convenient for patient application than those administered by other routes. However, the effectiveness of topical treatments in eradicating fungal infection is more limited since the stratum corneum acts as the skin barrier, resulting in long treatment duration and low patient's compliance. The goal of this work is to identify optimized drug delivery systems to improve topic clinical efficacy. Microemulsions i.e. liquid dispersions of oil and water stabilized with an interfacial film of surfactant are well known drug delivery systems. A thickening agent may be included to form microemulsion-based gels to increase skin adhesion. Microemulsions and microemulsion-based gels can be loaded with several hydrophilic and lipophilic drugs because they are composed of both water and oil phases. Microemulsions and microemulsion-based gels can also be used for the delivery of many drugs including antifungal drugs through stratum corneum due to their capacity to act as skin penetration enhancement. In addition to a comprehensive review of microemulsion and microemulsion-based gels as suitable carriers for skin delivery of various antifungal drugs, this review also aims to discuss the delivery of antifungal phytochemicals.

Synergy of the antibiotic colistin with echinocandin antifungals in Candida species.

PubMed

Zeidler, Ute; Bougnoux, Marie-Elisabeth; Lupan, Alexandru; Helynck, Olivier; Doyen, Antonia; Garcia, Zacarias; Sertour, Natacha; Clavaud, Cécile; Munier-Lehmann, Hélène; Saveanu, Cosmin; d'Enfert, Christophe

2013-06-01

Candida albicans is the most prevalent fungal pathogen of humans, causing a wide range of infections from harmless superficial to severe systemic infections. Improvement of the antifungal arsenal is needed since existing antifungals can be associated with limited efficacy, toxicity and antifungal resistance. Here we aimed to identify compounds that act synergistically with echinocandin antifungals and that could contribute to a faster reduction of the fungal burden. A total of 38 758 compounds were tested for their ability to act synergistically with aminocandin, a β-1,3-glucan synthase inhibitor of the echinocandin family of antifungals. The synergy between echinocandins and an identified hit was studied with chemogenomic screens and testing of individual Saccharomyces cerevisiae and C. albicans mutant strains. We found that colistin, an antibiotic that targets membranes in Gram-negative bacteria, is synergistic with drugs of the echinocandin family against all Candida species tested. The combination of colistin and aminocandin led to faster and increased permeabilization of C. albicans cells than either colistin or aminocandin alone. Echinocandin susceptibility was a prerequisite to be able to observe the synergy. A large-scale screen for genes involved in natural resistance of yeast cells to low doses of the drugs, alone or in combination, identified efficient sphingolipid and chitin biosynthesis as necessary to protect S. cerevisiae and C. albicans cells against the antifungal combination. These results suggest that echinocandin-mediated weakening of the cell wall facilitates colistin targeting of fungal membranes, which in turn reinforces the antifungal activity of echinocandins.

Quercetin and rutin as potential agents antifungal against Cryptococcus spp.

PubMed

Oliveira, V M; Carraro, E; Auler, M E; Khalil, N M

2016-01-01

Amphotericin B is a fungicidal substance that is treatment of choice for most systemic fungal infections affecting as cryptococcosis the immunocompromised patients. However, severe side effects have limited the utility of this drug. The aim of this study was to evaluate the antifungal effect of the combination of amphotericin B with quercetin or rutin and as a protective of citotoxic effect. The antifungal activity to amphotericin B, quercetin and rutin alone and in combination was determined in Candida sp and Cryptococcus neoformans strains. Cytotoxicity test on erythrocytes was performed by spectrophotometric absorbance of hemoglobin. The amphotericin B MIC was reduced when used in combination with quercetin or rutin to C. neoformans ATCC strain and reduced when combined with rutin to a clinical isolate of C. neoformans. In addition, the combination of quercetin with amphotericin B may reduce the toxicity of amphotericin B to red blood cells. Our results suggest that quercetin and rutin are potential agents to combine with amphotericin B in order to reduce the amphotericin dose to lessen side effects and improve antifungal efficacy.

Combined intrastromal injection of amphotericin B and topical fluconazole in the treatment of resistant cases of keratomycosis: a retrospective study

PubMed Central

Nada, Waled Mahdy; Al Aswad, Mahmoud A; El-Haig, Wael M

2017-01-01

Purpose To evaluate the efficacy of combination therapy of a single intrastromal injection of amphotericin B and topical fluconazole in resistant cases of fungal keratitis, and also topical amphotericin B as monotherapy in terms of the duration of the recovery period and toxic drug effects. Methods This retrospective 2-year study reviewed 68 cases of unilateral fungal keratitis diagnosed by clinical features and positive laboratory culture results. Forty-one cases were resistant and did not respond to monotherapy with an antifungal agent. Thus, they were treated with a single intrastromal injection of amphotericin B in addition to topical fluconazole as combined antifungal therapy, representing group A. Twenty-seven cases were treated with topical amphotericin B as antifungal monotherapy, representing group B. Topical atropine 1% and different antibiotic eye drops were added to the antifungal agents in both groups. Follow-up of patient records was performed monitoring cure rate, duration of recovery period, and toxic drug effects such as pain, burning sensation, and corneal melting. Results The results revealed that group A, treated with combination therapy, showed recovery of 34 cases (82.9%) with a mean duration of 24±6.42 days, significantly different from group B which showed recovery of 16 cases (59.3%) with a mean duration of 39.66±13.6 days. Group A also showed less manifestation of drug toxicity than group B. Conclusion Combined intrastromal injection of amphotericin B and topical fluconazole can provide a good modality in the treatment of resistant cases of fungal keratitis, exhibiting highly potent antifungal effects, shorter recovery period, and reduced corneal toxicity. PMID:28503064

Antifungal prophylaxis during neutropenia and immunodeficiency.

PubMed Central

Lortholary, O; Dupont, B

1997-01-01

Fungal infections represent a major source of morbidity and mortality in patients with almost all types of immunodeficiencies. These infections may be nosocomial (aspergillosis) or community acquired (cryptococcosis), or both (candidiasis). Endemic mycoses such as histoplasmosis, coccidioidomycosis, and penicilliosis may infect many immunocompromised hosts in some geographic areas and thereby create major public health problems. With the wide availability of oral azoles, antifungal prophylactic strategies have been extensively developed. However, only a few well-designed studies involving strict criteria have been performed, mostly in patients with hematological malignancies or AIDS. In these situations, the best dose and duration of administration of the antifungal drug often remain to be determined. In high-risk neutropenic or bone marrow transplant patients, fluconazole is effective for the prevention of superficial and/or systemic candidal infections but is not always able to prolong overall survival and potentially selects less susceptible or resistant Candida spp. Primary prophylaxis against aspergillosis remains investigative. At present, no standard general recommendation for primary antifungal prophylaxis can be proposed for AIDS patients or transplant recipients. However, for persistently immunocompromised patients who previously experienced a noncandidal systemic fungal infection, prolonged suppressive antifungal therapy is often indicated to prevent a relapse. Better strategies for controlling immune deficiencies should also help to avoid some potentially life-threatening deep mycoses. When prescribing antifungal prophylaxis, physicians should be aware of the potential emergence of resistant strains, drug-drug interactions, and the cost. Well-designed, randomized, multicenter clinical trials in high-risk immunocompromised hosts are urgently needed to better define how to prevent severe invasive mycoses. PMID:9227863

Keratomycosis due to Tintelnotia destructans refractory to common therapy treated successfully with systemic and local terbinafine in combination with polyhexamethylene biguanide.

PubMed

Behrens-Baumann, Wolfgang J; Hofmüller, Wolfram; Tammer, Ina; Tintelnot, Kathrin

2018-04-28

To report on a wearer of rigid gas-permeable contact lenses with a keratomycosis due to Tintelnotia-a new genus of Phaeosphaeriaceae-treated with terbinafine and polyhexamethylene biguanide. Chart review of a patient with fungal keratitis treated additionally with systemic and topical terbinafine 0.25% after symptoms increased under conventional antimycotic therapy with voriconazole. Antifungal susceptibility had been tested in vitro. After starting an additional treatment with systemic and topical terbinafine, the severe corneal infection was sufficiently resolved. The drug was well tolerated without any neurological, dermatological or gastroenterological problems. Terbinafine revealed a marked in vitro antifungal activity of 0.12 µg/ml. The fungus was identified as Tintelnotia destructans. Terbinafine might be considered as a therapeutic option in severe cases of fungal keratitis refractory to common antifungal therapy.

Successful Treatment of Fluconazole-Resistant Oropharyngeal Candidiasis by a Combination of Fluconazole and Terbinafine

PubMed Central

Ghannoum, Mahmoud A.; Elewski, Boni

1999-01-01

Increasing incidence of resistance to conventional antifungal therapy has demanded that novel therapies be introduced. Recent in vitro studies have shown that combinations involving azoles and allylamines may be effective in inhibiting fluconazole-resistant fungi. In this report, we describe the case of a 39-year-old woman who presented with white patches on her buccal mucosa, tongue, and palate with a bright erythematous erosive base. A fungal culture revealed Candida albicans. The patient failed to respond to the initially prescribed fluconazole therapy. Failure of therapy can be attributed to a developed resistance to fluconazole from the patient’s intermittent use of this antifungal agent at varying dosages for the preceding 2 years due to a diagnosis of onychomycosis. In vitro testing of the culture from the patient showed elevated MICs of fluconazole, itraconzole, and terbinafine (MICs were 32, 0.5, and 64 μg/ml, respectively). Our goal was to combine therapies of fluconazole and terbinafine in an attempt to clear the fungal infection. Impressively, this combination resulted in the clearing of the clinical symptoms and the patient has successfully been asymptomatic for more than 12 months posttreatment. PMID:10548586

Identification of New Antifungal Compounds Targeting Thioredoxin Reductase of Paracoccidioides Genus

PubMed Central

Abadio, Ana Karina Rodrigues; Kioshima, Erika Seki; Leroux, Vincent; Martins, Natalia Florêncio; Maigret, Bernard; Felipe, Maria Sueli Soares

2015-01-01

The prevalence of invasive fungal infections worldwide has increased in the last decades. The development of specific drugs targeting pathogenic fungi without producing collateral damage to mammalian cells is a daunting pharmacological challenge. Indeed, many of the toxicities and drug interactions observed with contemporary antifungal therapies can be attributed to “nonselective” interactions with enzymes or cell membrane systems found in mammalian host cells. A computer-aided screening strategy against the TRR1 protein of Paracoccidioides lutzii is presented here. Initially, a bank of commercially available compounds from Life Chemicals provider was docked to model by virtual screening simulations. The small molecules that interact with the model were ranked and, among the best hits, twelve compounds out of 3,000 commercially-available candidates were selected. These molecules were synthesized for validation and in vitro antifungal activity assays for Paracoccidioides lutzii and P. brasiliensis were performed. From 12 molecules tested, 3 harbor inhibitory activity in antifungal assays against the two pathogenic fungi. Corroborating these findings, the molecules have inhibitory activity against the purified recombinant enzyme TRR1 in biochemical assays. Therefore, a rational combination of molecular modeling simulations and virtual screening of new drugs has provided a cost-effective solution to an early-stage medicinal challenge. These results provide a promising technique to the development of new and innovative drugs. PMID:26569405

Ezetimibe-Statin Combination Therapy.

PubMed

Nußbaumer, Barbara; Glechner, Anna; Kaminski-Hartenthaler, Angela; Mahlknecht, Peter; Gartlehner, Gerald

2016-07-01

To date, most clinical comparisons of ezetimibe-statin combination therapy versus statin monotherapy have relied entirely on surrogate variables. In this systematic review, we study the efficacy and safety of ezetimibe-statin combination therapy in comparison to statin monotherapy in terms of the prevention of cardiovascular events in hyperlipidemic patients with atherosclerosis and/or diabetes mellitus. This review is based on a systematic literature search (1995 to July 2015) in PubMed, the Excerpta Medica Database (EMBASE), the Cochrane Library, and the ClinicalTrials.gov registry. Nine randomized, controlled trials with data from a total of 19 461 patients were included. Ezetimibe-statin combination therapy was associated with a lower risk of cardiovascular events than statin monotherapy: 33% of the patients treated with ezetimibe and a statin, and 35% of those treated with a statin alone, had a cardiovascular event within seven years (number needed to treat [NNT]: 50 over 7 years). Combination therapy was also significantly more effective in preventing a composite endpoint consisting of death due to cardiovascular disease, nonfatal myocardial infarction, unstable angina pectoris, coronary revascularization, and nonfatal stroke (hazard ratio [HR] 0.94, 95% confidence interval [0,89; 0,99]; p = 0.016). Diabetic patients benefited from combination therapy rather than monotherapy with respect to cardiovascular morbidity (HR 0.87 [0.78; 0.94]). On the other hand, the addition of ezetimibe to statin therapy did not lessen either cardiovascular or overall mortality. Serious undesired events occurred in 38% of the patients taking ezetimibe and a statin nd in 39% of the patients taking a statin alone (relative risk 1.09 [0.77; 1.55]). In high-risk patients with an acute coronary syndrome, combination therapy with ezetimibe and a statin lowered the risk of cardiovascular events in comparison to statin monotherapy. The risk of dying or suffering an adverse drug effect

Antifungal and antiviral products of marine organisms

PubMed Central

Cheung, Randy Chi Fai; Pan, Wen Liang; Chan, Yau Sang; Yin, Cui Ming; Dan, Xiu Li; Wang, He Xiang; Fang, Evandro Fei; Lam, Sze Kwan; Ngai, Patrick Hung Kui; Xia, Li Xin; Liu, Fang; Ye, Xiu Yun; Zhang, Guo Qing; Liu, Qing Hong; Sha, Ou; Lin, Peng; Ki, Chan; Bekhit, Adnan A; Bekhit, Alaa El-Din; Wan, David Chi Cheong

2017-01-01

Marine organisms including bacteria, fungi, algae, sponges, echinoderms, mollusks, and cephalochordates produce a variety of products with antifungal activity including bacterial chitinases, lipopeptides, and lactones; fungal (−)-sclerotiorin and peptaibols, purpurides B and C, berkedrimane B and purpuride; algal gambieric acids A and B, phlorotannins; 3,5-dibromo-2-(3,5-dibromo-2-methoxyphenoxy)phenol, spongistatin 1, eurysterols A and B, nortetillapyrone, bromotyrosine alkaloids, bis-indole alkaloid, ageloxime B and (−)-ageloxime D, haliscosamine, hamigeran G, hippolachnin A from sponges; echinoderm triterpene glycosides and alkene sulfates; molluscan kahalalide F and a 1485-Da peptide with a sequence SRSELIVHQR; and cepalochordate chitotriosidase and a 5026.9-Da antifungal peptide. The antiviral compounds from marine organisms include bacterial polysaccharide and furan-2-yl acetate; fungal macrolide, purpurester A, purpurquinone B, isoindolone derivatives, alterporriol Q, tetrahydroaltersolanol C and asperterrestide A, algal diterpenes, xylogalactofucan, alginic acid, glycolipid sulfoquinovosyldiacylglycerol, sulfated polysaccharide p-KG03, meroditerpenoids, methyl ester derivative of vatomaric acid, lectins, polysaccharides, tannins, cnidarian zoanthoxanthin alkaloids, norditerpenoid and capilloquinol; crustacean antilipopolysaccharide factors, molluscan hemocyanin; echinoderm triterpenoid glycosides; tunicate didemnin B, tamandarins A and B and; tilapia hepcidin 1–5 (TH 1–5), seabream SauMx1, SauMx2, and SauMx3, and orange-spotted grouper β-defensin. Although the mechanisms of antifungal and antiviral activities of only some of the afore-mentioned compounds have been elucidated, the possibility to use those known to have distinctly different mechanisms, good bioavailability, and minimal toxicity in combination therapy remains to be investigated. It is also worthwhile to test the marine antimicrobials for possible synergism with existing drugs. The

Commonly used oncology drugs decrease antifungal effectiveness against Candida and Aspergillus species.

PubMed

Butts, Arielle; Reitler, Parker; Ge, Wenbo; Fortwendel, Jarrod R; Palmer, Glen E

2018-04-30

The incidence of invasive fungal infections has risen significantly in recent decades as medical interventions have become increasingly aggressive. These infections are extremely difficult to treat due to the extremely limited repertoire of systemic antifungals, the development of drug resistance, and the extent of to which the patient's immune function is compromised. Even when the appropriate antifungal therapies are administered in a timely fashion, treatment failure is common, frequently even in the absence of in vitro microbial resistance. In this study, we screened a small collection of FDA approved oncolytic agents for compounds that impact the efficacy of the two most widely used classes of system antifungals against Candida albicans, Candida glabrata , and Aspergillus fumigatus We have identified several drugs that enhance fungal growth in the presence of the azole antifungals and examine the potential that these drugs directly affect fungal fitness, specifically antifungal susceptibility, and may be contributing to clinical treatment failure. Copyright © 2018 American Society for Microbiology.

Antifungal polypeptides

DOEpatents

Altier, Daniel J [Waukee, IA; Ellanskaya, Irina [Kyiv, UA; Ellanskaya, legal representative, Natalia; Gilliam, Jacob T [Norwalk, IA; Hunter-Cevera, Jennie [Elliott City, MD; Presnail, James K [Avondale, PA; Schepers, Eric [Port Deposit, MD; Simmons, Carl R [Des Moines, IA; Torok, Tamas [Richmond, CA; Yalpani, Nasser [Johnston, IA

2009-09-15

The invention relates to antifungal compositions and methods for protecting a plant from a fungal pathogen. Compositions including antifungal polypeptides isolated from a fungal fermentation broth are provided.

Current status of antifungal susceptibility testing methods.

PubMed

Arikan, Sevtap

2007-11-01

be further studied. Developments in methodology and applications of antifungal susceptibility testing will hopefully provide enhanced utility in clinical guidance of antifungal therapy. However, and particularly in immunosuppressed host, in vitro susceptibility is and will remain only one of several factors that influence clinical outcome.

Potential Use of Alginate-Based Carriers As Antifungal Delivery System

PubMed Central

Spadari, Cristina de Castro; Lopes, Luciana B.; Ishida, Kelly

2017-01-01

Fungal infections have become a major public health problem, growing in number and severity in recent decades due to an increase of immunocompromised patients. The use of therapeutic agents available to treat these fungal infections is limited by their toxicity, low bioavailability, antifungal resistance, and high cost of treatment. Thus, it becomes extremely important to search for new therapeutic options. The use of polymeric systems as drug carriers has emerged as a promising alternative to conventional formulations for antifungals. Alginate is a natural polymer that has been explored in the last decade for development of drug delivery systems due to its non-toxicity, biodegradability, biocompatibility, low cost, mucoadhesive, and non-immunogenic properties. Several antifungal agents have been incorporated in alginate-based delivery systems, including micro and nanoparticles, with great success, displaying promising in vitro and in vivo results for antifungal activities, reduction in the toxicity and the total drug dose used in the treatment, and improved bioavailability. This review aims at discussing the potential use and benefits of alginate-based nanocarriers and other delivery systems containing antifungal agents in the therapy of fungal infections. PMID:28194145

Synergy and antagonism between iron chelators and antifungal drugs in Cryptococcus.

PubMed

Lai, Yu-Wen; Campbell, Leona T; Wilkins, Marc R; Pang, Chi Nam Ignatius; Chen, Sharon; Carter, Dee A

2016-10-01

Fungal infections remain very difficult to treat, and developing new antifungal drugs is difficult and expensive. Recent approaches therefore seek to augment existing antifungals with synergistic agents that can lower the therapeutic dose, increase efficacy and prevent resistance from developing. Iron limitation can inhibit microbial growth, and iron chelators have been employed to treat fungal infections. In this study, chequerboard testing was used to explore combinations of iron chelators with antifungal agents against pathogenic Cryptococcus spp. with the aim of determining how disruption to iron homeostasis affects antifungal susceptibility. The iron chelators ethylenediaminetetraacetic acid (EDTA), deferoxamine (DFO), deferiprone (DFP), deferasirox (DSX), ciclopirox olamine and lactoferrin (LF) were paired with the antifungal agents amphotericin B (AmB), fluconazole, itraconazole, voriconazole and caspofungin. All chelators except for DFO increased the efficacy of AmB, and significant synergy was seen between AmB and LF for all Cryptococcus strains. Addition of exogenous iron rescued cells from the antifungal effect of LF alone but could not prevent inhibition by AmB + LF, indicating that synergy was not due primarily to iron chelation but to other properties of LF that were potentiated in the presence of AmB. Significant synergy was not seen consistently for other antifungal-chelator combinations, and EDTA, DSX and DFP antagonised the activity of azole drugs in strains of Cryptococcus neoformans var. grubii. This study highlights the range of interactions that can be induced by chelators and indicates that most antifungal drugs are not enhanced by iron limitation in Cryptococcus. Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

In vitro investigation of antifungal activity of allicin alone and in combination with azoles against Candida species.

PubMed

Khodavandi, Alireza; Alizadeh, Fahimeh; Aala, Farzad; Sekawi, Zamberi; Chong, Pei Pei

2010-04-01

Candidiasis is a term describing infections by yeasts from the genus Candida, and the type of infection encompassed by candidiasis ranges from superficial to systemic. Treatment of such infections often requires antifungals such as the azoles, but increased use of these drugs has led to selection of yeasts with increased resistance to these drugs. In this study, we used allicin, an allyl sulfur derivative of garlic, to demonstrate both its intrinsic antifungal activity and its synergy with the azoles, in the treatment of these yeasts in vitro. In this study, the MIC(50) and MIC(90) of allicin alone against six Candida spp. ranged from 0.05 to 25 microg/ml. However, when allicin was used in combination with fluconazole or ketoconazole, the MICs were decreased in some isolates. Our results demonstrated the existing synergistic effect between allicin and azoles in some of the Candida spp. such as C. albicans, C. glabrata and C. tropicalis, but synergy was not demonstrated in the majority of Candida spp. tested. Nonetheless, In vivo testing needs to be performed to support these findings.

Combination therapy in combating cancer

PubMed Central

Mokhtari, Reza Bayat; Homayouni, Tina S.; Baluch, Narges; Morgatskaya, Evgeniya; Kumar, Sushil; Das, Bikul; Yeger, Herman

2017-01-01

Combination therapy, a treatment modality that combines two or more therapeutic agents, is a cornerstone of cancer therapy. The amalgamation of anti-cancer drugs enhances efficacy compared to the mono-therapy approach because it targets key pathways in a characteristically synergistic or an additive manner. This approach potentially reduces drug resistance, while simultaneously providing therapeutic anti-cancer benefits, such as reducing tumour growth and metastatic potential, arresting mitotically active cells, reducing cancer stem cell populations, and inducing apoptosis. The 5-year survival rates for most metastatic cancers are still quite low, and the process of developing a new anti-cancer drug is costly and extremely time-consuming. Therefore, new strategies that target the survival pathways that provide efficient and effective results at an affordable cost are being considered. One such approach incorporates repurposing therapeutic agents initially used for the treatment of different diseases other than cancer. This approach is effective primarily when the FDA-approved agent targets similar pathways found in cancer. Because one of the drugs used in combination therapy is already FDA-approved, overall costs of combination therapy research are reduced. This increases cost efficiency of therapy, thereby benefiting the “medically underserved”. In addition, an approach that combines repurposed pharmaceutical agents with other therapeutics has shown promising results in mitigating tumour burden. In this systematic review, we discuss important pathways commonly targeted in cancer therapy. Furthermore, we also review important repurposed or primary anti-cancer agents that have gained popularity in clinical trials and research since 2012. PMID:28410237

Overcoming antifungal resistance

PubMed Central

Srinivasan, Anand; Lopez-Ribot, Jose L.; Ramasubramanian, Anand K.

2014-01-01

Fungal infections have become one of the major causes of morbidity and mortality in immunocompromised patients. Despite increased awareness and improved treatment strategies, the frequent development of resistance to the antifungal drugs used in clinical settings contributes to the increasing toll of mycoses. Although a natural phenomenon, antifungal drug resistance can compromise advances in the development of effective diagnostic techniques and novel antifungals. In this review, we will discuss the advent of cellular-microarrays, microfluidics, genomics, proteomics and other state-of-the art technologies in conquering antifungal drug resistance. PMID:24847655

Antifungal effects of phytocompounds on Candida species alone and in combination with fluconazole.

PubMed

Lu, Mengjiao; Li, Tao; Wan, Jianjian; Li, Xiuyun; Yuan, Lei; Sun, Shujuan

2017-02-01

Invasive fungal infections caused by Candida spp. remain the most predominant nosocomial fungal infections. Owing to the increased use of antifungal agents, resistance of Candida spp. to antimycotics has emerged frequently, especially to fluconazole (FLC). To cope with this issue, new efforts have been dedicated to discovering novel antimycotics or new agents that can enhance the susceptibility of Candida spp. to existing antimycotics. The secondary metabolites of plants represent a large library of compounds that are important sources for new drugs or compounds suitable for further modification. Research on the anti-Candida activities of phytocompounds has been carried out in recent years and the results showed that a series of phytocompounds have anti-Candida properties, such as phenylpropanoids, flavonoids, terpenoids and alkaloids. Among these phytocompounds, some displayed potent antifungal activity, with minimum inhibitory concentrations (MICs) of ≤8 µg/mL, and several compounds were even more effective against drug-resistant Candida spp. than FLC or itraconazole (e.g. honokiol, magnolol and shikonin). Interestingly, quite a few phytocompounds not only displayed anti-Candida activity alone but also synergised with FLC against Candida spp., even leading to a reversal of FLC resistance. This review focuses on summarising the anti-Candida activities of phytocompounds as well as the interactions of phytocompounds with FLC. In addition, we briefly overview the synergistic mechanisms and present the structure of the antimycotic phytocompounds. Hopefully, this analysis will provide insight into antifungal agent discovery and new approaches against antifungal drug resistance. Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Antifungal mechanism of the combination of Cinnamomum verum and Pelargonium graveolens essential oils with fluconazole against pathogenic Candida strains.

PubMed

Essid, Rym; Hammami, Majdi; Gharbi, Dorra; Karkouch, Ines; Hamouda, Thouraya Ben; Elkahoui, Salem; Limam, Ferid; Tabbene, Olfa

2017-09-01

The present study aimed to investigate the anti-Candida activity of ten essential oils (EOs) and to evaluate their potential synergism with conventional drugs. The effect on secreted aspartic protease (SAP) activity and the mechanism of action were also explored. The antifungal properties of essential oils were investigated using standard micro-broth dilution assay. Only Cinnamomum verum, Thymus capitatus, Syzygium aromaticum, and Pelargonium graveolens exhibited a broad spectrum of activity against a variety of pathogenic Candida strains. Chemical composition of active essential oils was performed by gas chromatography-mass spectrometry (GC-MS). Synergistic effect was observed with the combinations C. verum/fluconazole and P. graveolens/fluconazole, with FIC value 0.37. Investigation of the mechanism of action revealed that C. verum EO reduced the quantity of ergosterol to 83%. A total inhibition was observed for the combination C. verum/fluconazole. However, P. graveolens EO may disturb the permeability barrier of the fungal cell wall. An increase of MIC values of P. graveolens EO and the combination with fluconazole was observed with osmoprotectants (sorbitol and PEG6000). Furthermore, the combination with fluconazole may affect ergosterol biosynthesis and disturb fatty acid homeostasis in C. albicans cells as the quantity of ergosterol and oleic acid was reduced to 52.33 and 72%, respectively. The combination of P. graveolens and C. verum EOs with fluconazole inhibited 78.31 and 64.72% SAP activity, respectively. To our knowledge, this is the first report underlying the mechanism of action and the inhibitory effect of SAP activity of essential oils in synergy with fluconazole. Naturally occurring phytochemicals C. verum and P. graveolens could be effective candidate to enhance the efficacy of fluconazole-based therapy of C. albicans infections.

Candida antifungal drug resistance in sub-Saharan African populations: A systematic review

PubMed Central

Africa, Charlene Wilma Joyce; Abrantes, Pedro Miguel dos Santos

2017-01-01

Background: Candida infections are responsible for increased morbidity and mortality rates in at-risk patients, especially in developing countries where there is limited access to antifungal drugs and a high burden of HIV co-infection.  Objectives: This study aimed to identify antifungal drug resistance patterns within the subcontinent of Africa.  Methods: A literature search was conducted on published studies that employed antifungal susceptibility testing on clinical Candida isolates from sub-Saharan African countries using Pubmed and Google Scholar.  Results: A total of 21 studies from 8 countries constituted this review. Only studies conducted in sub-Saharan Africa and employing antifungal drug susceptibility testing were included. Regional differences in Candida species prevalence and resistance patterns were identified.  Discussion: The outcomes of this review highlight the need for a revision of antifungal therapy guidelines in regions most affected by Candida drug resistance.  Better controls in antimicrobial drug distribution and the implementation of regional antimicrobial susceptibility surveillance programmes are required in order to reduce the high Candida drug resistance levels seen to be emerging in sub-Saharan Africa. PMID:28154753

Combination therapy for solar lentigines.

PubMed

Farris, Patricia K

2004-01-01

Solar lentigines are benign, hyperpigmented lesions that present a significant cosmetic nuisance for many middle-aged and elderly patients with chronic accumulated sun exposure. While previous monotherapies designed to lighten these lesions offer relatively modest improvement, there are several new treatment options. Combination topical therapy using 2% mequinol/0.01% tretinoin [Solagé Topical Solution] has been shown to markedly reduce lesion darkness with few side effects. Chemical peels can give good results either alone or in combination with topical therapy. Cryotherapy is an effective and inexpensive way of treating solar lentigines while IPL and lasers are more costly treatment options. For patients desiring treatment, optimal cosmetic improvement can be achieved using a combination of topical and procedural therapies.

Relationship between intracranial pressure and antifungal agents levels in the CSF of patients with cryptococcal meningitis.

PubMed

Wirth, Fernanda; de Azevedo, Maria Isabel; Pilla, Carmen; Aquino, Valério Rodrigues; Neto, Gustavo Wissmann; Goldani, Luciano Zubaran

2018-04-01

The purpose of this study was to evaluate the influence of intracranial hypertension in the cerebrospinal fluid (CSF) levels of amphotericin B and fluconazole levels of patients with cryptococcal meningitis. CSF samples and intracranial pressure were obtained by means of routine punctures performed at days 1, 7, and 14 of therapy, respectively. Amphotericin B and fluconazole CSF levels were measured by HPLC method as previously described. The minimum inhibitory concentration for amphotericin B, fluconazole, 5΄flucytosine, and voriconazole of each Cryptococcus isolate was performed according to CLSI. The predominant Cryptococcus species found was C. neoformans, and the major underlying condition was AIDS. Only one CSF sample had a detectable level for amphotericin B during the 14 days of therapy. Fluconazole CSF levels progressively increased from day 1 to day 14 of therapy for most cases. Fluconazole levels in the CSF were above the minimum inhibitory concentrations (MICs) for Cryptococcus during the initial 14 days of antifungal therapy. Variations of intracranial pressure did not affect amphotericin B and fluconazole levels in the CSF. The generalized estimating correlation (GEE) and Spearman correlation test (SCT) showed no significant correlation between the amphotericin B or fluconazole concentrations in the CSF and intracranial pressure (P = .953 and P = .093, respectively for GEE test and P = .477 and P = .847, respectively, for SCT). Combination therapy of amphotericin B with fluconazole was effective in 60% of the patients considering CSF cultures were negative in 9 of 15 patients after 14 days of therapy. Further studies are necessary to evaluate the role of intracranial hypertension on the therapeutic efficacy of different antifungal agents in patients with cryptococcal meningitis.

Molecular identification and antifungal susceptibility profile of Candida species isolated from patients with vulvovaginitis in Tehran, Iran.

PubMed

Sharifynia, Somayeh; Falahati, Mehraban; Akhlaghi, Lame; Foroumadi, Alireza; Fateh, Roohollah

2017-01-01

Rapid and accurate identification and evaluation of antifungal susceptibility pattern of Candida isolates are crucial to determine suitable antifungal drugs for the treatment of patients with vulvovaginitis candidiasis. Vaginal samples were collected from 150 women with suspicious vaginal candidiasis, and then cultured on Sabouraoud's Dextrose Agar with chloramphenicol to isolate Candida species. After identification of Candida isolates using polymerase chain reaction-restriction fragment length polymorphism technique, antifungal susceptibility testing of four azolic antifungal drugs was carried out using broth microdilution method according to the CLSI M27-A3. Candida species were isolated from eighty suspected patients (61.79%). The most common pathogen was Candida albicans (63.75%). Resistance to fluconazole and ketoconazole was observed in 27.5% and 23.75% of Candida isolates, respectively, and only 2% of Candida isolates were resistant to miconazole. Interestingly, resistance to fluconazole in C. albicans was more than other Candida species. The results indicated that therapy should be selected according to the antifungal susceptibility tests for the prevention of treatment failure and miconazole therapy can be considered as the best therapeutic choice in the management of vulvovaginitis.

Molecular identification and antifungal susceptibility profile of Candida species isolated from patients with vulvovaginitis in Tehran, Iran

PubMed Central

Sharifynia, Somayeh; Falahati, Mehraban; Akhlaghi, Lame; Foroumadi, Alireza; Fateh, Roohollah

2017-01-01

Background: Rapid and accurate identification and evaluation of antifungal susceptibility pattern of Candida isolates are crucial to determine suitable antifungal drugs for the treatment of patients with vulvovaginitis candidiasis. Materials and Methods: Vaginal samples were collected from 150 women with suspicious vaginal candidiasis, and then cultured on Sabouraoud's Dextrose Agar with chloramphenicol to isolate Candida species. After identification of Candida isolates using polymerase chain reaction-restriction fragment length polymorphism technique, antifungal susceptibility testing of four azolic antifungal drugs was carried out using broth microdilution method according to the CLSI M27-A3. Results: Candida species were isolated from eighty suspected patients (61.79%). The most common pathogen was Candida albicans (63.75%). Resistance to fluconazole and ketoconazole was observed in 27.5% and 23.75% of Candida isolates, respectively, and only 2% of Candida isolates were resistant to miconazole. Interestingly, resistance to fluconazole in C. albicans was more than other Candida species. Conclusion: The results indicated that therapy should be selected according to the antifungal susceptibility tests for the prevention of treatment failure and miconazole therapy can be considered as the best therapeutic choice in the management of vulvovaginitis. PMID:29387119

Vincristine-associated Neuropathy With Antifungal Usage: A Kaiser Northern California Experience.

PubMed

Nikanjam, Mina; Sun, Aida; Albers, Mark; Mangalindin, Kristine; Song, Eyun; Vempaty, Hyma; Sam, Danny; Capparelli, Edmund V

2018-05-16

The dose-limiting toxicity for vincristine is peripheral neuropathy which can be potentiated with concurrent usage of azole antifungals. The current retrospective study assessed the incidence of concurrent vincristine and azole antifungal usage to determine if it led to increased neurotoxicity for the Kaiser Northern California pediatric acute lymphoblastic leukemia (ALL) and Hodgkin lymphoma patient population. Data were obtained from the electronic medical record (2007 to 2014). In total, 130 subjects received at least one dose of vincristine for ALL or Hodgkin lymphoma (median age 9, 88% ALL, 58% male, 47% Caucasian). Thirty one percent of patients received concurrent antifungal usage (fluconazole, 78%; voriconazole, 10%; fluconazole/voriconazole, 12%); however, concurrent antifungal usage accounted for <15% of vincristine doses. Grade 2 or greater neuropathy occurred in 51% of patients; grade 3 neuropathy was present in 8% of patients. No difference in the incidence of grade 2 or greater neuropathy was observed with the concurrent use of antifungal therapy (P=0.35), sex (P=0.59), type of cancer (P=0.41), ethnicity (P=0.29), or age (P=0.39), but was higher with increasing amount of vincristine doses (P=0.004). These results suggest that concurrent azole antifungal usage with vincristine for patients with ALL and Hodgkin lymphoma was low in the Kaiser Northern California population and limited usage as needed may be reasonable and safe.

AFM combined to ATR-FTIR reveals Candida cell wall changes under caspofungin treatment.

PubMed

Quilès, Fabienne; Accoceberry, Isabelle; Couzigou, Célia; Francius, Grégory; Noël, Thierry; El-Kirat-Chatel, Sofiane

2017-09-21

Fungal pathogens from Candida genus are responsible for severe life-threatening infections and the antifungal arsenal is still limited. Caspofungin, an antifungal drug used for human therapy, acts as a blocking agent of the cell wall synthesis by inhibiting the β-1,3-glucan-synthase encoded by FKS genes. Despite its efficiency, the number of genetic mutants that are resistant to caspofungin is increasing. An important challenge to improve antifungal therapy is to understand cellular phenomenon that are associated with drug resistance. Here we used atomic force microscopy (AFM) combined to Fourier transform infrared spectroscopy in attenuated total reflection mode (ATR-FTIR) to decipher the effect of low and high drug concentration on the morphology, mechanics and cell wall composition of two Candida strains, one susceptible and one resistant to caspofungin. Our results confirm that caspofungin induces a dramatic cell wall remodelling via activation of stress responses, even at high drug concentration. Additionally, we highlighted unexpected changes related to drug resistance, suggesting that caspofungin resistance associated with FKS gene mutations comes from a combination of effects: (i) an overall remodelling of yeast cell wall composition; and (ii) cell wall stiffening through chitin synthesis. This work demonstrates that AFM combined to ATR-FTIR is a valuable approach to understand at the molecular scale the biological mechanisms associated with drug resistance.

Integrated therapy for HIV and cryptococcosis.

PubMed

Srichatrapimuk, Sirawat; Sungkanuparph, Somnuek

2016-11-29

Cryptococcosis has been one of the most common opportunistic infections and causes of mortality among HIV-infected patients, especially in resource-limited countries. Cryptococcal meningitis is the most common form of cryptococcosis. Laboratory diagnosis of cryptococcosis includes direct microscopic examination, isolation of Cryptococcus from a clinical specimen, and detection of cryptococcal antigen. Without appropriate treatment, cryptococcosis is fatal. Early diagnosis and treatment is the key to treatment success. Treatment of cryptococcosis consists of three main aspects: antifungal therapy, intracranial pressure management for cryptococcal meningitis, and restoration of immune function with antiretroviral therapy (ART). Optimal integration of these three aspects is crucial to achieving successful treatment and reducing the mortality. Antifungal therapy consists of three phases: induction, consolidation, and maintenance. A combination of two drugs, i.e. amphotericin B plus flucytosine or fluconazole, is preferred in the induction phase. Fluconazole monotherapy is recommended during consolidation and maintenance phases. In cryptococcal meningitis, intracranial pressure rises along with CSF fungal burden and is associated with morbidity and mortality. Aggressive control of intracranial pressure should be done. Management options include therapeutic lumbar puncture, lumbar drain insertion, ventriculostomy, or ventriculoperitoneal shunt. Medical treatment such as corticosteroids, mannitol, and acetazolamide are ineffective and should not be used. ART has proven to have a great impact on survival rates among HIV-infected patients with cryptococcosis. The time to start ART in HIV-infected patients with cryptococcosis has to be deferred until 5 weeks after the start of antifungal therapy. In general, any effective ART regimen is acceptable. Potential drug interactions between antiretroviral agents and amphotericin B, flucytosine, and fluconazole are minimal. Of most

Defensins: antifungal lessons from eukaryotes

PubMed Central

Silva, Patrícia M.; Gonçalves, Sónia; Santos, Nuno C.

2014-01-01

Over the last years, antimicrobial peptides (AMPs) have been the focus of intense research toward the finding of a viable alternative to current antifungal drugs. Defensins are one of the major families of AMPs and the most represented among all eukaryotic groups, providing an important first line of host defense against pathogenic microorganisms. Several of these cysteine-stabilized peptides present a relevant effect against fungi. Defensins are the AMPs with the broader distribution across all eukaryotic kingdoms, namely, Fungi, Plantae, and Animalia, and were recently shown to have an ancestor in a bacterial organism. As a part of the host defense, defensins act as an important vehicle of information between innate and adaptive immune system and have a role in immunomodulation. This multidimensionality represents a powerful host shield, hard for microorganisms to overcome using single approach resistance strategies. Pathogenic fungi resistance to conventional antimycotic drugs is becoming a major problem. Defensins, as other AMPs, have shown to be an effective alternative to the current antimycotic therapies, demonstrating potential as novel therapeutic agents or drug leads. In this review, we summarize the current knowledge on some eukaryotic defensins with antifungal action. An overview of the main targets in the fungal cell and the mechanism of action of these AMPs (namely, the selectivity for some fungal membrane components) are presented. Additionally, recent works on antifungal defensins structure, activity, and cytotoxicity are also reviewed. PMID:24688483

Acquired Flucytosine Resistance during Combination Therapy with Caspofungin and Flucytosine for Candida glabrata Cystitis

PubMed Central

El Sissy, Carine; Bachelier-Bassi, Sophie; Scemla, Anne; Quesne, Gilles; Sitterlé, Emilie; Legendre, Christophe; Lortholary, Olivier; Bougnoux, Marie-Elisabeth

2015-01-01

Treatment of Candida glabrata cystitis remains a therapeutic challenge, and an antifungal combination using flucytosine is one option. We describe two patients with refractory C. glabrata cystitis who failed flucytosine combined with caspofungin with early-acquired high-level resistance to flucytosine due to nonsense mutations in the FUR1 gene. Rapidly acquired flucytosine resistance with microbiological failure should discourage combination of caspofungin and flucytosine during urinary candidiasis. PMID:26525799

Antifungal activity of fabrics knitted by metalized Silver/Polyester composite yarn

NASA Astrophysics Data System (ADS)

Özkan, İ.; Duru Baykal, P.

2017-10-01

In this study, antifungal properties of fabric knitted from metalized silver/polyester composite yarn were investigated. Intermingling is an alternative technique for yarn blending process. Yarns having different features can be combined by feeding the same intermingling jet. This process is defined as commingling. In the study, intermingling process was used to produce metalized silver/polyester composite yarn. Commingled yarns were knitted to single jersey fabrics by IPM brand sample type circular knitting machine. Antifungal activity test was applied to samples against Aspergillus Niger according to AATCC 30 test procedure. It has been identified that the application provides antifungal activity to fabric.

Short-Term Therapy with Luliconazole, a Novel Topical Antifungal Imidazole, in Guinea Pig Models of Tinea Corporis and Tinea Pedis

PubMed Central

Nanjoh, Yasuko; Kaneda, Hideo; Yamaguchi, Hideyo; Tsuboi, Ryoji

2012-01-01

Luliconazole is a novel topical antifungal imidazole with broad-spectrum and potent antifungal activity. The drug is under clinical development in the United States for management of dermatophytosis with a short-term treatment regimen. The present study was undertaken to investigate the clinical benefit of short-term therapy with luliconazole cream in guinea pig models of tinea corporis and tinea pedis induced with Trichophyton mentagrophytes. The dose-dependent therapeutic efficacy of topical luliconazole cream (0.02 to 1%), measured by macroscopic improvement of skin lesions and by fungal eradication as determined by a culture assay, was demonstrated using a tinea corporis model. The improvement in skin lesions seen with luliconazole cream was observed even at a concentration of 0.02%, and its efficacy at 0.1% was equal to that of 1% bifonazole cream. The efficacy of short-term therapy with 1% luliconazole cream, which is used for clinical management, was investigated using the tinea corporis model (4- and 8-day treatment regimens) and the tinea pedis model (7- and 14-day treatment regimens). The 1% luliconazole cream completely eradicated the fungus in half or less of the treatment time required for 1% terbinafine cream and 1% bifonazole cream, as determined by a culture assay for both models. These results clearly indicate that 1% luliconazole cream is sufficiently potent for short-term treatment for dermatophytosis compared to existing drugs. Luliconazole is expected to be useful in the clinical management of dermatophytosis. PMID:22391525

Short-term therapy with luliconazole, a novel topical antifungal imidazole, in guinea pig models of tinea corporis and tinea pedis.

PubMed

Koga, Hiroyasu; Nanjoh, Yasuko; Kaneda, Hideo; Yamaguchi, Hideyo; Tsuboi, Ryoji

2012-06-01

Luliconazole is a novel topical antifungal imidazole with broad-spectrum and potent antifungal activity. The drug is under clinical development in the United States for management of dermatophytosis with a short-term treatment regimen. The present study was undertaken to investigate the clinical benefit of short-term therapy with luliconazole cream in guinea pig models of tinea corporis and tinea pedis induced with Trichophyton mentagrophytes. The dose-dependent therapeutic efficacy of topical luliconazole cream (0.02 to 1%), measured by macroscopic improvement of skin lesions and by fungal eradication as determined by a culture assay, was demonstrated using a tinea corporis model. The improvement in skin lesions seen with luliconazole cream was observed even at a concentration of 0.02%, and its efficacy at 0.1% was equal to that of 1% bifonazole cream. The efficacy of short-term therapy with 1% luliconazole cream, which is used for clinical management, was investigated using the tinea corporis model (4- and 8-day treatment regimens) and the tinea pedis model (7- and 14-day treatment regimens). The 1% luliconazole cream completely eradicated the fungus in half or less of the treatment time required for 1% terbinafine cream and 1% bifonazole cream, as determined by a culture assay for both models. These results clearly indicate that 1% luliconazole cream is sufficiently potent for short-term treatment for dermatophytosis compared to existing drugs. Luliconazole is expected to be useful in the clinical management of dermatophytosis.

Epidemiology and outcomes of invasive candidiasis due to non-albicans species of Candida in 2,496 patients: data from the Prospective Antifungal Therapy (PATH) registry 2004-2008.

PubMed

Pfaller, Michael A; Andes, David R; Diekema, Daniel J; Horn, David L; Reboli, Annette C; Rotstein, Coleman; Franks, Billy; Azie, Nkechi E

2014-01-01

This analysis describes the epidemiology and outcomes of invasive candidiasis caused by non-albicans species of Candida in patients enrolled in the Prospective Antifungal Therapy Alliance (PATH Alliance) registry from 2004 to 2008. A total of 2,496 patients with non-albicans species of Candida isolates were identified. The identified species were C. glabrata (46.4%), C. parapsilosis (24.7%), C. tropicalis (13.9%), C. krusei (5.5%), C. lusitaniae (1.6%), C. dubliniensis (1.5%) and C. guilliermondii (0.4%); 111 infections involved two or more species of Candida (4.4%). Non-albicans species accounted for more than 50% of all cases of invasive candidiasis in 15 of the 24 sites (62.5%) that contributed more than one case to the survey. Among solid organ transplant recipients, patients with non-transplant surgery, and patients with solid tumors, the most prevalent non-albicans species was C. glabrata at 63.7%, 48.0%, and 53.8%, respectively. In 1,883 patients receiving antifungal therapy on day 3, fluconazole (30.5%) and echinocandins (47.5%) were the most frequently administered monotherapies. Among the 15 reported species, 90-day survival was highest for patients infected with either C. parapsilosis (70.7%) or C. lusitaniae (74.5%) and lowest for patients infected with an unknown species (46.7%) or two or more species (53.2%). In conclusion, this study expands the current knowledge of the epidemiology and outcomes of invasive candidiasis caused by non-albicans species of Candida in North America. The variability in species distribution in these centers underscores the importance of local epidemiology in guiding the selection of antifungal therapy.

Consensus guidelines for the use of empiric and diagnostic-driven antifungal treatment strategies in haematological malignancy, 2014.

PubMed

Morrissey, C O; Gilroy, N M; Macesic, N; Walker, P; Ananda-Rajah, M; May, M; Heath, C H; Grigg, A; Bardy, P G; Kwan, J; Kirsa, S W; Slavin, M; Gottlieb, T; Chen, S

2014-12-01

Invasive fungal disease (IFD) causes significant morbidity and mortality in patients undergoing allogeneic haemopoietic stem cell transplantation or chemotherapy for haematological malignancy. Much of these adverse outcomes are due to the limited ability of traditional diagnostic tests (i.e. culture and histology) to make an early and accurate diagnosis. As persistent or recurrent fevers of unknown origin (PFUO) in neutropenic patients despite broad-spectrum antibiotics have been associated with the development of IFD, most centres have traditionally administered empiric antifungal therapy (EAFT) to patients with PFUO. However, use of an EAFT strategy has not been shown to have an overall survival benefit and is associated with excessive antifungal therapy use. As a result, the focus has shifted to developing more sensitive and specific diagnostic tests for early and more targeted antifungal treatment. These tests, including the galactomannan enzyme-linked immunosorbent assay and Aspergillus polymerase chain reaction (PCR), have enabled the development of diagnostic-driven antifungal treatment (DDAT) strategies, which have been shown to be safe and feasible, reducing antifungal usage. In addition, the development of effective antifungal prophylactic strategies has changed the landscape in terms of the incidence and types of IFD that clinicians have encountered. In this review, we examine the current role of EAFT and provide up-to-date data on the newer diagnostic tests and algorithms available for use in EAFT and DDAT strategies, within the context of patient risk and type of antifungal prophylaxis used. © 2014 The Authors; Internal Medicine Journal © 2014 Royal Australasian College of Physicians.

Isobolographic Analysis of Pharmacodynamic Interactions between Antifungal Agents and Ciprofloxacin against Candida albicans and Aspergillus fumigatus▿

PubMed Central

Stergiopoulou, Theodouli; Meletiadis, Joseph; Sein, Tin; Papaioannidou, Paraskevi; Tsiouris, Ioannis; Roilides, Emmanuel; Walsh, Thomas J.

2008-01-01

Patients suffering from invasive mycoses often receive concomitant antifungal therapy and antibacterial agents. Assessment of pharmacodynamic interactions between antifungal and antibacterial agents is complicated by the absence of a common antifungal end point for both agents. Ciprofloxacin has no intrinsic antifungal activity but may interact with antifungal agents, since it inhibits DNA gyrase (topoisomerase II), which is abundant in fungi. We therefore employed isobolographic analysis adapted to incorporate a nonactive agent in order to analyze the potential in vitro interaction between the fluoroquinolone ciprofloxacin and several representative antifungal agents against Candida albicans and Aspergillus fumigatus strains by using a microdilution checkerboard technique. In agreement with earlier in vitro studies, conventional fractional inhibitory concentration index analysis was unable to detect interactions between ciprofloxacin and antifungal agents. However, isobolographic analysis revealed significant pharmacodynamic interactions between antifungal agents and ciprofloxacin against C. albicans and A. fumigatus strains. Amphotericin B demonstrated concentration-dependent interactions for both species, with synergy (interaction indices, 0.14 to 0.81) observed at ciprofloxacin concentrations of <10.64 μg/ml. Synergy (interaction indices, 0.10 to 0.86) was also found for voriconazole and caspofungin against A. fumigatus. Isobolographic analysis may help to elucidate the pharmacodynamic interactions between antifungal and non-antifungal agents and to develop better management strategies against invasive candidiasis and aspergillosis. PMID:18299413

Repaglinide in combination therapy.

PubMed

Moses, R

2002-12-01

Type 2 diabetes mellitus (T2DM) is a progressive disorder requiring increasingly aggressive treatment to achieve and maintain target blood glucose concentrations in the presence of deteriorating insulin secretion and increasing insulin resistance. Diet and lifestyle modification are often sufficient initially; however, most patients eventually require pharmacological intervention. With disease progression, monotherapy becomes less effective, so combination therapy is required, using drugs with complementary modes of action to maximise glycaemic control. The prandial glucose regulator repaglinide has been studied in combination with metformin (an inhibitor of hepatic glucose production), neutral protamine Hagedorn (NPH)-insulin (which has a long duration of effect, but at the risk of early hypoglycaemia and late hyperglycaemia in the dosing interval) and three thiazolidinediones (TZDs--troglitazone, rosiglitazone and pioglitazone, which stimulate nuclear receptors to increase insulin sensitivity and reduce insulin resistance) in patients whose diabetes was inadequately controlled by previous monotherapy or combination therapy. The combination of repaglinide and metformin resulted in reduced fasting plasma glucose concentrations (by 2.2 mmol/l) and HbA1c (by 1.4%). Combination therapy with repaglinide and bedtime NPH-insulin resulted in reductions in fasting plasma glucose (by 5.4 mmol/l) and HbA1c (by 0.7%). The combination of repaglinide and each TZD also resulted in consistent decreases in fasting plasma glucose concentrations and HbA1c. No severe hypoglycaemic episodes were reported in the three studies. In conclusion, repaglinide has additive, and often synergistic, effects on glycaemic control when given in combination regimens and should be a valuable option in the management of patients with T2DM.

Effect of Addition of Antifungal Agents on Physical and Biological Properties of a Tissue Conditioner: An In-Vitro Study.

PubMed

Rawat, Pragati; Agarwal, Swatantra; Tripathi, Siddhi

2017-09-01

Purpose: Tissue conditioners are used for healing of abused oral tissues. They may harbour microorganisms causing oral diseases such as candidiasis compromising the health of the patient. Also, addition of antifungal agents into tissue conditioner may alter its properties. This study compares the anti-fungal property and mechanical properties of tissue conditioner containing different antifungal agents. Methods: Three antifungal agents, one synthetic - fluconazole, and two natural - oregano oil and virgin coconut oil were added into the tissue conditioner (Viscogel) in different concentrations. The antifungal property, tensile bond strength and viscoelasticity of Viscogel containing these antifungal agents were assessed after 24 hours, three days and seven days. Results: While, the highest antifungal activity was shown by Viscogel containing fluconazole, the maximum tensile bond strength was found to be of Viscogel alone (control). Although Viscogel alone and in combination of fluconazole showed deterioration in viscoelasticity, Viscogel in combination of natural agents showed no significant changes over the period of seven days. Conclusion: Incorporation of the natural agents in the tissue conditioner can be used as an effective alternative to systemic or topical synthetic antifungal agents.

Systemic antifungal therapy for tinea capitis in children: An abridged Cochrane Review.

PubMed

Chen, Xiaomei; Jiang, Xia; Yang, Ming; Bennett, Cathy; González, Urbà; Lin, Xiufang; Hua, Xia; Xue, Siliang; Zhang, Min

2017-02-01

The comparative efficacy and safety profiles of systemic antifungal drugs for tinea capitis in children remain unclear. We sought to assess the effects of systemic antifungal drugs for tinea capitis in children. We used standard Cochrane methodological procedures. We included 25 randomized controlled trials with 4449 participants. Terbinafine and griseofulvin had similar effects for children with mixed Trichophyton and Microsporum infections (risk ratio 1.08, 95% confidence interval 0.94-1.24). Terbinafine was better than griseofulvin for complete cure of T tonsurans infections (risk ratio 1.47, 95% confidence interval 1.22-1.77); griseofulvin was better than terbinafine for complete cure of infections caused solely by Microsporum species (risk ratio 0.68, 95% confidence interval 0.53-0.86). Compared with griseofulvin or terbinafine, itraconazole and fluconazole had similar effects against Trichophyton infections. All included studies were at unclear or high risk of bias. Lower quality evidence resulted in a lower confidence in the estimate of effect. Significant clinical heterogeneity existed across studies. Griseofulvin or terbinafine are both effective; terbinafine is more effective for T tonsurans and griseofulvin for M canis infections. Itraconazole and fluconazole are alternative but not optimal choices for Trichophyton infections. Optimal regimens of antifungal agents need further studies. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Broth Microdilution In Vitro Screening: An Easy and Fast Method to Detect New Antifungal Compounds.

PubMed

de-Souza-Silva, Calliandra Maria; Guilhelmelli, Fernanda; Zamith-Miranda, Daniel; de Oliveira, Marco Antônio; Nosanchuk, Joshua Daniel; Silva-Pereira, Ildinete; Albuquerque, Patrícia

2018-02-14

Fungal infections have become an important medical condition in the last decades, but the number of available antifungal drugs is limited. In this scenario, the search for new antifungal drugs is necessary. The protocol reported here details a method to screen peptides for their antifungal properties. It is based on the broth microdilution susceptibility test from the Clinical and Laboratory Standards Institute (CLSI) M27-A3 guidelines with modifications to suit the research of antimicrobial peptides as potential new antifungals. This protocol describes a functional assay to evaluate the activity of antifungal compounds and may be easily modified to suit any particular class of molecules under investigation. Since the assays are performed in 96-well plates using small volumes, a large-scale screening can be completed in a short amount of time, especially if carried out in an automation setting. This procedure illustrates how a standardized and adjustable clinical protocol can help the bench-work pursuit of new molecules to improve the therapy of fungal diseases.

Adjuvant antifungal therapy using tissue tolerable plasma on oral mucosa and removable dentures in oral candidiasis patients: a randomised double-blinded split-mouth pilot study.

PubMed

Preissner, Saskia; Kastner, Isabell; Schütte, Eyke; Hartwig, Stefan; Schmidt-Westhausen, Andrea Maria; Paris, Sebastian; Preissner, Robert; Hertel, Moritz

2016-07-01

Extended use of antimycotics in oral candidiasis therapy gives rise to problems related to fungal drug resistance. The aim of this pilot study was to investigate the efficacy of tissue tolerable plasma (TTP) in denture stomatitis patients. It was hypothesised that (I): erythema and (IIa): complaint remission would be accelerated and (IIb): colony forming unit (CFU) reduction would be improved. The halves of the upper jaws of eight patients were randomly assigned to control (nystatin, chlorhexidine and placebo treatment) and test sides (nystatin, chlorhexidine and TTP administered six times each 7 days). The patients and the investigators, who were different from the therapists, were both blinded. Compared to the control sides, the erythema surface was reduced significantly more extensively on the test sides between 2 and 6 weeks of antifungal therapy (P ≤ 0.05). Visual analogue scale values and the frequency of moderate or heavy growth of Candida post-treatment did not differ significantly between both sides (P > 0.05). The primary hypothesis was confirmed, which may be interpreted as an accelerated remission. As drug therapy is usually limited to the time in which signs of infection are present, TTP might help reducing antifungal use. Even though the secondary hypotheses were not confirmed, persistence of Candida might be only colonisation. © 2016 Blackwell Verlag GmbH.

In Vitro Antifungal Susceptibility of Oral Candida Isolates from Patients Suffering from Caries and Chronic Periodontitis.

PubMed

De-la-Torre, Janire; Ortiz-Samperio, María Esther; Marcos-Arias, Cristina; Marichalar-Mendia, Xabier; Eraso, Elena; Echebarria-Goicouria, María Ángeles; Aguirre-Urizar, José Manuel; Quindós, Guillermo

2017-06-01

Caries and chronic periodontitis are common oral diseases where a higher Candida colonization is reported. Antifungal agents could be adjuvant drugs for the therapy of both clinical conditions. The aim of the current study has been to evaluate the in vitro activities of conventional and new antifungal drugs against oral Candida isolates from patients suffering from caries and/or chronic periodontitis. In vitro activities of amphotericin B, fluconazole, itraconazole, miconazole, nystatin, posaconazole and voriconazole against 126 oral Candida isolates (75 Candida albicans, 18 Candida parapsilosis, 11 Candida dubliniensis, six Candida guilliermondii, five Candida lipolytica, five Candida glabrata, four Candida tropicalis and two Candida krusei) from 61 patients were tested by the CLSI M27-A3 method. Most antifungal drugs were highly active, and resistance was observed in less than 5% of tested isolates. Miconazole was the most active antifungal drug, being more than 98% of isolates susceptible. Fluconazole, itraconazole, and the new triazoles, posaconazole and voriconazole, were also very active. Miconazole, fluconazole and voriconazole have excellent in vitro activities against all Candida isolates and could represent suitable treatment for a hypothetically adjunctive therapy of caries and chronic periodontitis.

Antifungal catheter lock therapy for the management of a persistent Candida albicans bloodstream infection in an adult receiving hemodialysis.

PubMed

Paul DiMondi, V; Townsend, Mary L; Johnson, Melissa; Durkin, Michael

2014-07-01

Antifungal catheter lock therapy (AfLT) with liposomal amphotericin B has been used in the treatment of pediatric central line infections caused by Candida species; however, reports describing the use of liposomal amphotericin B lock therapy in the adult hemodialysis patient population are lacking. Management of central line-associated candidemia with systemic therapy alone is often challenging due to the propensity of Candida species to form biofilms on foreign bodies. We describe a 64-year-old woman who was receiving hemodialysis 3 times/week and was hospitalized with persistent fungemia. Despite receiving intravenous micafungin, she had multiple positive blood cultures for Candida albicans, which finally cleared after 7 days. Her double-lumen catheter was considered the most likely nidus of infection. Although catheter removal would have been preferred, this was not possible given her vasculopathy, history of multiple bloodstream infections, and lack of other available sites for vascular access. Catheter exchange was performed, and liposomal amphotericin B AfLT was administered in combination with intravenous micafungin for a total of 6 days. During this time, the patient experienced no discernible adverse effects secondary to AfLT. At discharge, AfLT was discontinued, and intravenous micafungin was changed to oral fluconazole. After 6 months of treatment, the patient remained culture negative and maintained her dialysis access. To our knowledge, this is the first case report of liposomal amphotericin B catheter lock therapy used to manage a persistent C. albicans bloodstream infection in an adult receiving hemodialysis. AfLT is a novel concept for treating catheter-associated fungal infections. Liposomal amphotericin B was chosen based on its favorable in vitro activity against Candida species biofilms in catheter lock environments. We identified several barriers to implementing AfLT, and these issues may prohibit the use of AfLT. This case report

Acquired Flucytosine Resistance during Combination Therapy with Caspofungin and Flucytosine for Candida glabrata Cystitis.

PubMed

Charlier, Caroline; El Sissy, Carine; Bachelier-Bassi, Sophie; Scemla, Anne; Quesne, Gilles; Sitterlé, Emilie; Legendre, Christophe; Lortholary, Olivier; Bougnoux, Marie-Elisabeth

2016-01-01

Treatment of Candida glabrata cystitis remains a therapeutic challenge, and an antifungal combination using flucytosine is one option. We describe two patients with refractory C. glabrata cystitis who failed flucytosine combined with caspofungin with early-acquired high-level resistance to flucytosine due to nonsense mutations in the FUR1 gene. Rapidly acquired flucytosine resistance with microbiological failure should discourage combination of caspofungin and flucytosine during urinary candidiasis. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Enhancement of the antifungal activity of antimicrobial drugs by Eugenia uniflora L.

PubMed

Santos, Karla K A; Matias, Edinardo F F; Tintino, Saulo R; Souza, Celestina E S; Braga, Maria F B M; Guedes, Gláucia M M; Costa, José G M; Menezes, Irwin R A; Coutinho, Henrique Douglas Melo

2013-07-01

Candidiasis is the most frequent infection by opportunistic fungi such as Candida albicans, Candida tropicalis, and Candida krusei. Ethanol extract from Eugenia uniflora was assayed, for its antifungal activity, either alone or combined with four selected chemotherapeutic antimicrobial agents, including anphotericin B, mebendazole, nistatin, and metronidazole against these strains. The obtained results indicated that the association of the extract of E. uniflora to metronidazole showed a potential antifungal activity against C. tropicalis. However, no synergistic activity against the other strains was observed, as observed when the extract was associated with the other, not enhancing their antifungal activity.

Enhancement of the Antifungal Activity of Antimicrobial Drugs by Eugenia uniflora L.

PubMed Central

Santos, Karla K.A.; Matias, Edinardo F.F.; Tintino, Saulo R.; Souza, Celestina E.S.; Braga, Maria F.B.M.; Guedes, Gláucia M.M.; Costa, José G.M.; Menezes, Irwin R.A.

2013-01-01

Abstract Candidiasis is the most frequent infection by opportunistic fungi such as Candida albicans, Candida tropicalis, and Candida krusei. Ethanol extract from Eugenia uniflora was assayed, for its antifungal activity, either alone or combined with four selected chemotherapeutic antimicrobial agents, including anphotericin B, mebendazole, nistatin, and metronidazole against these strains. The obtained results indicated that the association of the extract of E. uniflora to metronidazole showed a potential antifungal activity against C. tropicalis. However, no synergistic activity against the other strains was observed, as observed when the extract was associated with the other, not enhancing their antifungal activity. PMID:23819641

Identification and quantification of antifungal compounds produced by lactic acid bacteria and propionibacteria.

PubMed

Le Lay, Céline; Coton, Emmanuel; Le Blay, Gwenaëlle; Chobert, Jean-Marc; Haertlé, Thomas; Choiset, Yvan; Van Long, Nicolas Nguyen; Meslet-Cladière, Laurence; Mounier, Jérôme

2016-12-19

Fungal growth in bakery products represents the most frequent cause of spoilage and leads to economic losses for industrials and consumers. Bacteria, such as lactic acid bacteria and propionibacteria, are commonly known to play an active role in preservation of fermented food, producing a large range of antifungal metabolites. In a previous study (Le Lay et al., 2016), an extensive screening performed both in vitro and in situ allowed for the selection of bacteria exhibiting an antifungal activity. In the present study, active supernatants against Penicillium corylophilum and Aspergillus niger were analyzed to identify and quantify the antifungal compounds associated with the observed activity. Supernatant treatments (pH neutralization, heating and addition of proteinase K) suggested that organic acids played the most important role in the antifungal activity of each tested supernatant. Different methods (HPLC, mass spectrometry, colorimetric and enzymatic assays) were then applied to analyze the supernatants and it was shown that the main antifungal compounds corresponded to lactic, acetic and propionic acids, ethanol and hydrogen peroxide, as well as other compounds present at low levels such as phenyllactic, hydroxyphenyllactic, azelaic and caproic acids. Based on these results, various combinations of the identified compounds were used to evaluate their effect on conidial germination and fungal growth of P. corylophilum and Eurotium repens. Some combinations presented the same activity than the bacterial culture supernatant thus confirming the involvement of the identified molecules in the antifungal activity. The obtained results suggested that acetic acid was mainly responsible for the antifungal activity against P. corylophilum and played an important role in E. repens inhibition. Copyright © 2016 Elsevier B.V. All rights reserved.

Use of phylogenetical analysis to predict susceptibility of pathogenic Candida spp. to antifungal drugs.

PubMed

Maheux, Andrée F; Sellam, Adnane; Piché, Yves; Boissinot, Maurice; Pelletier, René; Boudreau, Dominique K; Picard, François J; Trépanier, Hélène; Boily, Marie-Josée; Ouellette, Marc; Roy, Paul H; Bergeron, Michel G

2016-12-01

Successful treatment of a Candida infection relies on 1) an accurate identification of the pathogenic fungus and 2) on its susceptibility to antifungal drugs. In the present study we investigated the level of correlation between phylogenetical evolution and susceptibility of pathogenic Candida spp. to antifungal drugs. For this, we compared a phylogenetic tree, assembled with the concatenated sequences (2475-bp) of the ATP2, TEF1, and TUF1 genes from 20 representative Candida species, with published minimal inhibitory concentrations (MIC) of the four principal antifungal drug classes commonly used in the treatment of candidiasis: polyenes, triazoles, nucleoside analogues, and echinocandins. The phylogenetic tree revealed three distinct phylogenetic clusters among Candida species. Species within a given phylogenetic cluster have generally similar susceptibility profiles to antifungal drugs and species within Clusters II and III were less sensitive to antifungal drugs than Cluster I species. These results showed that phylogenetical relationship between clusters and susceptibility to several antifungal drugs could be used to guide therapy when only species identification is available prior to information pertaining to its resistance profile. An extended study comprising a large panel of clinical samples should be conducted to confirm the efficiency of this approach in the treatment of candidiasis. Copyright © 2016. Published by Elsevier B.V.

Hybrid combinations containing natural products and antimicrobial drugs that interfere with bacterial and fungal biofilms.

PubMed

Zacchino, Susana A; Butassi, Estefanía; Cordisco, Estefanía; Svetaz, Laura A

2017-12-15

Biofilms contribute to the pathogenesis of many chronic and difficult-to eradicate infections whose treatment is complicated due to the intrinsic resistance to conventional antibiotics. As a consequence, there is an urgent need for strategies that can be used for the prevention and treatment of biofilm-associated infections. The combination therapy comprising an antimicrobial drug with a low molecular weight (MW) natural product and an antimicrobial drug (antifungal or antibacterial) appeared as a good alternative to eradicate biofilms. The aims of this review were to perform a literature search on the different natural products that have showed the ability of potentiating the antibiofilm capacity of antimicrobial drugs, to analyze which are the antimicrobial drugs most used in combination, and to have a look on the microbial species most used to prepare biofilms. Seventeen papers, nine on combinations against antifungal biofilms and eight against antibacterial biofilms were collected. Within the text, the following topics have been developed: breaf history of the discovery of biofilms; stages in the development of a biofilm; the most used methodologies to assess antibiofilm-activity; the natural products with capacity of eradicating biofilms when acting alone; the combinations of low MW natural products with antibiotics or antifungal drugs as a strategy for eradicating microbial biofilms and a list of the low MW natural products that potentiate the inhibition capacity of antifungal and antibacterial drugs against biofilms. Regarding combinations against antifungal biofilms, eight over the nine collected works were carried out with in vitro studies while only one was performed with in vivo assays by using Caenorhabditis elegans nematode. All studies use biofilms of the Candida genus. A 67% of the potentiators were monoterpenes and sesquiterpenes and six over the nine works used FCZ as the antifungal drug. The activity of AmpB and Caspo was enhanced in one and two

Augmenting antifungal activity of oxidizing agent with kojic acid: Control of Penicillium strains infecting crops

USDA-ARS?s Scientific Manuscript database

Oxidative treatment is a strategy for preventing Penicillium contamination in foods or crops. Antifungal efficacy of oxidant [hydrogen peroxide (H2O2)], biotic effector [kojic acid (KA)] and abiotic stress (heat), alone or in combination, was investigated in Penicillium. The levels of antifungal int...

Trypanocide, cytotoxic, and antifungal activities of Momordica charantia.

PubMed

Santos, Karla K A; Matias, Edinardo F F; Sobral-Souza, Celestina E; Tintino, Saulo R; Morais-Braga, Maria F B; Guedes, Glaucia M M; Santos, Francisco A V; Sousa, Ana Carla A; Rolón, Miriam; Vega, Celeste; de Arias, Antonieta Rojas; Costa, José G M; Menezes, Irwin R A; Coutinho, Henrique D M

2012-02-01

Chagas disease, caused by Trypanosoma cruzi, is a public health problem. Currently, chemotherapy is the only available treatment for this disease, and the drugs used, nifurtimox and benzonidazol, present high toxicity levels. An alternative for replacing these drugs are natural extracts from Momordica charantia L. (Cucurbitaceae) used in traditional medicine because of their antimicrobial and biological activities. In this study, we evaluated the extract of M. charantia for its antiepimastigote, antifungal, and cytotoxic activities. An ethanol extract of leaves from M. charantia was prepared. To research in vitro antiepimastigote activity, T. cruzi CL-B5 clone was used. Epimastigotes were inoculated at a concentration of 1 × 10(5) cells/mL in 200 µl tryptose-liver infusion. For the cytotoxicity assay, J774 macrophages were used. The antifungal activity was evaluated by microdilution using strains of Candida albicans, Candida tropicalis, and Candida krusei. The effective concentration capable of killing 50% of parasites (IC(50)) was 46.06 µg/mL. The minimum inhibitory concentration (MIC) was ≤ 1024 µg/mL. Metronidazole showed a potentiation of its antifungal effect when combined with an extract of M. charantia. Our results indicate that M. charantia could be a source of plant-derived natural products with antiepimastigote and antifungal-modifying activity with moderate toxicity.

Susceptibility of Candida albicans biofilms to azithromycin, tigecycline and vancomycin and the interaction between tigecycline and antifungals.

PubMed

Ku, Tsun Sheng N; Palanisamy, Suresh K A; Lee, Samuel A

2010-11-01

Despite growing data on antimicrobial lock therapy (ALT) in treating bacterial catheter-related bloodstream infections (CR-BSIs), ALT has not been established as a treatment option for CR-BSI caused by Candida albicans. Based on our finding that high-dose doxycycline exhibited antifungal activity against mature C. albicans biofilms, we evaluated additional antibacterial agents with Gram-positive activity [azithromycin, tigecycline (TIG) and vancomycin]. After screening these antibiotics, it was found that TIG had substantial antifungal activity against mature C. albicans biofilms. Therefore, TIG was assayed alone and in combination with fluconazole (FLC), amphotericin B (AmB) or caspofungin (CAS). TIG at 2048 μg/mL resulted in a >50% reduction in the growth of planktonic C. albicans cells. TIG inhibited the formation of biofilms from 128 μg/mL. Against mature biofilms, 2048 μg/mL TIG reduced metabolic activity by 84.2%. Furthermore, addition of 512 μg/mL TIG to FLC at all concentrations tested provided additional reduction in the metabolic activity of mature biofilms. However, this was not superior to 512 μg/mL TIG alone. TIG at 512 μg/mL increased the antifungal effect of lower concentrations of AmB (0.03125-0.25 μg/mL), but at 0.03125 μg/mL and 0.0625 μg/mL this effect was not superior to 512 μg/mL TIG alone. TIG inhibited the antifungal effect of higher concentrations of AmB (≥ 2 μg/mL). TIG at 512 μg/mL inhibited the antifungal activity of CAS at lower concentrations (0.25-8 μg/mL). These data indicate that high-dose TIG is highly active in vitro against planktonic cells, forming biofilms and mature biofilms of C. albicans. Published by Elsevier B.V.

Single-drug therapy or selective decontamination of the digestive tract as antifungal prophylaxis in critically ill patients: a systematic review.

PubMed

van Till, Jw Olivier; van Ruler, Oddeke; Lamme, Bas; Weber, Roy J P; Reitsma, Johannes B; Boermeester, Marja A

2007-01-01

The objective of this study was to determine and compare the effectiveness of different prophylactic antifungal therapies in critically ill patients on the incidence of yeast colonisation, infection, candidemia, and hospital mortality. A systematic review was conducted of prospective trials including adult non-neutropenic patients, comparing single-drug antifungal prophylaxis (SAP) or selective decontamination of the digestive tract (SDD) with controls and with each other. Thirty-three studies were included (11 SAP and 22 SDD; 5,529 patients). Compared with control groups, both SAP and SDD reduced the incidence of yeast colonisation (SAP: odds ratio [OR] 0.38, 95% confidence interval [CI] 0.20 to 0.70; SDD: OR 0.12, 95% CI 0.05 to 0.29) and infection (SAP: OR 0.54, 95% CI 0.39 to 0.75; SDD: OR 0.29, 95% CI 0.18 to 0.45). Treatment effects were significantly larger in SDD trials than in SAP trials. The incidence of candidemia was reduced by SAP (OR 0.32, 95% CI 0.12 to 0.82) but not by SDD (OR 0.59, 95% CI 0.25 to 1.40). In-hospital mortality was reduced predominantly by SDD (OR 0.73, 95% CI 0.59 to 0.93, numbers needed to treat 15; SAP: OR 0.80, 95% CI 0.64 to 1.00). Effectiveness of prophylaxis reduced with an increased proportion of included surgical patients. Antifungal prophylaxis (SAP or SDD) is effective in reducing yeast colonisation and infections across a range of critically ill patients. Indirect comparisons suggest that SDD is more effective in reducing yeast-related outcomes, except for candidemia.

Combination therapy for erectile dysfunction: an update review.

PubMed

Dhir, Rohit R; Lin, Hao-Cheng; Canfield, Steven E; Wang, Run

2011-05-01

The introduction of oral phosphodiesterase-5 inhibitors (PDE5Is) in the late 1990s and early 2000s revolutionized the field of sexual medicine and PDE5Is are currently first-line monotherapy for erectile dysfunction (ED). However, a significant proportion of patients with complex ED will be therapeutic non-responders to PDE5I monotherapy. Combination therapy has recently been adopted for more refractory cases of ED, but a critical evaluation of current combination therapies is lacking. A thorough PubMed and Cochrane Library search was conducted focusing on the effectiveness of combination therapies for ED in therapeutic non-responders to PDE5I therapy. Journal articles spanning the time period between January 1990 and December 2010 were reviewed. Criteria included all pertinent review articles, randomized controlled trials, cohort studies and retrospective analyses. References from retrieved articles were also manually scanned for additional relevant publications. Published combination therapies include PDE5I plus vacuum erectile device (VED), intraurethral medication, intracavernosal injection (ICI), androgen supplement, α-blocker or miscellaneous combinations. Based on this review, some of these combination treatments appeared to be quite effective in preliminary testing. Caution must be advised, however, as the majority of combination therapy articles in the last decade have numerous limitations including study biases and small subject size. Regardless of limitations, present combination therapy research provides a solid foundation for future studies in complex ED management.

Trehalose pathway as an antifungal target.

PubMed

Perfect, John R; Tenor, Jennifer L; Miao, Yi; Brennan, Richard G

2017-02-17

With an increasing immunocompromised population which is linked to invasive fungal infections, it is clear that our present 3 classes of antifungal agents may not be sufficient to provide optimal management to these fragile patients. Furthermore, with widespread use of antifungal agents, drug-resistant fungal infections are on the rise. Therefore, there is some urgency to develop the antifungal pipeline with the goal of new antifungal agent discovery. In this review, a simple metabolic pathway, which forms the disaccharide, trehalose, will be characterized and its potential as a focus for antifungal target(s) explained. It possesses several important features for development of antifungal agents. First, it appears to have fungicidal characteristics and second, it is broad spectrum with importance across both ascomycete and basidiomycete species. Finally, this pathway is not found in mammals so theoretically specific inhibitors of the trehalose pathway and its enzymes in fungi should be relatively non-toxic for mammals. The trehalose pathway and its critical enzymes are now in a position to have directed antifungal discovery initiated in order to find a new class of antifungal drugs.

Combining Clozapine and Talk Therapies.

ERIC Educational Resources Information Center

Mulroy, Kevin

Clozapine is an antipsychotic medication used in the treatment of schizophrenia. This paper reviews articles concerning clozapine therapy. It considers its benefits and dangers in various situations, and how it can be successfully combined with talk therapies. Studies are reviewed concerning patients in outpatient clinics, partial hospitalization…

Comparative study of the in vitro activity of various antifungal drugs against Scedosporium spp. in aerobic and hyperbaric atmosphere versus normal atmosphere.

PubMed

Farina, C; Marchesi, G; Passera, M; Diliberto, C; Russello, G

2012-06-01

Scedosporium spp. have been observed with increasing frequency over the last decade in immunocompromised patients and trauma patients. This mould is often multi-drug resistant and its mortality rate remains very high. The primary goal of this study was to obtain data concerning the in vitro susceptibility of 13 Scedosporium strains comparing the in vitro incubation in aerobic versus hyperbaric conditions. Chemosensitivity of thirteen Scedosporium strains was evaluated after a 72h-incubation in a normoxic (21% O2) normobaric (1 ATA) atmosphere versus a hyperoxic (100% O2) hyperbaric (2-3 ATA), and after a re-incubation at room temperature for an additional 72h. All S. apiospermum and S. prolificans strains showed no growth after incubation in hyperbaric hyperoxic atmosphere. However, when plates were then maintained at room temperature in aerobic conditions, growth was systematically observed from 36 to 96h, and Minimal inhibitory concentration (MIC) values were the same obtained after incubation in aerobic conditions. These results suggest impressive in vitro fungistatic activity of the hyperoxic hyperbaric atmosphere, even if its effect is strictly time-dependent. This preliminary in vitro study has potential clinical relevance because it focuses on examining in vitro combination therapy using hyperoxic hyperbaric conditions plus a single antifungal agent, rather than using combinations of different antifungal drugs, to potentially increase the antifungal activity. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Serum galactomannan versus a combination of galactomannan and polymerase chain reaction-based Aspergillus DNA detection for early therapy of invasive aspergillosis in high-risk hematological patients: a randomized controlled trial.

PubMed

Aguado, José María; Vázquez, Lourdes; Fernández-Ruiz, Mario; Villaescusa, Teresa; Ruiz-Camps, Isabel; Barba, Pere; Silva, Jose T; Batlle, Montserrat; Solano, Carlos; Gallardo, David; Heras, Inmaculada; Polo, Marta; Varela, Rosario; Vallejo, Carlos; Olave, Teresa; López-Jiménez, Javier; Rovira, Montserrat; Parody, Rocío; Cuenca-Estrella, Manuel

2015-02-01

The benefit of the combination of serum galactomannan (GM) assay and polymerase chain reaction (PCR)-based detection of serum Aspergillus DNA for the early diagnosis and therapy of invasive aspergillosis (IA) in high-risk hematological patients remains unclear. We performed an open-label, controlled, parallel-group randomized trial in 13 Spanish centers. Adult patients with acute myeloid leukemia and myelodysplastic syndrome on induction therapy or allogeneic hematopoietic stem cell transplant recipients were randomized (1:1 ratio) to 1 of 2 arms: "GM-PCR group" (the results of serial serum GM and PCR assays were provided to treating physicians) and "GM group" (only the results of serum GM were informed). Positivity in either assay prompted thoracic computed tomography scan and initiation of antifungal therapy. No antimold prophylaxis was permitted. Overall, 219 patients underwent randomization (105 in the GM-PCR group and 114 in the GM group). The cumulative incidence of "proven" or "probable" IA (primary study outcome) was lower in the GM-PCR group (4.2% vs 13.1%; odds ratio, 0.29 [95% confidence interval, .09-.91]). The median interval from the start of monitoring to the diagnosis of IA was lower in the GM-PCR group (13 vs 20 days; P = .022), as well as the use of empirical antifungal therapy (16.7% vs 29.0%; P = .038). Patients in the GM-PCR group had higher proven or probable IA-free survival (P = .027). A combined monitoring strategy based on serum GM and Aspergillus DNA was associated with an earlier diagnosis and a lower incidence of IA in high-risk hematological patients. Clinical Trials Registration. NCT01742026. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Candida albicans gastrointestinal colonization and invasion in the mouse: effect of antibacterial dosing, antifungal therapy and immunosuppression.

PubMed

Kinsman, O S; Pitblado, K

1989-12-01

Infant mice infected with Candida albicans by the oral-intragastric route became colonized in the gut and were persistently colonized into adulthood. Faecal levels of Candida were correlated with total gastrointestinal Candida and provided a useful means of detecting yeast overgrowth or elimination. Antibacterial agents promoting Candida overgrowth when given by the oral or parenteral route included ceftriaxone, augmentin and cefoperazone. Ceftizoxime had less effect. Ceftazidime and latamoxef produced raised levels only by the oral route. Gentamicin, vancomycin and metronidazole did not affect the Candida levels. Dosing with some antibacterials promoted an increase in gastrointestinal Candida and invasion to a greater extent than immunosuppression. Antifungal therapy to reduce gastrointestinal colonization was investigated using amphotericin B, nystatin, ketoconazole, intraconazole and fluconazole. Fluconazole was most effective at reducing faecal Candida.

Tissue Penetration of Antifungal Agents

PubMed Central

Felton, Timothy; Troke, Peter F.

2014-01-01

SUMMARY Understanding the tissue penetration of systemically administered antifungal agents is critical for a proper appreciation of their antifungal efficacy in animals and humans. Both the time course of an antifungal drug and its absolute concentrations within tissues may differ significantly from those observed in the bloodstream. In addition, tissue concentrations must also be interpreted within the context of the pathogenesis of the various invasive fungal infections, which differ significantly. There are major technical obstacles to the estimation of concentrations of antifungal agents in various tissue subcompartments, yet these agents, even those within the same class, may exhibit markedly different tissue distributions. This review explores these issues and provides a summary of tissue concentrations of 11 currently licensed systemic antifungal agents. It also explores the therapeutic implications of their distribution at various sites of infection. PMID:24396137

Antifungal mechanisms supporting boric acid therapy of Candida vaginitis.

PubMed

De Seta, Francesco; Schmidt, Martin; Vu, Bao; Essmann, Michael; Larsen, Bryan

2009-02-01

Boric acid is a commonly cited treatment for recurrent and resistant yeast vaginitis, but data about the extent and mechanism of its antifungal activity are lacking. The aim of this study was to use in vitro methods to understand the spectrum and mechanism of boric acid as a potential treatment for vaginal infection. Yeast and bacterial isolates were tested by agar dilution to determine the intrinsic antimicrobial activity of boric acid. Established microbial physiology methods illuminated the mechanism of the action of boric acid against Candida albicans. C. albicans strains (including fluconazole-resistant strains) were inhibited at concentrations attainable intravaginally; as were bacteria. Broth dilution MICs were between 1563 and 6250 mg/L and boric acid proved fungistatic (also reflected by a decrease in CO(2) generation); prolonged culture at 50,000 mg/L was fungicidal. Several organic acids in yeast nitrogen broth yielded a lower pH than equimolar boric acid and sodium borate but were less inhibitory. Cold or anaerobic incubation protected yeast at high boric acid concentrations. Cells maintained integrity for 6 h in boric acid at 37 degrees C, but after 24 h modest intrusion of propidium iodide occurred; loss of plate count viability preceded uptake of vital stain. Growth at sub-MIC concentrations of boric acid decreased cellular ergosterol. The drug efflux pump CDR1 did not protect Candida as CDR1 expression was abrogated by boric acid. Boric acid interfered with the development of biofilm and hyphal transformation. Boric acid is fungistatic to fungicidal depending on concentration and temperature. Inhibition of oxidative metabolism appears to be a key antifungal mechanism, but inhibition of virulence probably contributes to therapeutic efficacy in vivo.

Species-specific antifungal susceptibility patterns of Scedosporium and Pseudallescheria species.

PubMed

Lackner, Michaela; de Hoog, G Sybren; Verweij, Paul E; Najafzadeh, Mohammad J; Curfs-Breuker, Ilse; Klaassen, Corné H; Meis, Jacques F

2012-05-01

Since the separation of Pseudallescheria boydii and P. apiosperma in 2010, limited data on species-specific susceptibility patterns of these and other species of Pseudallescheria and its anamorph Scedosporium have been reported. This study presents the antifungal susceptibility patterns of members affiliated with both entities. Clinical and environmental isolates (n = 332) from a wide range of sources and origins were identified down to species level and tested according to CLSI M38-A2 against eight antifungal compounds. Whereas P. apiosperma (geometric mean MIC/minimal effective concentration [MEC] values of 0.9, 2.4, 7.4, 16.2, 0.2, 0.8, 1.5, and 6.8 μg/ml for voriconazole, posaconazole, isavuconazole, itraconazole, micafungin, anidulafungin, caspofungin, and amphotericin B, respectively) and P. boydii (geometric mean MIC/MEC values of 0.7, 1.3, 5.7, 13.8, 0.5, 1.4, 2.3, and 11.8 μg/ml for voriconazole, posaconazole, isavuconazole, itraconazole, micafungin, anidulafungin, caspofungin, and amphotericin B, respectively) had similar susceptibility patterns, those for S. aurantiacum, S. prolificans, and S. dehoogii were different from each other. Voriconazole was the only drug with significant activity against S. aurantiacum isolates. The MIC distributions of all drugs except voriconazole did not show a normal distribution and often showed two subpopulations, making a species-based prediction of antifungal susceptibility difficult. Therefore, antifungal susceptibility testing of all clinical isolates remains essential for targeted antifungal therapy. Voriconazole was the only compound with low MIC values (MIC(90) of ≤ 2 μg/ml) for P. apiosperma and P. boydii. Micafungin and posaconazole showed moderate activity against the majority of Scedosporium strains.

Species-Specific Antifungal Susceptibility Patterns of Scedosporium and Pseudallescheria Species

PubMed Central

Lackner, Michaela; de Hoog, G. Sybren; Verweij, Paul E.; Najafzadeh, Mohammad J.; Curfs-Breuker, Ilse; Klaassen, Corné H.

2012-01-01

Since the separation of Pseudallescheria boydii and P. apiosperma in 2010, limited data on species-specific susceptibility patterns of these and other species of Pseudallescheria and its anamorph Scedosporium have been reported. This study presents the antifungal susceptibility patterns of members affiliated with both entities. Clinical and environmental isolates (n = 332) from a wide range of sources and origins were identified down to species level and tested according to CLSI M38-A2 against eight antifungal compounds. Whereas P. apiosperma (geometric mean MIC/minimal effective concentration [MEC] values of 0.9, 2.4, 7.4, 16.2, 0.2, 0.8, 1.5, and 6.8 μg/ml for voriconazole, posaconazole, isavuconazole, itraconazole, micafungin, anidulafungin, caspofungin, and amphotericin B, respectively) and P. boydii (geometric mean MIC/MEC values of 0.7, 1.3, 5.7, 13.8, 0.5, 1.4, 2.3, and 11.8 μg/ml for voriconazole, posaconazole, isavuconazole, itraconazole, micafungin, anidulafungin, caspofungin, and amphotericin B, respectively) had similar susceptibility patterns, those for S. aurantiacum, S. prolificans, and S. dehoogii were different from each other. Voriconazole was the only drug with significant activity against S. aurantiacum isolates. The MIC distributions of all drugs except voriconazole did not show a normal distribution and often showed two subpopulations, making a species-based prediction of antifungal susceptibility difficult. Therefore, antifungal susceptibility testing of all clinical isolates remains essential for targeted antifungal therapy. Voriconazole was the only compound with low MIC values (MIC90 of ≤2 μg/ml) for P. apiosperma and P. boydii. Micafungin and posaconazole showed moderate activity against the majority of Scedosporium strains. PMID:22290955

Athlete's foot: oral antifungals

PubMed Central

2015-01-01

Introduction Around 15% to 30% of people are likely to have athlete's foot at any one time. The infection can spread to other parts of the body and to other people. Methods and outcomes We conducted a systematic overview, aiming to answer the following clinical question: What are the effects of oral treatments for athlete's foot? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2014 (BMJ Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this overview). Results At this update, searching of electronic databases retrieved 335 studies. After deduplication and removal of conference abstracts, 210 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 162 studies and the further review of 48 full publications. Of the 48 full articles evaluated, one systematic review was included. We performed a GRADE evaluation for six PICO combinations. Conclusions In this systematic overview, we categorised the efficacy for one intervention based on information relating to the effectiveness and safety of oral antifungals versus placebo and different oral antifungals versus each other.

Promises and Dangers of Combination Therapy.

PubMed

Kruis, Wolfgang; Nguyen, Phuong G; Morgenstern, Julia

2017-01-01

The efficiency of the existing methods of treating inflammatory bowel disease (IBD) is limited. There are 2 ways to address this problem - either create new treatment modalities or optimize current therapies. Optimisation may be accomplished by using combinations of established therapeutic strategies. With regard to topically acting compounds such as 5-aminosalicylic acid, combining oral and rectal preparations is a commonly used method. Another commonly used combination is anti-tumor necrosis factor (TNF)-α antibody modalities together with immunosuppressants (thiopurines, methotrexate). Several aspects favour those combinations such as increased effectivity, prevention of immunogenicity and perhaps less adverse events. Currently, discussion on directly additive therapeutic effects is in progress, which have been demonstrated in some clinical trials. As on date, the combination of infliximab with azathioprine is most likely the most effective treatment of Crohn's disease. On the other hand, a combination therapy with both compounds affecting the immune system has, of course, risks. For sure, the frequency with which serious infectious complications are arising is increasing. Furthermore, the number of patients experiencing malignancies such as hepato-splenic lymphoma or melanoma is strongly suspected to be on the rise. In summary, combinations of current treatments for IBD are widely established. Various strategies have been studied and significant improvements of therapeutic effects have been demonstrated. Unfortunately, some of those proven combinations increase therapeutic risks, for example, increase the frequency of serious infections and also of some malignancies. Therefore, great caution has to be exercised when applying combination therapies. © 2017 S. Karger AG, Basel.

Antifungal susceptibility of 175 Aspergillus isolates from various clinical and environmental sources.

PubMed

Sabino, Raquel; Carolino, Elisabete; Veríssimo, Cristina; Martinez, Marife; Clemons, Karl V; Stevens, David A

2016-10-01

Some environmental Aspergillus spp. isolates have been described as resistant to antifungals, potentially causing an emerging medical problem. In the present work, the antifungal susceptibility profile of 41 clinical and 134 environmental isolates of Aspergillus was determined using the CLSI microdilution method. The aim of this study was to compare environmental and clinical isolates with respect to their susceptibility, and assess the potential implications for therapy of isolates encountered in different environments. To our knowledge, this is the first report comparing antifungal susceptibility profiles of Aspergillus collected from different environmental sources (poultries, swineries, beach sand, and hospital environment). Significant differences were found in the distribution of the different species sections for the different sources. Significant differences were also found in the susceptibility profile of the different Aspergillus sections recovered from the various sources. Clear differences were found between the susceptibility of clinical and environmental isolates for caspofungin, amphotericin B and posaconazole, with clinical isolates showing overall greater susceptibility, except for caspofungin. In comparison to clinical isolates, hospital environmental isolates showed significantly less susceptibility to amphotericin B and posaconazole. These data indicate that species section identity and the site from which the isolate was recovered influence the antifungal susceptibility profile, which may affect initial antifungal choices. © The Author 2016. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Combination treatment of oral terbinafine with topical terbinafine and 10% urea ointment in hyperkeratotic type tinea pedis.

PubMed

Shi, Tian-Wei; Zhang, Jiang-An; Zhang, Xian-Wei; Yu, Hong-Xing; Tang, Yong-Bo; Yu, Jian-Bin

2014-09-01

Hyperkeratotic-type tinea pedis is chronic and recalcitrant to topical antifungal agents. Some topical antifungal agents are effective; however, long duration of therapy is required, which often reduce the treatment compliance of patients. To seek for short period therapy of hyperkeratotic type tinea pedis, in this study, we observed the efficacy and safety of treatment of topical terbinafine and 10% urea ointment combined oral terbinafine. Participants with hyperkeratotic type tinea pedis were randomly assigned to two groups. Patients in group I were treated with oral terbinafine for 2 weeks and topical terbinafine and 10% urea ointment for 4 weeks, whereas in group II, only the above topical agents were applied for 12 weeks. Clinical improvement rates and fungal eradication rates were compared between the two groups at 24 weeks after the initiation of treatment. The group I had stopped the topical therapy 8 weeks earlier than group II. There were no significant differences in mycological eradication rates and clinical improvement rates between the two groups, besides, no major side effects were noted in both groups. The short combination therapy with oral terbinafine was effective and safe; it should be a valuable option for patients with hyperkeratotic type tinea pedis. © 2014 Blackwell Verlag GmbH.

Dysregulation of Ion Homeostasis by Antifungal Agents

PubMed Central

Zhang, Yongqiang; Muend, Sabina; Rao, Rajini

2012-01-01

Ion-signaling and transduction networks are central to fungal development and virulence because they regulate gene expression, filamentation, host association, and invasion, pathogen stress response and survival. Dysregulation of ion homeostasis rapidly mediates cell death, forming the mechanistic basis by which a growing number of amphipathic but structurally unrelated compounds elicit antifungal activity. Included in this group is carvacrol, a terpenoid phenol that is a prominent component of oregano and other plant essential oils. Carvacrol triggers an early dose-dependent Ca2+ burst and long lasting pH changes in the model yeast Saccharomyces cerevisiae. The distinct phases of ionic transients and a robust transcriptional response that overlaps with Ca2+ stress and nutrient starvation point to specific signaling events elicited by plant terpenoid phenols, rather than a non-specific lesion of the membrane, as was previously considered. We discuss the potential use of plant essential oils and other agents that disrupt ion-signaling pathways as chemosensitizers to augment conventional antifungal therapy, and to convert fungistatic drugs with strong safety profiles into fungicides. PMID:22493595

Dysregulation of ion homeostasis by antifungal agents.

PubMed

Zhang, Yongqiang; Muend, Sabina; Rao, Rajini

2012-01-01

Ion-signaling and transduction networks are central to fungal development and virulence because they regulate gene expression, filamentation, host association, and invasion, pathogen stress response and survival. Dysregulation of ion homeostasis rapidly mediates cell death, forming the mechanistic basis by which a growing number of amphipathic but structurally unrelated compounds elicit antifungal activity. Included in this group is carvacrol, a terpenoid phenol that is a prominent component of oregano and other plant essential oils. Carvacrol triggers an early dose-dependent Ca(2+) burst and long lasting pH changes in the model yeast Saccharomyces cerevisiae. The distinct phases of ionic transients and a robust transcriptional response that overlaps with Ca(2+) stress and nutrient starvation point to specific signaling events elicited by plant terpenoid phenols, rather than a non-specific lesion of the membrane, as was previously considered. We discuss the potential use of plant essential oils and other agents that disrupt ion-signaling pathways as chemosensitizers to augment conventional antifungal therapy, and to convert fungistatic drugs with strong safety profiles into fungicides.

In vitro antifungal susceptibility of Malassezia pachydermatis from dogs with and without skin lesions.

PubMed

Cafarchia, Claudia; Figueredo, Luciana A; Iatta, Roberta; Montagna, Maria Teresa; Otranto, Domenico

2012-03-23

Canine Malassezia dermatitis is frequently treated with systemic ketoconazole (KTZ) and itraconazole (ITZ). However, no information is available on the antifungal susceptibility to azoles and allilamine of Malassezia pachydermatis isolates from dogs with or without skin lesions. The present study was designed to evaluate the in vitro antifungal susceptibility of M. pachydermatis strains from dogs with or without skin lesions to KTZ, ITZ, miconazole (MICO), fluconazole (FLZ), posaconazole (POS), voriconazole (VOR) and terbinafine (TER) using the Clinical and Laboratory Standards Institute reference Broth Microdilution Method (CLSI M27-A2). The association between the susceptibility to antifungal compounds and the origin of M. pachydermatis, from skin with or without lesions has been also assessed. A total of 62 M. pachydermatis strains from healthy dogs (i.e., Group A=30) or with skin lesions (i.e., Group B=32) were tested. ITZ, KTZ and POS showed the highest activity against M. pachydermatis strains, whereas MICO TER and FLZ the lowest. A higher number of Malassezia resistant strains were registered among isolates from Group B than those from Group A. This study indicates that M. pachydermatis strains were susceptible to ITZ, KTZ, and POS. However, dogs with lesions may harbour strains with low susceptibility to antifungal agents and displaying cross-resistance phenomena to azole. The antifungal therapy in Malassezia infections requires careful appraisal of choice of drugs especially in cases of unresponsiveness to antifungal treatment or recurrent infections. Copyright © 2011 Elsevier B.V. All rights reserved.

A Screening Assay Based on Host-Pathogen Interaction Models Identifies a Set of Novel Antifungal Benzimidazole Derivatives▿

PubMed Central

Burger-Kentischer, Anke; Finkelmeier, Doris; Keller, Petra; Bauer, Jörg; Eickhoff, Holger; Kleymann, Gerald; Abu Rayyan, Walid; Singh, Anurag; Schröppel, Klaus; Lemuth, Karin; Wiesmüller, Karl-Heinz; Rupp, Steffen

2011-01-01

Fungal infections are a serious health problem in clinics, especially in the immune-compromised patient. Disease ranges from widespread superficial infections like vulvovaginal infections to life-threatening systemic candidiasis. Especially for systemic mycoses, only a limited arsenal of antifungals is available. The most commonly used classes of antifungal compounds used include azoles, polyenes, and echinocandins. Due to emerging resistance to standard therapy, significant side effects, and high costs for several antifungals, there is a medical need for new antifungals in the clinic and general practice. In order to expand the arsenal of compounds with antifungal activities, we screened a compound library including more than 35,000 individual compounds derived from organic synthesis as well as combinatorial compound collections representing mixtures of compounds for antimycotic activity. In total, more than 100,000 compounds were screened using a new type of activity-selectivity assay, analyzing both the antifungal activity and the compatibility with human cells at the same time. One promising hit, an (S)-2-aminoalkyl benzimidazole derivative, was developed among a series of lead compounds showing potent antifungal activity. (S)-2-(1-Aminoisobutyl)-1-(3-chlorobenzyl) benzimidazole showed the highest antifungal activity and the best compatibility with human cells in several cell culture models and against a number of clinical isolates of several species of pathogenic Candida yeasts. Transcriptional profiling indicates that the newly discovered compound is a potential inhibitor of the ergosterol pathway, in contrast to other benzimidazole derivatives, which target microtubules. PMID:21746957

Enhanced efficacy of synergistic combinations of antimicrobial peptides with caspofungin versus Candida albicans in insect and murine models of systemic infection.

PubMed

MacCallum, D M; Desbois, A P; Coote, P J

2013-08-01

The objective of this study was to determine whether combinations of antimicrobial peptides (AMPs) with caspofungin display enhanced antifungal activity versus Candida albicans in vitro and in vivo. Three conventional AMPs that satisfied criteria favouring their potential development as novel antifungals were selected for investigation. Colistin sulphate was also included as a cyclic peptide antibiotic used in the clinic. Minimum inhibitory concentrations (MICs) were determined for each antifungal agent and checkerboard assays were used to determine fractional inhibitory concentration index (FICI) values for dual combinations of AMPs or colistin with caspofungin. Viability assays were performed for the same combinations in order to investigate fungicidal interactions. Synergistic antifungal combinations were then tested for efficacy in vivo and compared to monotherapies in wax moth larva and murine models of systemic C. albicans infection. In combination with caspofungin, each of the AMPs [hMUC7-12, DsS3(1-16), hLF(1-11)] and colistin were synergistic and candidacidal in vitro. The treatment of infected wax moth larvae with combinations of caspofungin with hMUC7-12, DsS3(1-16) or colistin resulted in significant enhancements in survival compared to treatment with monotherapies. Notably, the treatment of C. albicans-infected mice with a combination of caspofungin and DsS3(1-16) resulted in the enhancement of survival compared to groups treated with just the individual agents. This study demonstrates that combination therapies containing caspofungin and AMPs or colistin merit further development as potential novel treatments for C. albicans infections.

Artificial intelligence in drug combination therapy.

PubMed

Tsigelny, Igor F

2018-02-09

Currently, the development of medicines for complex diseases requires the development of combination drug therapies. It is necessary because in many cases, one drug cannot target all necessary points of intervention. For example, in cancer therapy, a physician often meets a patient having a genomic profile including more than five molecular aberrations. Drug combination therapy has been an area of interest for a while, for example the classical work of Loewe devoted to the synergism of drugs was published in 1928-and it is still used in calculations for optimal drug combinations. More recently, over the past several years, there has been an explosion in the available information related to the properties of drugs and the biomedical parameters of patients. For the drugs, hundreds of 2D and 3D molecular descriptors for medicines are now available, while for patients, large data sets related to genetic/proteomic and metabolomics profiles of the patients are now available, as well as the more traditional data relating to the histology, history of treatments, pretreatment state of the organism, etc. Moreover, during disease progression, the genetic profile can change. Thus, the ability to optimize drug combinations for each patient is rapidly moving beyond the comprehension and capabilities of an individual physician. This is the reason, that biomedical informatics methods have been developed and one of the more promising directions in this field is the application of artificial intelligence (AI). In this review, we discuss several AI methods that have been successfully implemented in several instances of combination drug therapy from HIV, hypertension, infectious diseases to cancer. The data clearly show that the combination of rule-based expert systems with machine learning algorithms may be promising direction in this field. © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Amphotericin B-silver hybrid nanoparticles: synthesis, properties and antifungal activity.

PubMed

Tutaj, Krzysztof; Szlazak, Radoslaw; Szalapata, Katarzyna; Starzyk, Joanna; Luchowski, Rafal; Grudzinski, Wojciech; Osinska-Jaroszuk, Monika; Jarosz-Wilkolazka, Anna; Szuster-Ciesielska, Agnieszka; Gruszecki, Wieslaw I

2016-05-01

High antifungal activity is reported, in comparison with commercially available products, of a novel hybrid system based on silver nanoparticles synthesized using a popular antifungal macrocyclic polyene amphotericin B (AmB) acting both as a reducing and stabilizing/capping agent. The synthesis reaction proceeds in an alkaline environment which prevents aggregation of AmB itself and promotes nanoparticle formation. The innovative approach produces monodisperse (PDI=0.05), AmB-coated silver nanoparticles (AmB-AgNPs) with the diameter ~7nm. The products were characterized using imaging (electron microscopy) and spectroscopic (UV-vis and infrared absorption, dynamic light scattering and Raman scattering) methods. The nanoparticles were tested against Candida albicans, Aspergillus niger and Fusarium culmorum species. For cytotoxicity studies CCD-841CoTr and THP-1 cell lines were used. Particularly high antifungal activity of AmB-AgNPs is interpreted as the result of synergy between the antifungal activity of amphotericin B and silver antimicrobial properties (Ag(+) ions release). Amphotericin B (AmB) is a common agent used for the treatment against severe fungal infections. In this article, the authors described a new approach in using a combination of AmB and silver nanoparticles, in which the silver nanoparticles were synthesized and stabilized by AmB. Experimental data confirmed synergistic antifungal effects between amphotericin B and silver. This novel synthesis process could potentially be important in future drug development and fabrication. Copyright © 2016 Elsevier Inc. All rights reserved.

Antifungal stewardship considerations for adults and pediatrics.

PubMed

Hamdy, Rana F; Zaoutis, Theoklis E; Seo, Susan K

2017-08-18

Antifungal stewardship refers to coordinated interventions to monitor and direct the appropriate use of antifungal agents in order to achieve the best clinical outcomes and minimize selective pressure and adverse events. Antifungal utilization has steadily risen over time in concert with the increase in number of immunocompromised adults and children at risk for invasive fungal infections (IFI). Challenges in diagnosing IFI often lead to delays in treatment and poorer outcomes. There are also emerging data linking prior antifungal exposure and suboptimal dosing to the emergence of antifungal resistance, particularly for Candida. Antimicrobial stewardship programs can take a multi-pronged bundle approach to ensure suitable prescribing of antifungals via post-prescription review and feedback and/or prior authorization. Institutional guidelines can also be developed to guide diagnostic testing in at-risk populations; appropriate choice, dose, and duration of antifungal agent; therapeutic drug monitoring; and opportunities for de-escalation and intravenous-to-oral conversion.

Candida Species Biofilms’ Antifungal Resistance

PubMed Central

Silva, Sónia; Rodrigues, Célia F.; Araújo, Daniela; Rodrigues, Maria Elisa; Henriques, Mariana

2017-01-01

Candida infections (candidiasis) are the most prevalent opportunistic fungal infection on humans and, as such, a major public health problem. In recent decades, candidiasis has been associated to Candida species other than Candida albicans. Moreover, biofilms have been considered the most prevalent growth form of Candida cells and a strong causative agent of the intensification of antifungal resistance. As yet, no specific resistance factor has been identified as the sole responsible for the increased recalcitrance to antifungal agents exhibited by biofilms. Instead, biofilm antifungal resistance is a complex multifactorial phenomenon, which still remains to be fully elucidated and understood. The different mechanisms, which may be responsible for the intrinsic resistance of Candida species biofilms, include the high density of cells within the biofilm, the growth and nutrient limitation, the effects of the biofilm matrix, the presence of persister cells, the antifungal resistance gene expression and the increase of sterols on the membrane of biofilm cells. Thus, this review intends to provide information on the recent advances about Candida species biofilm antifungal resistance and its implication on intensification of the candidiasis. PMID:29371527

Antifungal Susceptibility and Phylogeny of Opportunistic Members of the Order Mucorales

PubMed Central

Vitale, Roxana G.; de Hoog, G. Sybren; Schwarz, Patrick; Dannaoui, Eric; Deng, Shuwen; Machouart, Marie; Voigt, Kerstin; van de Sande, Wendy W. J.; Dolatabadi, Somayeh; Meis, Jacques F.

2012-01-01

The in vitro susceptibilities of 66 molecularly identified strains of the Mucorales to eight antifungals (amphotericin B, terbinafine, itraconazole, posaconazole, voriconazole, caspofungin, micafungin, and 5-fluorocytosine) were tested. Molecular phylogeny was reconstructed based on the nuclear ribosomal large subunit to reveal taxon-specific susceptibility profiles. The impressive phylogenetic diversity of the Mucorales was reflected in susceptibilities differing at family, genus, and species levels. Amphotericin B was the most active drug, though somewhat less against Rhizopus and Cunninghamella species. Posaconazole was the second most effective antifungal agent but showed reduced activity in Mucor and Cunninghamella strains, while voriconazole lacked in vitro activity for most strains. Genera attributed to the Mucoraceae exhibited a wide range of MICs for posaconazole, itraconazole, and terbinafine and included resistant strains. Cunninghamella also comprised strains resistant to all azoles tested but was fully susceptible to terbinafine. In contrast, the Lichtheimiaceae completely lacked strains with reduced susceptibility for these antifungals. Syncephalastrum species exhibited susceptibility profiles similar to those of the Lichtheimiaceae. Mucor species were more resistant to azoles than Rhizopus species. Species-specific responses were obtained for terbinafine where only Rhizopus arrhizus and Mucor circinelloides were resistant. Complete or vast resistance was observed for 5-fluorocytosine, caspofungin, and micafungin. Intraspecific variability of in vitro susceptibility was found in all genera tested but was especially high in Mucor and Rhizopus for azoles and terbinafine. Accurate molecular identification of etiologic agents is compulsory to predict therapy outcome. For species of critical genera such as Mucor and Rhizopus, exhibiting high intraspecific variation, susceptibility testing before the onset of therapy is recommended. PMID:22075600

Antifungal susceptibility and phylogeny of opportunistic members of the order mucorales.

PubMed

Vitale, Roxana G; de Hoog, G Sybren; Schwarz, Patrick; Dannaoui, Eric; Deng, Shuwen; Machouart, Marie; Voigt, Kerstin; van de Sande, Wendy W J; Dolatabadi, Somayeh; Meis, Jacques F; Walther, Grit

2012-01-01

The in vitro susceptibilities of 66 molecularly identified strains of the Mucorales to eight antifungals (amphotericin B, terbinafine, itraconazole, posaconazole, voriconazole, caspofungin, micafungin, and 5-fluorocytosine) were tested. Molecular phylogeny was reconstructed based on the nuclear ribosomal large subunit to reveal taxon-specific susceptibility profiles. The impressive phylogenetic diversity of the Mucorales was reflected in susceptibilities differing at family, genus, and species levels. Amphotericin B was the most active drug, though somewhat less against Rhizopus and Cunninghamella species. Posaconazole was the second most effective antifungal agent but showed reduced activity in Mucor and Cunninghamella strains, while voriconazole lacked in vitro activity for most strains. Genera attributed to the Mucoraceae exhibited a wide range of MICs for posaconazole, itraconazole, and terbinafine and included resistant strains. Cunninghamella also comprised strains resistant to all azoles tested but was fully susceptible to terbinafine. In contrast, the Lichtheimiaceae completely lacked strains with reduced susceptibility for these antifungals. Syncephalastrum species exhibited susceptibility profiles similar to those of the Lichtheimiaceae. Mucor species were more resistant to azoles than Rhizopus species. Species-specific responses were obtained for terbinafine where only Rhizopus arrhizus and Mucor circinelloides were resistant. Complete or vast resistance was observed for 5-fluorocytosine, caspofungin, and micafungin. Intraspecific variability of in vitro susceptibility was found in all genera tested but was especially high in Mucor and Rhizopus for azoles and terbinafine. Accurate molecular identification of etiologic agents is compulsory to predict therapy outcome. For species of critical genera such as Mucor and Rhizopus, exhibiting high intraspecific variation, susceptibility testing before the onset of therapy is recommended.

In vitro antifungal activity of topical and systemic antifungal drugs against Malassezia species.

PubMed

Carrillo-Muñoz, Alfonso Javier; Rojas, Florencia; Tur-Tur, Cristina; de Los Ángeles Sosa, María; Diez, Gustavo Ortiz; Espada, Carmen Martín; Payá, María Jesús; Giusiano, Gustavo

2013-09-01

The strict nutritional requirements of Malassezia species make it difficult to test the antifungal susceptibility. Treatments of the chronic and recurrent infections associated with Malassezia spp. are usually ineffective. The objective of this study was to obtain in vitro susceptibility profile of 76 clinical isolates of Malassezia species against 16 antifungal drugs used for topical or systemic treatment. Isolates were identified by restriction fragment length polymorphism. Minimal inhibitory concentrations (MIC) were obtained by a modified microdilution method based on the Clinical Laboratory Standards Institute reference document M27-A3. The modifications allowed a good growth of all tested species. High in vitro antifungal activity of most tested drugs was observed, especially triazole derivatives, except for fluconazole which presented the highest MICs and widest range of concentrations. Ketoconazole and itraconazole demonstrated a great activity. Higher MICs values were obtained with Malassezia furfur indicating a low susceptibility to most of the antifungal agents tested. Malassezia sympodialis and Malassezia pachydermatis were found to be more-susceptible species than M. furfur, Malassezia globosa, Malassezia slooffiae and Malassezia restricta. Topical substances were also active but provide higher MICs than the compounds for systemic use. The differences observed in the antifungals activity and interspecies variability demonstrated the importance to studying the susceptibility profile of each species to obtain reliable information for defining an effective treatment regimen. © 2013 Blackwell Verlag GmbH.

In vitro antifungal susceptibility of Trichophyton violaceum isolated from tinea capitis patients.

PubMed

Deng, S; de Hoog, G S; Verweij, P E; Zoll, J; Ilkit, M; Morsali, F; Abliz, P; Wang, X; Zhan, P; Yang, L; Hasimu, H; Liao, W; Pan, W; Seyedmousavi, S

2015-04-01

Trichophyton violaceum is an anthropophilic dermatophyte that is endemic to parts of Africa and Asia and is sporadic in Europe. T. violaceum mainly causes tinea capitis in both children and adolescents. Although the infections caused by T. violaceum are of considerable medical importance, its antifungal susceptibility profile remains poorly examined. In this study, we tested the in vitro antifungal susceptibility of a set of clinical T. violaceum isolates obtained from tinea capitis patients, using the CLSI broth microdilution method. We tested eight antifungals and used isolates collected from Western China (21), Eastern China (12), the Middle East (1), Europe (20), South Africa (7) and Canada (1). The geometric means of the MICs of the antifungals for all isolates were as follows (in increasing order): posaconazole, 0.021 mg/L; terbinafine, 0.023 mg/L; voriconazole, 0.062 mg/L; amphotericin B, 0.20 mg/L; itraconazole, 0.34 mg/L; caspofungin, 0.56 mg/L; fluconazole, 4.23 mg/L; and flucytosine, 8.46 mg/L. No statistically significant differences in the susceptibility profiles of T. violaceum were detected within the geographical regions tested. Posaconazole, terbinafine and voriconazole were shown to be the most potent antifungal agents against T. violaceum isolates obtained from tinea capitis patients worldwide. These results might help clinicians in developing appropriate therapies that have a high probability of successfully treating tinea capitis due to T. violaceum. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

The antifungal action of dandruff shampoos.

PubMed

Bulmer, A C; Bulmer, G S

1999-01-01

The disease commonly known as "dandruff" is caused by numerous host factors in conjunction with the normal flora yeast Malassezia furfur (Pityrosporum ovale). Indeed, clinical studies have shown that administration of antifungal agents correlates with an improved clinical condition. Almost all commercially available hair shampoos publicize that they contain some form of antifungal agent(s). However, few studies have been published in which antifungal activity of commercially available hair shampoos have been contrasted experimentally. In this study six commercially available shampoos (in the Philippines) were assessed for antifungal activity against a human (dandruff) isolate of M. furfur: (a) Head & Shoulders (Proctor & Gamble); (b) Gard Violet (Colgate-Palmolive); (c) Nizoral 1% (Janssen); (d) Nizoral 2% (Janssen); (e) Pantene Blue (Proctor & Gamble); and (f) Selsun Blue (Abbott). The results demonstrated that all six of the assayed hair shampoos have some antifungal effect on the test yeast. However, there was consider variation in potency of antifungal activity. Nizoral 1% and Nizoral 2% shampoo preparations were the most effective. The 1% Nizoral shampoo was consistently 10X better at killing yeast cells than the next closest rival shampoo. The 2% Nizoral shampoo was 10X better than the Nizoral 1% product and 100 times better than any of the other products assayed. The study demonstrated that shampoos containing a proven antifungal compound were the most effective in controlling the causative yeast.

In vivo application of a small molecular weight antifungal protein of Penicillium chrysogenum (PAF)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Palicz, Zoltán; Jenes, Ágnes; Gáll, Tamás

2013-05-15

The antifungal protein of Penicillium chrysogenum (PAF) inhibits the growth of important pathogenic filamentous fungi, including members of the Aspergillus family and some dermatophytes. Furthermore, PAF was proven to have no toxic effects on mammalian cells in vitro. To prove that PAF could be safely used in therapy, experiments were carried out to investigate its in vivo effects. Adult mice were inoculated with PAF intranasally in different concentrations, up to 2700 μg·kg{sup −1} daily, for 2 weeks. Even at the highest concentration – a concentration highly toxic in vitro for all affected molds – used, animals neither died due tomore » the treatment nor were any side effects observed. Histological examinations did not find pathological reactions in the liver, in the kidney, and in the lungs. Mass spectrometry confirmed that a measurable amount of PAF was accumulated in the lungs after the treatment. Lung tissue extracts from PAF treated mice exerted significant antifungal activity. Small-animal positron emission tomography revealed that neither the application of physiological saline nor that of PAF induced any inflammation while the positive control lipopolysaccharide did. The effect of the drug on the skin was examined in an irritative dermatitis model where the change in the thickness of the ears following PAF application was found to be the same as in control and significantly less than when treated with phorbol-12-myristate-13-acetate used as positive control. Since no toxic effects of PAF were found in intranasal application, our result is the first step for introducing PAF as potential antifungal drug in therapy. - Highlights: • PAF, the antifungal protein of Penicillium chrysogenum, was not toxic in mice. • Its intranasal application didn't induce pathological reactions in the lung. • PAF retained its antifungal activity in lung extracts. • Its application on the skin did not cause inflammation.« less

The In Vitro Efficacy of Essential Oils and Antifungal Drugs Against Prototheca zopfii.

PubMed

Grzesiak, Barbara; Głowacka, Anna; Krukowski, Henryk; Lisowski, Andrzej; Lassa, Henryka; Sienkiewicz, Monika

2016-08-01

The algae of the genus Prototheca are environmental pathogens whose main reservoir is the habitat of cows. They can cause protothecosis in domestic and wild animals, as well as human beings, with the main etiological agents being Prototheca zopfii in animals and Prototheca wickerhamii in humans. The aim of the study was to evaluate the in vitro activity of selected essential oils and antifungal antibiotics against P. zopfii isolates. The material consisted of nine P. zopfii strains isolated from the milk of cows suffering from mastitis. Eight essential oils produced by POLLENA-AROMA, Poland, and nine antifungal agents were tested. The effects of essential oils on P. zopfii were evaluated by microdilution with liquid Sabouraud dextrose broth, and susceptibility to antifungal agents was tested using the disk-diffusion method. All used essential oils inhibited the activity of P. zopfii isolates, with MIC values ranging from 0.2 to 10.5 μl/ml. Cinnamon, clove, and thyme demonstrated the highest activity against the tested P. zopfii strains at concentrations ranging from 0.6 to 1.0 μl/ml. Of the antifungal agents, the tested strains were the most sensitive to nystatin (100 %). The tested essential oils can be used to complement protothecosis therapy in animals and human beings.

Evaluation of the antifungal effect of EDTA, a metal chelator agent, on Candida albicans biofilm.

PubMed

Casalinuovo, I A; Sorge, R; Bonelli, G; Di Francesco, P

2017-03-01

Candida albicans biofilm is frequently found on artificial surfaces and the infections related to biofilm are difficult to eliminate, as they require the removal of artificial devices and treatment with antifungal drugs. Nowadays, fungal growth in biofilms is difficult to eradicate with conventional antifungal drugs such as fluconazole. Among chelating agents, disodium salt-Ethylene Diamine Tetraacetic Acid (EDTA) is known to have antifungal activity. In this study, we examined the in vitro activity of the EDTA and the antifungal drug fluconazole against C. albicans mature biofilm. C. albicans ATCC 20191, fluconazole-susceptible strain, was grown at an inoculum starter of 1 x 106 cells/ml for 72 h in 24-well microtiter plates and was further treated for 24 h with EDTA and/or fluconazole. Antifungal activities in biofilms were expressed as reduction in optical density (OD) determined by a 2,3-bis (2-methoxy-4-nitro-5-sulfo-phenyl)-2H-tetrazolium-5-carboxanilide (XTT) colorimetric assay and compared to untreated biofilms. Colorimetric readings revealed that EDTA alone (at 25 and 2.5 mM) significantly reduced fungal metabolic activity in preformed biofilms. Also, EDTA combined with fluconazole significantly reduced the growth of biofilm when compared to biofilm treated with fluconazole alone (at 25 and 2.5 µg/ml). Our data suggest that the employment of EDTA or other chemicals destabilizers of the biofilm matrix, in combination with antifungal drugs, could lead to the development of new strategies for the management of infections associated to Candida biofilm. Another relevant result of our study suggests that the initial cell concentration, probably through mechanisms of quorum sensing, affects the cellular viability during the process of biofilm formation.

A Class 1 Histone Deacetylase with Potential as an Antifungal Target.

PubMed

Bauer, Ingo; Varadarajan, Divyavaradhi; Pidroni, Angelo; Gross, Silke; Vergeiner, Stefan; Faber, Birgit; Hermann, Martin; Tribus, Martin; Brosch, Gerald; Graessle, Stefan

2016-11-01

Histone deacetylases (HDACs) remove acetyl moieties from lysine residues at histone tails and nuclear regulatory proteins and thus significantly impact chromatin remodeling and transcriptional regulation in eukaryotes. In recent years, HDACs of filamentous fungi were found to be decisive regulators of genes involved in pathogenicity and the production of important fungal metabolites such as antibiotics and toxins. Here we present proof that one of these enzymes, the class 1 type HDAC RpdA, is of vital importance for the opportunistic human pathogen Aspergillus fumigatus Recombinant expression of inactivated RpdA shows that loss of catalytic activity is responsible for the lethal phenotype of Aspergillus RpdA null mutants. Furthermore, we demonstrate that a fungus-specific C-terminal region of only a few acidic amino acids is required for both the nuclear localization and catalytic activity of the enzyme in the model organism Aspergillus nidulans Since strains with single or multiple deletions of other classical HDACs revealed no or only moderate growth deficiencies, it is highly probable that the significant delay of germination and the growth defects observed in strains growing under the HDAC inhibitor trichostatin A are caused primarily by inhibition of catalytic RpdA activity. Indeed, even at low nanomolar concentrations of the inhibitor, the catalytic activity of purified RpdA is considerably diminished. Considering these results, RpdA with its fungus-specific motif represents a promising target for novel HDAC inhibitors that, in addition to their increasing impact as anticancer drugs, might gain in importance as antifungals against life-threatening invasive infections, apart from or in combination with classical antifungal therapy regimes. This paper reports on the fungal histone deacetylase RpdA and its importance for the viability of the fungal pathogen Aspergillus fumigatus and other filamentous fungi, a finding that is without precedent in other

Potential Antifungal Targets against a Candida Biofilm Based on an Enzyme in the Arachidonic Acid Cascade—A Review

PubMed Central

Liu, Xinning; Wang, Decai; Yu, Cuixiang; Li, Tao; Liu, Jianqiao; Sun, Shujuan

2016-01-01

Candida is an important opportunistic fungal pathogen, especially in biofilm associated infections. The formation of a Candida biofilm can decrease Candida sensitivity to antifungal drugs and cause drug resistance. Although many effective antifungal drugs are available, their applications are limited due to their high toxicity and cost. Seeking new antifungal agents that are effective against biofilm-associated infection is an urgent need. Many research efforts are underway, and some progress has been made in this field. It has been shown that the arachidonic acid cascade plays an important role in fungal morphogenesis and pathogenicity. Notably, prostaglandin E2 (PGE2) can promote the formation of a Candida biofilm. Recently, the inhibition of PGE2 has received much attention. Studies have shown that cyclooxygenase (COX) inhibitors, such as aspirin, ibuprofen, and indomethacin, combined with fluconazole can significantly reduce Candida adhesion and biofilm development and increase fluconazole susceptibility; the MIC of fluconazole can be decrease from 64 to 2 μg/ml when used in combination with ibuprofen. In addition, in vivo studies have also confirmed the antifungal activities of these inhibitors. In this article, we mainly review the relationship between PGE2 and Candida biofilm, summarize the antifungal activities of COX inhibitors and analyze the possible antifungal activity of microsomal prostaglandin E synthase-1 (MPGES-1) inhibitors; additionally, other factors that influence PGE2 production are also discussed. Hopefully this review can disclose potential antifungal targets based on the arachidonic acid cascade and provide a prevailing strategy to alleviate Candida albicans biofilm formation. PMID:27999568

Combination Therapy for Treatment of Infections with Gram-Negative Bacteria

PubMed Central

Cosgrove, Sara E.; Maragakis, Lisa L.

2012-01-01

Summary: Combination antibiotic therapy for invasive infections with Gram-negative bacteria is employed in many health care facilities, especially for certain subgroups of patients, including those with neutropenia, those with infections caused by Pseudomonas aeruginosa, those with ventilator-associated pneumonia, and the severely ill. An argument can be made for empiric combination therapy, as we are witnessing a rise in infections caused by multidrug-resistant Gram-negative organisms. The wisdom of continued combination therapy after an organism is isolated and antimicrobial susceptibility data are known, however, is more controversial. The available evidence suggests that the greatest benefit of combination antibiotic therapy stems from the increased likelihood of choosing an effective agent during empiric therapy, rather than exploitation of in vitro synergy or the prevention of resistance during definitive treatment. In this review, we summarize the available data comparing monotherapy versus combination antimicrobial therapy for the treatment of infections with Gram-negative bacteria. PMID:22763634

Cognitive Behavioral Therapy, Sertraline, or a Combination in Childhood Anxiety

PubMed Central

Walkup, John T.; Albano, Anne Marie; Piacentini, John; Birmaher, Boris; Compton, Scott N.; Sherrill, Joel T.; Ginsburg, Golda S.; Rynn, Moira A.; McCracken, James; Waslick, Bruce; Iyengar, Satish; March, John S.; Kendall, Philip C.

2009-01-01

Background Anxiety disorders are common psychiatric conditions affecting children and adolescents. Although cognitive behavioral therapy and selective serotonin-reuptake inhibitors have shown efficacy in treating these disorders, little is known about their relative or combined efficacy. Methods In this randomized, controlled trial, we assigned 488 children between the ages of 7 and 17 years who had a primary diagnosis of separation anxiety disorder, generalized anxiety disorder, or social phobia to receive 14 sessions of cognitive behavioral therapy, sertraline (at a dose of up to 200 mg per day), a combination of sertraline and cognitive behavioral therapy, or a placebo drug for 12 weeks in a 2:2:2:1 ratio. We administered categorical and dimensional ratings of anxiety severity and impairment at baseline and at weeks 4, 8, and 12. Results The percentages of children who were rated as very much or much improved on the Clinician Global Impression-Improvement scale were 80.7% for combination therapy (P<0.001), 59.7% for cognitive behavioral therapy (P<0.001), and 54.9% for sertraline (P<0.001); all therapies were superior to placebo (23.7%). Combination therapy was superior to both monotherapies (P<0.001). Results on the Pediatric Anxiety Rating Scale documented a similar magnitude and pattern of response; combination therapy had a greater response than cognitive behavioral therapy, which was equivalent to sertraline, and all therapies were superior to placebo. Adverse events, including suicidal and homicidal ideation, were no more frequent in the sertraline group than in the placebo group. No child attempted suicide. There was less insomnia, fatigue, sedation, and restlessness associated with cognitive behavioral therapy than with sertraline. Conclusions Both cognitive behavioral therapy and sertraline reduced the severity of anxiety in children with anxiety disorders; a combination of the two therapies had a superior response rate. (ClinicalTrials.gov number, NCT

Cognitive behavioral therapy, sertraline, or a combination in childhood anxiety.

PubMed

Walkup, John T; Albano, Anne Marie; Piacentini, John; Birmaher, Boris; Compton, Scott N; Sherrill, Joel T; Ginsburg, Golda S; Rynn, Moira A; McCracken, James; Waslick, Bruce; Iyengar, Satish; March, John S; Kendall, Philip C

2008-12-25

Anxiety disorders are common psychiatric conditions affecting children and adolescents. Although cognitive behavioral therapy and selective serotonin-reuptake inhibitors have shown efficacy in treating these disorders, little is known about their relative or combined efficacy. In this randomized, controlled trial, we assigned 488 children between the ages of 7 and 17 years who had a primary diagnosis of separation anxiety disorder, generalized anxiety disorder, or social phobia to receive 14 sessions of cognitive behavioral therapy, sertraline (at a dose of up to 200 mg per day), a combination of sertraline and cognitive behavioral therapy, or a placebo drug for 12 weeks in a 2:2:2:1 ratio. We administered categorical and dimensional ratings of anxiety severity and impairment at baseline and at weeks 4, 8, and 12. The percentages of children who were rated as very much or much improved on the Clinician Global Impression-Improvement scale were 80.7% for combination therapy (P<0.001), 59.7% for cognitive behavioral therapy (P<0.001), and 54.9% for sertraline (P<0.001); all therapies were superior to placebo (23.7%). Combination therapy was superior to both monotherapies (P<0.001). Results on the Pediatric Anxiety Rating Scale documented a similar magnitude and pattern of response; combination therapy had a greater response than cognitive behavioral therapy, which was equivalent to sertraline, and all therapies were superior to placebo. Adverse events, including suicidal and homicidal ideation, were no more frequent in the sertraline group than in the placebo group. No child attempted suicide. There was less insomnia, fatigue, sedation, and restlessness associated with cognitive behavioral therapy than with sertraline. Both cognitive behavioral therapy and sertraline reduced the severity of anxiety in children with anxiety disorders; a combination of the two therapies had a superior response rate. (ClinicalTrials.gov number, NCT00052078.) 2008 Massachusetts Medical

Topical antifungal agents: an update.

PubMed

Diehl, K B

1996-10-01

So many topical antifungal agents have been introduced that it has become very difficult to select the proper agent for a given infection. Nonspecific agents have been available for many years, and they are still effective in many situations. These agents include Whitfield's ointment, Castellani paint, gentian violet, potassium permanganate, undecylenic acid and selenium sulfide. Specific antifungal agents include, among others, the polyenes (nystatin, amphotericin B), the imidazoles (metronidazole, clotrimazole) and the allylamines (terbinafine, naftifine). Although the choice of an antifungal agent should be based on an accurate diagnosis, many clinicians believe that topical miconazole is a relatively effective agent for the treatment of most mycotic infections. Terbinafine and other newer drugs have primary fungicidal effects. Compared with older antifungal agents, these newer drugs can be used in lower concentrations and shorter therapeutic courses. Studies are needed to evaluate the clinical efficacies and cost advantages of both newer and traditional agents.

21 CFR 333.210 - Antifungal active ingredients.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 5 2014-04-01 2014-04-01 false Antifungal active ingredients. 333.210 Section 333.210 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... Antifungal Drug Products § 333.210 Antifungal active ingredients. The active ingredient of the product...

21 CFR 333.210 - Antifungal active ingredients.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Antifungal active ingredients. 333.210 Section 333.210 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... Antifungal Drug Products § 333.210 Antifungal active ingredients. The active ingredient of the product...

21 CFR 333.210 - Antifungal active ingredients.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 5 2013-04-01 2013-04-01 false Antifungal active ingredients. 333.210 Section 333.210 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... Antifungal Drug Products § 333.210 Antifungal active ingredients. The active ingredient of the product...

21 CFR 333.210 - Antifungal active ingredients.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 5 2012-04-01 2012-04-01 false Antifungal active ingredients. 333.210 Section 333.210 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... Antifungal Drug Products § 333.210 Antifungal active ingredients. The active ingredient of the product...

21 CFR 333.210 - Antifungal active ingredients.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 5 2011-04-01 2011-04-01 false Antifungal active ingredients. 333.210 Section 333.210 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... Antifungal Drug Products § 333.210 Antifungal active ingredients. The active ingredient of the product...

[Allergic bronchopulmonary aspergillosis: Evaluation of a maintenance therapy with nebulized Ambisome®].

PubMed

Godet, C; Couturaud, F; Ragot, S; Laurent, F; Brun, A L; Bergeron, A; Cadranel, J

2017-05-01

Allergic bronchopulmonary aspergillosis (ABPA) affects 3-13% of patients with asthma. Its natural history includes possibly life-threatening exacerbations and evolution towards fixed obstructive ventilatory disorders or even irreversible lung fibrosis lesions. ABPA prognosis is directly associated with exacerbation control and the main objective of the treatment is to decrease their frequency and duration. Recommendations regarding dosage and duration of treatment are not very precise. The currently used combination of itraconazole and corticosteroid therapy has many limitations. The interests of a therapeutic strategy using nebulized liposomal amphotericin B (LAmB) are to heighten antifungal lung tissue concentration, to circumvent drug interactions and decrease the potential toxicity of systemic antifungal treatments. Finally, this association leads to improved eradication of Aspergillus, thereby limiting the risk of side effects and the emergence of treatment-resistant Aspergillus strains. This is a phase II, multicentre, randomized, single blind, controlled therapeutic study, with the objective of comparing the potential benefit on exacerbation control of a maintenance therapy by LAmB nebulization. The main objective of the study is to compare the incidence of severe clinical exacerbations in ABPA treatment, between a maintenance treatment strategy with nebulized LAmB and a conventional strategy without antifungal maintenance therapy. The results will guide practitioners in the management of ABPA treatments and help to define the place of aerosols of LAmB on "evidence base medicine" criteria. Copyright © 2017 SPLF. Published by Elsevier Masson SAS. All rights reserved.

Combination therapy for type 2 diabetes: repaglinide plus rosiglitazone.

PubMed

Raskin, P; McGill, J; Saad, M F; Cappleman, J M; Kaye, W; Khutoryansky, N; Hale, P M

2004-04-01

This 24-week, randomized, multicentre, open-label, parallel-group clinical trial compared efficacy and safety of repaglinide monotherapy, rosiglitazone monotherapy, and combination therapy (repaglinide plus rosiglitazone) in Type 2 diabetes after unsatisfactory response to sulphonylurea or metformin monotherapy. Enrolled patients (n = 252) were adults having Type 2 diabetes for at least 1 year, with HbA(1c) values > 7.0% after previous monotherapy (sulphonylurea or metformin, >/= 50% maximal dose). Prior therapy was withdrawn for 2 weeks, followed by randomization to repaglinide, rosiglitazone, or repaglinide/rosiglitazone. Study treatments were initiated with a 12-week dose optimization period (doses optimized according to labelling), followed by a 12-week maintenance period. Efficacy endpoints were changes in HbA(1c) values (primary) or fasting plasma glucose values (secondary). Baseline HbA(1c) values were comparable (9.3% for repaglinide, 9.0% for rosiglitazone, 9.1% for combination). Mean changes in HbA(1c) values at the end of treatment were greater for repaglinide/rosiglitazone therapy (-1.43%) than for repaglinide (-0.17%) or rosiglitazone (-0.56%) monotherapy. Reductions of fasting plasma glucose values were also greater for combination therapy (-5.2 mmol/l, -94 mg/dl) than for repaglinide monotherapy (-3.0 mmol/l, -54 mg/dl) or rosiglitazone monotherapy (-3.7 mmol/l, -67 mg/dl). Minor hypoglycaemic events occurred in 9% of combination therapy patients, vs. 6% for repaglinide and 2% for rosiglitazone. Individual weight gains for combination therapy were correlated to HbA(1c) response. The combination therapy regimen was well tolerated. In patients previously showing unsatisfactory response to oral monotherapy, glycaemic reductions were greater for the repaglinide/rosiglitazone combination regimen than for use of either repaglinide or rosiglitazone alone.

Antifungal Efficacy of an Intravenous Formulation Containing Monomeric Amphotericin B, 5-Fluorocytosine, and Saline for Sodium Supplementation.

PubMed

Alvarez, Celeste; Andes, David R; Kang, Jeong Yeon; Krug, Carmen; Kwon, Glen S

2017-05-01

Amphotericin B (AmB) and 5-fluorocytosine (5-FC) exhibit additive to synergistic activity against systemic mycoses. Incompatibility of prescribed formulations precludes concomitant IV administration, a route with distinct advantages. Previously, we used PEG-DSPE micelles to produce a reformulation of Fungizone (AmB-SD), AmB solubilized by sodium deoxycholate, called mAmB-90. Herein, we describe a second reformulation that facilitates co-delivery of mAmB-90 and 5-FC, and evaluate the effect of PEG-DSPE micelles on the combination's activity against Candida albicans. We assessed the effect of 5-FC addition on the stability, in vitro toxicity, and antifungal efficacy of mAmB-90. The aggregation state and particle size of mAmB-90 combined with 5-FC (FmAmB-90) was evaluated over 48 h. Hemolytic activity was measured in vitro. Antifungal activity was determined in vitro against C. albicans. The efficacy of monotherapy and combination treatment was evaluated in a neutropenic mouse model of disseminated candidiasis. The aggregation state, particle size, and hemolytic activity of mAmB-90 were unaffected by 5-FC. While antifungal activity was similar in vitro, mAmB-90 alone and combined with 5-FC was more potent than AmB-SD in vivo. Short-term stability and in vivo efficacy of our formulation suggest potential to simultaneously deliver AmB and 5-FC for potent antifungal efficacy.

Antifungal activity of low molecular weight chitosan against clinical isolates of Candida spp.

PubMed

Alburquenque, Claudio; Bucarey, Sergio A; Neira-Carrillo, Andrónico; Urzúa, Blanca; Hermosilla, Germán; Tapia, Cecilia V

2010-12-01

Chitosan is a natural polymer derived from chitin, a structural component of fungi, insects and shrimp, which exerts antimicrobial effects against bacteria and fungi. The aim of this study was to investigate the in vitro antifungal activity of low molecular weight chitosan (LMWC), and the potential synergy between chitosan and a currently used antifungal drug, fluconazole. The in vitro minimal inhibitory concentrations (MICs) of chitosan and fluconazole against 105 clinical Candida isolates were measured by the broth microdilution method. LMWC exhibited a significant antifungal activity, inhibiting over 89.9% of the clinical isolates examined (68.6% of which was completely inhibited). The species included several fluconazole-resistant strains and less susceptible species such as C. glabrata, which was inhibited at a concentration of 4.8 mg/l LMWC. Although some strains were susceptible at pH 7.0, a greater antifungal activity of LMWC was observed at pH 4.0. There was no evidence of a synergistic effect of the combination of LMWC and fluconazole at pH 7.0. This is the first report in which the antifungal activity of LMWC was investigated with clinical Candida strains. The use of LMWC as an antifungal compound opens new therapeutic perspectives, as the low toxicity of LMWC in humans supports its use in new applications in an environment of pH 4.0-4.5, such as a topical agent for vulvovaginal candidiasis.

Synergic effects of tactolimus and azole antifungal agents against azole-resistant Candida albican strains.

PubMed

Maesaki, S; Marichal, P; Hossain, M A; Sanglard, D; Vanden Bossche, H; Kohno, S

1998-12-01

We investigated the effects of combining tacrolimus and azole antifungal agents in azole-resistant strains of Candida albicans by comparing the accumulation of [3H]itraconazole. The CDR1-expressing resistant strain C26 accumulated less itraconazole than the CaMDR-expressing resistant strain C40 or the azole-sensitive strain B2630. A CDR1-expressing Saccharomyces cerevisiae mutant, DSY415, showed a marked reduction in the accumulation of both fluconazole and itraconazole. A CaMDR-expressing S. cerevisiae mutant, DSY416, also showed lower accumulation of fluconazole, but not of itraconazole. The addition of sodium azide, an electron-transport chain inhibitor, increased the intracellular accumulation of itraconazole only in the C26 strain, and not in the C40 or B2630 strains. Addition of tacrolimus, an inhibitor of multidrug resistance proteins, resulted in the highest increase in itraconazole accumulation in the C26 strain. The combination of itraconazole and tacrolimus was synergic in azole-resistant C. albicans strains. In the C26 strain, the MIC of itraconazole decreased from >8 to 0.5 mg/L when combined with tacrolimus. Our results showed that two multidrug resistance phenotypes (encoded by the CDR1 and CaMDR genes) in C. albicans have different substrate specificity for azole antifungal agents and that a combination of tacrolimus and azole antifungal agents is effective against azole-resistant strains of C. albicans.

Antifungal Monoterpene Derivatives from the Plant Endophytic Fungus Pestalotiopsis foedan.

PubMed

Xu, Dan; Zhang, Bing-Yang; Yang, Xiao-Long

2016-10-01

A new monoterpene lactone, (1R,4R,5R,8S)-8-hydroxy-4,8-dimethyl-2-oxabicyclo[3.3.1]nonan-3-one (1), along with one related known compound, (2R)-2-[(1R)-4-methylcyclohex-3-en-1-yl]propanoic acid (2), were isolated from the liquid culture of the plant endophytic fungus Pestalotiopsis foedan obtained from the branch of Bruguiera sexangula. The structure and absolute configuration of 1 were determined on the basis of extensive analysis of NMR spectra combined with computational methods via calculation of the optical rotation (OR) and 13 C-NMR. Both compounds exhibited strong antifungal activities against Botrytis cinerea and Phytophthora nicotianae with MIC values of 3.1 and 6.3 μg/ml, respectively, which are comparable to those of the known antifungal drug ketoconazole. Compound 2 also showed modest antifungal activity against Candida albicans with a MIC value of 50 μg/ml. © 2016 Wiley-VHCA AG, Zürich.

Activation of Melanin Synthesis in Alternaria infectoria by Antifungal Drugs.

PubMed

Fernandes, Chantal; Prados-Rosales, Rafael; Silva, Branca M A; Nakouzi-Naranjo, Antonio; Zuzarte, Mónica; Chatterjee, Subhasish; Stark, Ruth E; Casadevall, Arturo; Gonçalves, Teresa

2015-12-28

The importance of Alternaria species fungi to human health ranges from their role as etiological agents of serious infections with poor prognoses in immunosuppressed individuals to their association with respiratory allergic diseases. The present work focuses on Alternaria infectoria, which was used as a model organism of the genus, and was designed to unravel melanin production in response to antifungals. After we characterized the pigment produced by A. infectoria, we studied the dynamics of 1,8-dihydroxynaphthalene (DHN)-melanin production during growth, the degree of melanization in response to antifungals, and how melanization affected susceptibility to several classes of therapeutic drugs. We demonstrate that A. infectoria increased melanin deposition in cell walls in response to nikkomycin Z, caspofungin, and itraconazole but not in response to fluconazole or amphotericin B. These results indicate that A. infectoria activates DHN-melanin synthesis in response to certain antifungal drugs, possibly as a protective mechanism against these drugs. Inhibition of DHN-melanin synthesis by pyroquilon resulted in a lower minimum effective concentration (MEC) of caspofungin and enhanced morphological changes (increased hyphal balloon size), characterized by thinner and less organized A. infectoria cell walls. In summary, A. infectoria synthesizes melanin in response to certain antifungal drugs, and its susceptibility is influenced by melanization, suggesting the therapeutic potential of drug combinations that affect melanin synthesis. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Activation of Melanin Synthesis in Alternaria infectoria by Antifungal Drugs

PubMed Central

Fernandes, Chantal; Prados-Rosales, Rafael; Silva, Branca M. A.; Nakouzi-Naranjo, Antonio; Zuzarte, Mónica; Chatterjee, Subhasish; Stark, Ruth E.; Casadevall, Arturo

2015-01-01

The importance of Alternaria species fungi to human health ranges from their role as etiological agents of serious infections with poor prognoses in immunosuppressed individuals to their association with respiratory allergic diseases. The present work focuses on Alternaria infectoria, which was used as a model organism of the genus, and was designed to unravel melanin production in response to antifungals. After we characterized the pigment produced by A. infectoria, we studied the dynamics of 1,8-dihydroxynaphthalene (DHN)-melanin production during growth, the degree of melanization in response to antifungals, and how melanization affected susceptibility to several classes of therapeutic drugs. We demonstrate that A. infectoria increased melanin deposition in cell walls in response to nikkomycin Z, caspofungin, and itraconazole but not in response to fluconazole or amphotericin B. These results indicate that A. infectoria activates DHN-melanin synthesis in response to certain antifungal drugs, possibly as a protective mechanism against these drugs. Inhibition of DHN-melanin synthesis by pyroquilon resulted in a lower minimum effective concentration (MEC) of caspofungin and enhanced morphological changes (increased hyphal balloon size), characterized by thinner and less organized A. infectoria cell walls. In summary, A. infectoria synthesizes melanin in response to certain antifungal drugs, and its susceptibility is influenced by melanization, suggesting the therapeutic potential of drug combinations that affect melanin synthesis. PMID:26711773

Melanins Protect Sporothrix brasiliensis and Sporothrix schenckii from the Antifungal Effects of Terbinafine.

PubMed

Almeida-Paes, Rodrigo; Figueiredo-Carvalho, Maria Helena Galdino; Brito-Santos, Fábio; Almeida-Silva, Fernando; Oliveira, Manoel Marques Evangelista; Zancopé-Oliveira, Rosely Maria

2016-01-01

Terbinafine is a recommended therapeutic alternative for patients with sporotrichosis who cannot use itraconazole due to drug interactions or side effects. Melanins are involved in resistance to antifungal drugs and Sporothrix species produce three different types of melanin. Therefore, in this study we evaluated whether Sporothrix melanins impact the efficacy of antifungal drugs. Minimal inhibitory concentrations (MIC) and minimal fungicidal concentrations (MFC) of two Sporothrix brasiliensis and four Sporothrix schenckii strains grown in the presence of the melanin precursors L-DOPA and L-tyrosine were similar to the MIC determined by the CLSI standard protocol for S. schenckii susceptibility to amphotericin B, ketoconazole, itraconazole or terbinafine. When MICs were determined in the presence of inhibitors to three pathways of melanin synthesis, we observed, in four strains, an increase in terbinafine susceptibility in the presence of tricyclazole, a DHN-melanin inhibitor. In addition, one S. schenckii strain grown in the presence of L-DOPA had a higher MFC value when compared to the control. Growth curves in presence of 2×MIC concentrations of terbinafine showed that pyomelanin and, to a lesser extent, eumelanin were able to protect the fungi against the fungicidal effect of this antifungal drug. Our results suggest that melanin protects the major pathogenic species of the Sporothrix complex from the effects of terbinafine and that the development of new antifungal drugs targeting melanin synthesis may improve sporotrichosis therapies.

Pirfenidone enhances the efficacy of combined radiation and sunitinib therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Choi, Seo-Hyun; Nam, Jae-Kyung; Jang, Junho

Radiotherapy is a widely used treatment for many tumors. Combination therapy using anti-angiogenic agents and radiation has shown promise; however, these combined therapies are reported to have many limitations in clinical trials. Here, we show that radiation transformed tumor endothelial cells (ECs) to fibroblasts, resulting in reduced vascular endothelial growth factor (VEGF) response and increased Snail1, Twist1, Type I collagen, and transforming growth factor (TGF)-β release. Irradiation of radioresistant Lewis lung carcinoma (LLC) tumors greater than 250 mm{sup 3} increased collagen levels, particularly in large tumor vessels. Furthermore, concomitant sunitinib therapy did not show a significant difference in tumor inhibition versusmore » radiation alone. Thus, we evaluated multimodal therapy that combined pirfenidone, an inhibitor of TGF-induced collagen production, with radiation and sunitinib treatment. This trimodal therapy significantly reduced tumor growth, as compared to radiation alone. Immunohistochemical analysis revealed that radiation-induced collagen deposition and tumor microvessel density were significantly reduced with trimodal therapy, as compared to radiation alone. These data suggest that combined therapy using pirfenidone may modulate the radiation-altered tumor microenvironment, thereby enhancing the efficacy of radiation therapy and concurrent chemotherapy. - Highlights: • Radiation changes tumor endothelial cells to fibroblasts. • Radio-resistant tumors contain collagen deposits, especially in tumor vessels. • Pirfenidone enhances the efficacy of combined radiation and sunitinib therapy. • Pirfenidone reduces radiation-induced collagen deposits in tumors.« less

EPICO 3.0. Antifungal prophylaxis in solid organ transplant recipients.

PubMed

Zaragoza, Rafael; Aguado, José María; Ferrer, Ricard; Rodríguez, Alejandro H; Maseda, Emilio; Llinares, Pedro; Grau, Santiago; Muñoz, Patricia; Fortún, Jesús; Bouzada, Mercedes; Pozo, Juan Carlos Del; León, Rafael

donor, choledochojejunostomy, increased transfusion requirements, renal failure without replacement therapy, early reoperation, or multifocal colonization or infection with Candida; intestinal and pancreas transplant with no risk factors for echinocandin treatment. Liposomal amphotericin B antifungal prophylaxis should be considered in lung transplant (inhalant form) and liver transplant with major risk factors. Antifungal prophylaxis with voriconazole should be considered in lung transplant, and heart transplant with hemodialysis, surgical re-exploration after transplantation, environmental colonization by Aspergillus, or CMV infection. The management of antifungal prophylaxis in solid organ transplant recipients requires the application of knowledge and skills that are detailed in our recommendations and the algorithm developed therein. These recommendations, based on the DELPHI methodology, may help to identify potential patients, standardize their management and improve overall prognosis. Copyright © 2016 Asociación Española de Micología. Publicado por Elsevier España, S.L.U. All rights reserved.

Silver nanoparticles from Pilimelia columellifera subsp. pallida SL19 strain demonstrated antifungal activity against fungi causing superficial mycoses.

PubMed

Wypij, Magdalena; Czarnecka, Joanna; Dahm, Hanna; Rai, Mahendra; Golinska, Patrycja

2017-09-01

In this study, we present the in vitro antifungal activity of silver nanoparticles (AgNPs) synthesized from acidophilic actinobacterium Pilimelia columellifera subsp. pallida SL19 strain, alone and in combination with antibiotics viz., amphotericin B, fluconazole, and ketoconazole against pathogenic fungi, namely Candida albicans, Malassezia furfur, and Trichophyton erinacei. The minimum inhibitory concentration (MIC) and minimum biocidal concentration (MBC) of AgNPs against test fungi were evaluated. The fractional inhibitory concentration (FIC) index was determined to estimate antifungal activity of AgNPs combined with antibiotics. Antifungal activity of AgNPs varied among the tested fungal strains. M. furfur was found to be most sensitive to biogenic silver nanoparticles, followed by C. albicans and T. erinacei. The lowest MIC of AgNPs was noticed against M. furfur (16 μg ml -1 ). Synergistic effect was observed on C. albicans when AgNP were combined with amphotericin B and ketoconazole and on M. furfur with fluconazole and ketoconazole (FIC index of 0.5). Cytotoxic effect of AgNPs on HeLa and 3T3 cell lines was evaluated. The IC 50 values were found to be 55 and 25 μg ml -1 , respectively. The present study indicates that silver nanoparticles from P. columellifera subsp. pallida SL19 strain have antifungal activity, both alone and in combination with antibiotics, and offer a valuable contribution to nanomedicine. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Combined Aspirin and Anticoagulant Therapy in Patients with Atrial Fibrillation

PubMed Central

So, Charlotte H.; Eckman, Mark H.

2016-01-01

Background The combined use of aspirin and oral anticoagulant therapy in patients with atrial fibrillation (AF) and stable coronary artery disease (CAD) has been questioned due to an increased risk of major bleeding with little to no benefit in preventing ischemic events. Objective (1) To better understand patterns and indications for combined antiplatelet and anticoagulant therapy and identify patients who might reasonably be treated with oral anticoagulant (OAC) therapy alone. (2) To perform an updated literature review regarding the use of combined antiplatelet and OAC therapy in patients with AF and stable CAD. Design and Participants Retrospective review. Patients within the University of Cincinnati Health System with a diagnosis of non-valvular AF, excluding those with acute coronary syndrome or revascularization within the last 12 months. Main Measures Numbers and indications for combined antiplatelet and anticoagulant therapy and sequence of events leading to the initiation of each. Key Results Of 948 patients receiving OAC, 430 (45%) were receiving concomitant OAC and aspirin. Among patients receiving combined antiplatelet and anticoagulant therapy, 49% and 42% of patients respectively, had CAD or DM. In a more detailed analysis including chart review of 219 patients receiving combined OAC and aspirin, 27% had a diagnosis of CAD and 14% had a diagnosis of DM prior to the development of AF. These patients were initially treated with aspirin. Warfarin was added when they subsequently developed AF but aspirin wasn’t discontinued. A surprisingly large proportion of patients (22.8%) had no obvious indication for dual therapy. Conclusions Prior myocardial infarction, CAD, vascular disease and DM (among others) increase the likelihood of receiving combined antiplatelet and anticoagulant therapy among patients with AF. A literature review suggests this may lead to increased major bleeding with little benefit in decreasing either AF-related stroke or

Vertebral osteomyelitis due to Aspergillus fumigatus in a patient with chronic granulomatous disease successfully treated with antifungal agents and interferon-gamma.

PubMed

Al-Tawfiq, Jaffar A; Al-Abdely, Hail M

2010-05-01

We report a case of invasive aspergillosis due to Aspergillus fumigatus involving the cervical and thoracic vertebrae and upper mediastinum of a 17 year-old Saudi male with chronic granulomatous disease (CGD). The patient did not respond to a long course of liposomal amphotericin B but did to surgical drainage and a combination of caspofungin and itraconazole with subsequent suppression with oral voriconazole. Fourteen months after the start of therapy, the patient had anterior dislocation of T2 thoracic vertebra with cord transection and quadriplegia. He was then treated intravenously with liquid itraconazole and interferon-gamma. The patient made a remarkable recovery over a 2-year period and was eventually able to walk independently. Thus, a combination of antifungals and interferon-gamma may have resulted in the positive outcome in this case.

Risks and safety of combination therapy for hypothyroidism.

PubMed

Jonklaas, Jacqueline

2016-08-01

Hypothyroidism is currently a condition that can be treated, but not cured. Although levothyroxine reverses stigmata of hypothyroidism in most individuals, some patients feel dissatisfied with 'monotherapy', and this has stimulated interest in 'combination therapy' with both levothyroxine and liothyronine. A search of PubMed was conducted using terms including hypothyroidism, treatment, benefits, risks, and safety. Based on the articles identified, the body of evidence regarding the efficacy of traditional levothyroxine is reviewed. Concerns with levothyroxine therapy including impaired quality of life in treated patients, thyroxine-predominant hormone ratios, and inadvertent iatrogenic thyroid disease are discussed. The trials of combination therapy performed since 1999 were reviewed. The heterogeneity of these trials, both in terms of design and results, is discussed. The potential for new trials to determine whether combination therapy can reverse the dissatisfaction associated with monotherapy, while avoiding non-physiologic hormone ratios, inadvertent thyrotoxicosis, and unacceptable side effects is discussed. Expert commentary: Research regarding which therapy fully reverses hypothyroidism at a tissue and cellular level is ongoing. The field would be advanced by the development of an extended release preparation of liothyronine. In the future regeneration of functional thyroid follicles from stem cells may offer hope for curing hypothyroidism.

Nanomedicine of synergistic drug combinations for cancer therapy – strategies and perspectives

PubMed Central

Xue, Hui Yi; Eoh, June Young; Wu, Xiao Yu

2016-01-01

Nanomedicine of synergistic drug combinations has shown increasing significance in cancer therapy due to its promise in providing superior therapeutic benefits to the current drug combination therapy used in clinical practice. In this article, we will examine the rationale, principles, and advantages of applying nanocarriers to improve anticancer drug combination therapy, review the use of nanocarriers for delivery of a variety of combinations of different classes of anticancer agents including small molecule drugs and biologics, and discuss the challenges and future perspectives of the nanocarrier-based combination therapy. The goal of this review is to provide better understanding of this increasingly important new paradigm of cancer treatment and key considerations for rational design of nanomedicine of synergistic drug combinations for cancer therapy. PMID:27287891

Cuticular antifungals in spiders: density- and condition dependence.

PubMed

González-Tokman, Daniel; Ruch, Jasmin; Pulpitel, Tamara; Ponton, Fleur

2014-01-01

Animals living in groups face a high risk of disease contagion. In many arthropod species, cuticular antimicrobials constitute the first protective barrier that prevents infections. Here we report that group-living spiders produce cuticular chemicals which inhibit fungal growth. Given that cuticular antifungals may be costly to produce, we explored whether they can be modulated according to the risk of contagion (i.e. under high densities). For this purpose, we quantified cuticular antifungal activity in the subsocial crab spider Diaea ergandros in both natural nests and experimentally manipulated nests of varying density. We quantified the body-condition of spiders to test whether antifungal activity is condition dependent, as well as the effect of spider density on body-condition. We predicted cuticular antifungal activity to increase and body-condition to decrease with high spider densities, and that antifungal activity would be inversely related to body-condition. Contrary to our predictions, antifungal activity was neither density- nor condition-dependent. However, body-condition decreased with density in natural nests, but increased in experimental nests. We suggest that pathogen pressure is so important in nature that it maintains high levels of cuticular antifungal activity in spiders, impacting negatively on individual energetic condition. Future studies should identify the chemical structure of the isolated antifungal compounds in order to understand the physiological basis of a trade-off between disease prevention and energetic condition caused by group living, and its consequences in the evolution of sociality in spiders.

Cuticular Antifungals in Spiders: Density- and Condition Dependence

PubMed Central

González-Tokman, Daniel; Ruch, Jasmin; Pulpitel, Tamara; Ponton, Fleur

2014-01-01

Animals living in groups face a high risk of disease contagion. In many arthropod species, cuticular antimicrobials constitute the first protective barrier that prevents infections. Here we report that group-living spiders produce cuticular chemicals which inhibit fungal growth. Given that cuticular antifungals may be costly to produce, we explored whether they can be modulated according to the risk of contagion (i.e. under high densities). For this purpose, we quantified cuticular antifungal activity in the subsocial crab spider Diaea ergandros in both natural nests and experimentally manipulated nests of varying density. We quantified the body-condition of spiders to test whether antifungal activity is condition dependent, as well as the effect of spider density on body-condition. We predicted cuticular antifungal activity to increase and body-condition to decrease with high spider densities, and that antifungal activity would be inversely related to body-condition. Contrary to our predictions, antifungal activity was neither density- nor condition-dependent. However, body-condition decreased with density in natural nests, but increased in experimental nests. We suggest that pathogen pressure is so important in nature that it maintains high levels of cuticular antifungal activity in spiders, impacting negatively on individual energetic condition. Future studies should identify the chemical structure of the isolated antifungal compounds in order to understand the physiological basis of a trade-off between disease prevention and energetic condition caused by group living, and its consequences in the evolution of sociality in spiders. PMID:24637563

Antifungal Efficacy of an Intravenous Formulation Containing Monomeric Amphotericin B, 5-Fluorocytosine, and Saline for Sodium Supplementation

PubMed Central

Alvarez, Celeste; Andes, David R.; Kang, Jeong Yeon; Krug, Carmen; Kwon, Glen S.

2017-01-01

Purpose Amphotericin B (AmB) and 5-fluorocytosine (5-FC) exhibit additive to synergistic activity against systemic mycoses. Incompatibility of prescribed formulations precludes concomitant IV administration, a route with distinct advantages. Previously, we used PEG-DSPE micelles to produce a reformulation of Fungizone (AmB-SD), AmB solubilized by sodium deoxycholate, called mAmB-90. Herein, we describe a second reformulation that facilitates co-delivery of mAmB-90 and 5-FC, and evaluate the effect of PEG-DSPE micelles on the combination’s activity against Candida albicans. Methods We assessed the effect of 5-FC addition on the stability, in vitro toxicity, and antifungal efficacy of mAmB-90. The aggregation state and particle size of mAmB-90 combined with 5-FC (FmAmB-90) was evaluated over 48 hours. Hemolytic activity was measured in vitro. Antifungal activity was determined in vitro against C. albicans. The efficacy of monotherapy and combination treatment was evaluated in a neutropenic mouse model of disseminated candidiasis. Results The aggregation state, particle size, and hemolytic activity of mAmB-90 were unaffected by 5-FC. While antifungal activity was similar in vitro, mAmB-90 alone and combined with 5-FC was more potent than AmB-SD in vivo. Conclusions Short-term stability and in vivo efficacy of our formulation suggest potential to simultaneously deliver AmB and 5-FC for potent antifungal efficacy. PMID:28205003

Antibacterial and Antifungal Compounds from Marine Fungi

PubMed Central

Xu, Lijian; Meng, Wei; Cao, Cong; Wang, Jian; Shan, Wenjun; Wang, Qinggui

2015-01-01

This paper reviews 116 new compounds with antifungal or antibacterial activities as well as 169 other known antimicrobial compounds, with a specific focus on January 2010 through March 2015. Furthermore, the phylogeny of the fungi producing these antibacterial or antifungal compounds was analyzed. The new methods used to isolate marine fungi that possess antibacterial or antifungal activities as well as the relationship between structure and activity are shown in this review. PMID:26042616

Reversal of efflux mediated antifungal resistance underlies synergistic activity of two monoterpenes with fluconazole.

PubMed

Ahmad, Aijaz; Khan, Amber; Manzoor, Nikhat

2013-01-23

Thymol (THY) and carvacrol (CARV), the principal chemical components of thyme oil have long been known for their wide use in medicine due to antimicrobial and disinfectant properties. This study, however, draws attention to a possible synergistic antifungal effect of these monoterpenes with azole antimycotic-fluconazole. Resistance to azoles in Candida albicans involves over-expression of efflux-pump genes MDR1, CDR1, CDR2 or mutations and over-expression of target gene ERG11. The inhibition of drug efflux pumps is considered a feasible strategy to overcome clinical antifungal resistance. To put forward this approach, we investigated the combination effects of these monoterpenes and FLC against 38 clinically obtained FLC-sensitive, and eleven FLC-resistant Candida isolates. Synergism was observed with combinations of THY-FLC and CARV-FLC evaluated by checkerboard microdilution method and nature of the interactions was calculated by FICI. In addition, antifungal activity was assessed using agar-diffusion and time-kill curves. The drug efflux activity was determined using two dyes, Rhodamine6G (R6G) and fluorescent Hoechst 33342. No significant differences were observed in dye uptakes between FLC-susceptible and resistant isolates, incubated in glucose free buffer. However, a significantly higher efflux was recorded in FLC-resistant isolates when glucose was added. Both monoterpenes inhibited efflux by 70-90%, showing their high potency to block drug transporter pumps. Significant differences, in the expression levels of CDR1 and MDR1, induced by monoterpenes revealed reversal of FLC-resistance. The selectively fungicidal characteristics and ability to restore FLC susceptibility in resistant isolates signify a promising candidature of THY and CARV as antifungal agents in combinational treatments for candidiasis. Copyright © 2012 Elsevier B.V. All rights reserved.

Melanins Protect Sporothrix brasiliensis and Sporothrix schenckii from the Antifungal Effects of Terbinafine

PubMed Central

Almeida-Paes, Rodrigo; Figueiredo-Carvalho, Maria Helena Galdino; Brito-Santos, Fábio; Almeida-Silva, Fernando; Oliveira, Manoel Marques Evangelista; Zancopé-Oliveira, Rosely Maria

2016-01-01

Terbinafine is a recommended therapeutic alternative for patients with sporotrichosis who cannot use itraconazole due to drug interactions or side effects. Melanins are involved in resistance to antifungal drugs and Sporothrix species produce three different types of melanin. Therefore, in this study we evaluated whether Sporothrix melanins impact the efficacy of antifungal drugs. Minimal inhibitory concentrations (MIC) and minimal fungicidal concentrations (MFC) of two Sporothrix brasiliensis and four Sporothrix schenckii strains grown in the presence of the melanin precursors L-DOPA and L-tyrosine were similar to the MIC determined by the CLSI standard protocol for S. schenckii susceptibility to amphotericin B, ketoconazole, itraconazole or terbinafine. When MICs were determined in the presence of inhibitors to three pathways of melanin synthesis, we observed, in four strains, an increase in terbinafine susceptibility in the presence of tricyclazole, a DHN-melanin inhibitor. In addition, one S. schenckii strain grown in the presence of L-DOPA had a higher MFC value when compared to the control. Growth curves in presence of 2×MIC concentrations of terbinafine showed that pyomelanin and, to a lesser extent, eumelanin were able to protect the fungi against the fungicidal effect of this antifungal drug. Our results suggest that melanin protects the major pathogenic species of the Sporothrix complex from the effects of terbinafine and that the development of new antifungal drugs targeting melanin synthesis may improve sporotrichosis therapies. PMID:27031728

Curcumin and its promise as an anticancer drug: An analysis of its anticancer and antifungal effects in cancer and associated complications from invasive fungal infections.

PubMed

Chen, Jin; He, Zheng-Min; Wang, Feng-Ling; Zhang, Zheng-Sheng; Liu, Xiu-zhen; Zhai, Dan-Dan; Chen, Wei-Dong

2016-02-05

Invasive fungal infections (IFI) are important complications of cancer, and they have become a major cause of morbidity and mortality in cancer patients. Effective anti-infection therapy is necessary to inhibit significant deterioration from these infections. However, they are difficult to treat, and increasing antifungal drug resistance often leads to a relapse. Curcumin, a natural component that is isolated from the rhizome of Curcuma longa plants, has attracted great interest among many scientists studying solid cancers over the last half century. Interestingly, curcumin provides an ideal alternative to current therapies because of its relatively safe profile, even at high doses. To date, curcumin's potent antifungal activity against different strains of Candida, Cryptococcus, Aspergillus, Trichosporon and Paracoccidioides have been reported, indicating that curcumin anticancer drugs may also possess an antifungal role, helping cancer patients to resist IFI complications. The aim of this review is to discuss curcumin's dual pharmacological activities regarding its applications as a natural anticancer and antifungal agent. These dual pharmacological activities are expected to lead to clinical trials and to improve infection survival among cancer patients. Copyright © 2015 Elsevier B.V. All rights reserved.

Characterization of Antifungal Activity and Nail Penetration of ME1111, a New Antifungal Agent for Topical Treatment of Onychomycosis

PubMed Central

Takei-Masuda, Naomi; Kubota, Natsuki; Takahata, Sho; Ohyama, Makoto; Kaneda, Kaori; Iida, Maiko; Maebashi, Kazunori

2015-01-01

Fungal nail infection (onychomycosis) is a prevalent disease in many areas of the world, with a high incidence approaching 23%. Available antifungals to treat the disease suffer from a number of disadvantages, necessitating the discovery of new efficacious and safe antifungals. Here, we evaluate the in vitro antifungal activity and nail penetration ability of ME1111, a novel antifungal agent, along with comparator drugs, including ciclopirox, amorolfine, terbinafine, and itraconazole. ME1111 showed potent antifungal activity against Trichophyton rubrum and Trichophyton mentagrophytes (the major etiologic agents of onychomycosis) strains isolated in Japan and reference fungal strains with an MIC range of 0.12 to 0.5 mg/liter and an MIC50 and MIC90 of 0.5 mg/liter for both. Importantly, none of the tested isolates showed an elevated ME1111 MIC. Moreover, the antifungal activity of ME1111 was minimally affected by 5% wool keratin powder in comparison to the other antifungals tested. The ME1111 solution was able to penetrate human nails and inhibit fungal growth in a dose-dependent manner according to the TurChub assay. In contrast, 8% ciclopirox and 5% amorolfine nail lacquers showed no activity under the same conditions. ME1111 demonstrated approximately 60-fold-greater selectivity in inhibition of Trichophyton spp. than of human cell lines. Our findings demonstrate that ME1111 possesses potent antidermatophyte activity, maintains this activity in the presence of keratin, and possesses excellent human nail permeability. These results suggest that ME1111 is a promising topical medication for the treatment of onychomycosis and therefore warrants further clinical evaluation. PMID:26643333

Rapid antifungal susceptibility testing by matrix-assisted laser desorption ionization-time of flight mass spectrometry analysis.

PubMed

Vella, Antonietta; De Carolis, Elena; Vaccaro, Luisa; Posteraro, Patrizia; Perlin, David S; Kostrzewa, Markus; Posteraro, Brunella; Sanguinetti, Maurizio

2013-09-01

The widespread use of antifungal agents, which is likely to expand with their enhanced availability, has promoted the emergence of drug-resistant strains. Antifungal susceptibility testing (AFST) is now an essential procedure for guiding appropriate antifungal therapy. Recently, we developed a matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS)-based method that enables the detection of fungal isolates with reduced echinocandin susceptibility, relying on the proteome changes that are detectable after a 15-h exposure of fungal cells to serial drug concentrations. Here, we describe a simplified version of this approach that facilitates discrimination of the susceptible and resistant isolates of Candida albicans after a 3-h incubation in the presence of "breakpoint" level drug concentrations of the echinocandin caspofungin (CSF). Spectra at concentrations of 0 (null), 0.03 (intermediate), and 32 (maximal) μg/ml of CSF were used to create individual composite correlation index (CCI) matrices for 65 C. albicans isolates, including 13 fks1 mutants. Isolates are then classified as susceptible or resistant to CSF if the CCI values of spectra at 0.03 and 32 μg/ml are higher or lower, respectively, than the CCI values of spectra at 0.03 and 0 μg/ml. In this way, the drug resistance of C. albicans isolates to echinocandin antifungals can be quickly assessed. Furthermore, the isolate categorizations determined using MALDI-TOF MS-based AFST (ms-AFST) were consistent with the wild-type and mutant FKS1 genotypes and the AFST reference methodology. The ms-AFST approach may provide a rapid and reliable means of detecting emerging antifungal resistance and accelerating the initiation of appropriate antifungal treatment.

Antifungal effects of Lavandula binaludensis and Cuminum cyminum essential oils against Candida albicans strains isolated from patients with recurrent vulvovaginal candidiasis.

PubMed

Minooeianhaghighi, M H; Sepehrian, L; Shokri, H

2017-03-01

Recurrent vulvovaginal candidiasis (RVVC), which affects approximately 5% of women of reproductive age, is defined as 4 or more episodes of symptomatic Candida vaginitis within a year. The purposes of this study were to determine the chemical compositions and antifungal susceptibility of Cuminum cyminum (C. cyminum) and Lavandula binaludensis (L. binaludensis) essential oils and their combination against Candida albicans (C. albicans) strains isolated from patients with RVVC. C. albicans isolates were identified via germ tube test, CHROMagar and RapID Yeast Plus System. The essential oils were obtained by hydrodistillation in a Clevenger apparatus and analyzed by gas chromatography-mass spectroscopy (GC-MS). The broth microdilution method was used as antifungal susceptibility test (CLSI-M27-A3). The GC-MS analysis allowed 13 components to be determined; the main components of C. cyminum and L. binaludensis essential oils were γ-terpinene (21.07%) and 1,8-cineole (71.56%), respectively. L. binaludensis and C. cyminum oils were effective in inhibiting C. albicans growth at mean concentrations of 7.91±1.61μg/mL and 8.00±1.89μg/mL, respectively. In addition, the combination of C. cyminum with L. binaludensis oils were more active causing inhibition in all C. albicans isolates, with concentrations varying from 3.90 to 11.71μg/mL (mean value: 7.22±1.69μg/mL). The results suggested the potential substitution of the antifungal chemicals by C. cyminum and L. binaludensis essential oils as natural inhibitors to control the growth of the most important pathogenic Candida species and alternative therapies for RVVC. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Pharmacokinetics and Pharmacodynamics of Fluconazole for Cryptococcal Meningoencephalitis: Implications for Antifungal Therapy and In Vitro Susceptibility Breakpoints

PubMed Central

Sudan, Ajay; Livermore, Joanne; Howard, Susan J.; Al-Nakeeb, Zaid; Sharp, Andrew; Goodwin, Joanne; Gregson, Lea; Warn, Peter A.; Felton, Tim W.; Perfect, John R.; Harrison, Thomas S.

2013-01-01

Fluconazole is frequently the only antifungal agent that is available for induction therapy for cryptococcal meningitis. There is relatively little understanding of the pharmacokinetics and pharmacodynamics (PK-PD) of fluconazole in this setting. PK-PD relationships were estimated with 4 clinical isolates of Cryptococcus neoformans. MICs were determined using Clinical and Laboratory Standards Institute (CLSI) methodology. A nonimmunosuppressed murine model of cryptococcal meningitis was used. Mice received two different doses of fluconazole (125 mg/kg of body weight/day and 250 mg/kg of body weight/day) orally for 9 days; a control group of mice was not given fluconazole. Fluconazole concentrations in plasma and in the cerebrum were determined using high-performance liquid chromatography (HPLC). The cryptococcal density in the brain was estimated using quantitative cultures. A mathematical model was fitted to the PK-PD data. The experimental results were extrapolated to humans (bridging study). The PK were linear. A dose-dependent decline in fungal burden was observed, with near-maximal activity evident with dosages of 250 mg/kg/day. The MIC was important for understanding the exposure-response relationships. The mean AUC/MIC ratio associated with stasis was 389. The results of the bridging study suggested that only 66.7% of patients receiving 1,200 mg/kg would achieve or exceed an AUC/MIC ratio of 389. The potential breakpoints for fluconazole against Cryptococcus neoformans follow: susceptible, ≤2 mg/liter; resistant, >2 mg/liter. Fluconazole may be an inferior agent for induction therapy because many patients cannot achieve the pharmacodynamic target. Clinical breakpoints are likely to be significantly lower than epidemiological cutoff values. The MIC may guide the appropriate use of fluconazole. If fluconazole is the only option for induction therapy, then the highest possible dose should be used. PMID:23571544

Topical antifungals for seborrhoeic dermatitis

PubMed Central

Okokon, Enembe O; Verbeek, Jos H; Ruotsalainen, Jani H; Ojo, Olumuyiwa A; Bakhoya, Victor Nyange

2015-01-01

symptoms were less clear and were inconsistent, possibly because of difficulties encountered in measuring these symptoms. Evidence was insufficient to conclude that dose or mode of delivery influenced treatment outcome. Only one study reported on treatment compliance. No study assessed quality of life. One study assessed the maximum rash-free period but provided insufficient data for analysis. One small study in patients with HIV compared the effect of lithium versus placebo on seborrhoeic dermatitis of the face, but treatment outcomes were similar. Authors' conclusions Ketoconazole and ciclopirox are more effective than placebo, but limited evidence suggests that either of these agents is more effective than any other agent within the same class. Very few studies have assessed symptom clearance for longer periods than four weeks. Ketoconazole produced findings similar to those of steroids, but side effects were fewer. Treatment effect on overall quality of life remains unknown. Better outcome measures, studies of better quality and better reporting are all needed to improve the evidence base for antifungals for seborrhoeic dermatitis. Plain Language Summary Antifungal treatments applied to the skin to treat seborrhoeic dermatitis Background Seborrhoeic dermatitis is a chronic inflammatory skin condition found throughout the world, with rashes with varying degrees of redness, scaling and itching. It affects people of both sexes but is more common among men. The disease usually starts after puberty and can lead to personal discomfort and cosmetic concerns when rashes occur at prominent skin sites. Drugs that act against moulds, also called antifungal agents, have been commonly used on their own or in combination. Review question Do antifungal treatments applied to the skin clear up the rashes and itching of seborrhoeic dermatitis? Study characteristics We included 51 studies with 9052 participants. Trials typically were four weeks long, and very few trials were longer. In

[INVESTIGATION ON ANTIFUNGAL SUSCEPTIBILITY OF CANDIDA YEASTS IN PREGNANT PATIENTS WITH CONFIRMED VULVOVAGINAL CANDIDIASIS AND THEIR NEWBORNS.

PubMed

Chokoeva, A; Kouzmanov, A; Ivanova, Z; Zisova, L; Amalie, G; Petleshkova, P; Miteva-Katrandzhieva, Ts; Krasteva, M; Uchikova, E

patients with VVC immediately before birth (n = 22, 91.67 +/- 0.06%). Positive Candida colonization was detected in 14 (58.33%) of their newborns (n = 24), as no statistically significant difference was established, depending on the mode of delivery. The investigated antifungal susceptibility with test Fungifast (ELITech Microbiology Reagents), found 100% sensitivity of Candida albicans to Amphotericin B, Flucytosin and Voriconazole. Intermediate susceptibility to Itraconazole was found in 6 of 23 (26%) maternal isolates, and 5 of 23 (22%) isolates were moderately sensitive to Fluconazole. Candida krusei showed complete resistance to Fluconazole and Itraconazole. Within the group of antifungals for topical application (Econazole, Ketoconazole, Miconazole, Nystatin), the results established that 100% of the studied fungi were sensitive to Nystatin, while within the groups of azoles for vaginal and topical use - C.krusei was 100% resistant, as the sensitivity of C. albicans varied between 60-80%. Conclusion Our recommendation, based on the esablished results is that in pregnant with uncomplicated VVC as a first-line therapy should be considered the group of vaginal azoles and Nystatin, while the systemic therapy should be considered carefully and only after the firSt trimester. In cases of oral and intestinal candidiasis in neonatology, we recommend a therapy with minimal absorbable antifungals as Nystatin and miconazole (amphotericin B is available in our country), while systemic antifungal should be initiated only as a second choice. The exact etiological diagnosis is especially important because in our country there is a tendency for increased incidence of non-albicans fungus resistant to therapy, and that changes the therapeutic behavior.

A Class 1 Histone Deacetylase with Potential as an Antifungal Target

PubMed Central

Bauer, Ingo; Varadarajan, Divyavaradhi; Pidroni, Angelo; Gross, Silke; Vergeiner, Stefan; Faber, Birgit; Hermann, Martin; Tribus, Martin; Brosch, Gerald

2016-01-01

ABSTRACT Histone deacetylases (HDACs) remove acetyl moieties from lysine residues at histone tails and nuclear regulatory proteins and thus significantly impact chromatin remodeling and transcriptional regulation in eukaryotes. In recent years, HDACs of filamentous fungi were found to be decisive regulators of genes involved in pathogenicity and the production of important fungal metabolites such as antibiotics and toxins. Here we present proof that one of these enzymes, the class 1 type HDAC RpdA, is of vital importance for the opportunistic human pathogen Aspergillus fumigatus. Recombinant expression of inactivated RpdA shows that loss of catalytic activity is responsible for the lethal phenotype of Aspergillus RpdA null mutants. Furthermore, we demonstrate that a fungus-specific C-terminal region of only a few acidic amino acids is required for both the nuclear localization and catalytic activity of the enzyme in the model organism Aspergillus nidulans. Since strains with single or multiple deletions of other classical HDACs revealed no or only moderate growth deficiencies, it is highly probable that the significant delay of germination and the growth defects observed in strains growing under the HDAC inhibitor trichostatin A are caused primarily by inhibition of catalytic RpdA activity. Indeed, even at low nanomolar concentrations of the inhibitor, the catalytic activity of purified RpdA is considerably diminished. Considering these results, RpdA with its fungus-specific motif represents a promising target for novel HDAC inhibitors that, in addition to their increasing impact as anticancer drugs, might gain in importance as antifungals against life-threatening invasive infections, apart from or in combination with classical antifungal therapy regimes. PMID:27803184

Effectiveness of Manual Therapy Combined With Physical Therapy in Treatment of Patellofemoral Pain Syndrome: Systematic Review.

PubMed

Espí-López, Gemma Victoria; Arnal-Gómez, Anna; Balasch-Bernat, Mercè; Inglés, Marta

2017-06-01

The purpose of this study was to conduct a review of randomized controlled trials (RCTs) to determine the treatment effectiveness of the combination of manual therapy (MT) with other physical therapy techniques. Systematic searches of scientific literature were undertaken on PubMed and the Cochrane Library (2004-2014). The following terms were used: "patellofemoral pain syndrome," "physical therapy," "manual therapy," and "manipulation." RCTs that studied adults diagnosed with patellofemoral pain syndrome (PFPS) treated by MT and physical therapy approaches were included. The quality of the studies was assessed by the Jadad Scale. Five RCTs with an acceptable methodological quality (Jadad ≥ 3) were selected. The studies indicated that MT combined with physical therapy has some effect on reducing pain and improving function in PFPS, especially when applied on the full kinetic chain and when strengthening hip and knee muscles. The different combinations of MT and physical therapy programs analyzed in this review suggest that giving more emphasis to proximal stabilization and full kinetic chain treatments in PFPS will help better alleviation of symptoms.

Antifungal prescribing pattern and attitude towards the treatment of oral candidiasis among dentists in Jordan.

PubMed

Al-Shayyab, Mohammad H; Abu-Hammad, Osama A; Al-Omiri, Mahmoud K; Dar-Odeh, Najla S

2015-08-01

The aim of this study was to evaluate the attitude of Jordanian dentists towards the treatment of oral candidiasis and their current antifungal prescribing habits, shedding more light on the possible influence of their socio-professional factors on the pattern of prescribing and practice. A structured validated questionnaire was developed and tested; it was then emailed to a random sample of 600 Jordanian dental practitioners during the period of this cross-sectional survey. The questionnaire recorded practitioners' personal details and their attitude and prescribing of antifungal therapy for oral candidiasis. Statistical significance was based on probability values of <0.05 and was measured using the chi-square and Fisher's exact tests. Multiple logistic regression analysis was used to analyse the influence of respondents' socio-professional factors on their attitude towards oral candidiasis. Of the 423 questionnaires returned, only 330 were included. The attitude of respondents was significantly influenced by their experience [odds ratio (OR) = 0.14; P < 0.001] and workplace (OR = 4.70; P < 0.001). Nystatin was the most commonly prescribed antifungal agent (78.2%), followed by miconazole (62.4%), which was prescribed for topical use. Systemic antifungals were prescribed by 21.2% of respondents, with a significant (P < 0.05) association with the country in which their qualification was obtained. The attitude towards the treatment of oral candidiasis is much better among the least-experienced dentists working in private practice. Nystatin and miconazole are the most popular choices of antifungal agents among Jordanian dentists. © 2015 FDI World Dental Federation.

Candida Infective Endocarditis: an Observational Cohort Study with a Focus on Therapy

PubMed Central

Johnson, Melissa; Bayer, Arnold S.; Bradley, Suzanne; Giannitsioti, Efthymia; Miró, José M.; Tornos, Pilar; Tattevin, Pierre; Strahilevitz, Jacob; Spelman, Denis; Athan, Eugene; Nacinovich, Francisco; Fortes, Claudio Q.; Lamas, Cristiane; Barsic, Bruno; Fernández-Hidalgo, Nuria; Muñoz, Patricia; Chu, Vivian H.

2015-01-01

Candida infective endocarditis is a rare disease with a high mortality rate. Our understanding of this infection is derived from case series, case reports, and small prospective cohorts. The purpose of this study was to evaluate the clinical features and use of different antifungal treatment regimens for Candida infective endocarditis. This prospective cohort study was based on 70 cases of Candida infective endocarditis from the International Collaboration on Endocarditis (ICE)-Prospective Cohort Study and ICE-Plus databases collected between 2000 and 2010. The majority of infections were acquired nosocomially (67%). Congestive heart failure (24%), prosthetic heart valve (46%), and previous infective endocarditis (26%) were common comorbidities. Overall mortality was high, with 36% mortality in the hospital and 59% at 1 year. On univariate analysis, older age, heart failure at baseline, persistent candidemia, nosocomial acquisition, heart failure as a complication, and intracardiac abscess were associated with higher mortality. Mortality was not affected by use of surgical therapy or choice of antifungal agent. A subgroup analysis was performed on 33 patients for whom specific antifungal therapy information was available. In this subgroup, 11 patients received amphotericin B-based therapy and 14 received echinocandin-based therapy. Despite a higher percentage of older patients and nosocomial infection in the echinocandin group, mortality rates were similar between the two groups. In conclusion, Candida infective endocarditis is associated with a high mortality rate that was not impacted by choice of antifungal therapy or by adjunctive surgical intervention. Additionally, echinocandin therapy was as effective as amphotericin B-based therapy in the small subgroup analysis. PMID:25645855

Combination therapy for malaria in Africa: hype or hope?

PubMed Central

Bloland, P. B.; Ettling, M.; Meek, S.

2000-01-01

The development of resistance to drugs poses one of the greatest threats to malaria control. In Africa, the efficacy of readily affordable antimalarial drugs is declining rapidly, while highly efficacious drugs tend to be too expensive. Cost-effective strategies are needed to extend the useful life spans of antimalarial drugs. Observations in South-East Asia on combination therapy with artemisinin derivatives and mefloquine indicate that the development of resistance to both components is slowed down. This suggests the possibility of a solution to the problem of drug resistance in Africa, where, however, there are major obstacles in the way of deploying combination therapy effectively. The rates of transmission are relatively high, a large proportion of asymptomatic infection occurs in semi-immune persons, the use of drugs is frequently inappropriate and ill-informed, there is a general lack of laboratory diagnoses, and public health systems in sub-Saharan Africa are generally weak. Furthermore, the cost of combination therapy is comparatively high. We review combination therapy as used in South-East Asia and outline the problems that have to be overcome in order to adopt it successfully in sub-Saharan Africa. PMID:11196485

Evidence-Based Guidelines for Empirical Therapy of Neutropenic Fever in Korea

PubMed Central

Kim, Sung-Han; Kim, Soo Young; Kim, Chung-Jong; Park, Wan Beom; Song, Young Goo; Choi, Jung-Hyun

2011-01-01

Neutrophils play an important role in immunological function. Neutropenic patients are vulnerable to infection, and except fever is present, inflammatory reactions are scarce in many cases. Additionally, because infections can worsen rapidly, early evaluation and treatments are especially important in febrile neutropenic patients. In cases in which febrile neutropenia is anticipated due to anticancer chemotherapy, antibiotic prophylaxis can be used, based on the risk of infection. Antifungal prophylaxis may also be considered if long-term neutropenia or mucosal damage is expected. When fever is observed in patients suspected to have neutropenia, an adequate physical examination and blood and sputum cultures should be performed. Initial antibiotics should be chosen by considering the risk of complications following the infection; if the risk is low, oral antibiotics can be used. For initial intravenous antibiotics, monotherapy with a broad-spectrum antibiotic or combination therapy with two antibiotics is recommended. At 3-5 days after beginning the initial antibiotic therapy, the condition of the patient is assessed again to determine whether the fever has subsided or symptoms have worsened. If the patient's condition has improved, intravenous antibiotics can be replaced with oral antibiotics; if the condition has deteriorated, a change of antibiotics or addition of antifungal agents should be considered. If the causative microorganism is identified, initial antimicrobial or antifungal agents should be changed accordingly. When the cause is not detected, the initial agents should continue to be used until the neutrophil count recovers. PMID:21716917

Synthesis, characterization, and antifungal evaluation of novel 1,2,3-triazolium-functionalized starch derivative.

PubMed

Tan, Wenqiang; Zhang, Jingjing; Luan, Fang; Wei, Lijie; Li, Qing; Dong, Fang; Guo, Zhanyong

2017-08-01

1,2,3-Triazolium-functionalized starch derivative was obtained by straightforward quaternization of the synthesized starch derivative bearing 1,2,3-triazole with benzyl bromide by combining the robust attributes of cuprous-catalyzed azide-alkyne cycloaddition. These novel starch derivatives were characterized by FTIR, UV-vis, 1 H NMR, 13 C NMR, and elemental analysis. Their antifungal activities against Colletotrichum lagenarium, Watermelon fusarium, and Phomopsis asparagi were investigated by hypha measurement in vitro. The fungicidal assessment revealed that compared with starch and starch derivative bearing 1,2,3-triazole with inhibitory indices of below 15% at 1.0mg/mL, 1,2,3-triazolium-functionalized starch derivative had superior antifungal activity with inhibitory rates of over 60%. Especially, the best inhibitory index of 1,2,3-triazolium-functionalized starch derivative against Colletotrichum lagenarium attained 90% above at 1.0mg/mL. The results obviously showed that quaternization of 1,2,3-triazole with benzyl bromide could effectively enhance antifungal activity of the synthesized starch derivatives. The synthetic strategy described here could be utilized for the development of starch as novel antifungal biomaterial. Copyright © 2017 Elsevier B.V. All rights reserved.

In vitro antifungal susceptibility to six antifungal agents of 229 Candida isolates from patients with diabetes mellitus.

PubMed

Manfredi, M; McCullough, M J; Polonelli, L; Conti, S; Al-Karaawi, Z M; Vescovi, P; Porter, S R

2006-06-01

The most common antifungal drugs in current clinical use for the treatment of oral candidosis are polyenes and azoles, mainly used topically. Poor glycaemic control in association with other local factors, such as the presence of oral dental prostheses, salivary pH, salivary flow rate and tobacco habits, may lead to the development of oral candidosis. Topical antifungal agents are frequently used to prevent the development of candidal infections in patients with poor metabolic control, particularly in the elderly wearing dentures. The aim of this study was to assess the antifungal susceptibility of Candida isolates to six antifungal agents using a commercially available kit, Fungitest. The isolated were collected from patients affected by diabetes mellitus from two different geographic localities (London, UK, and Parma, Italy) and from a group of healthy non-diabetic subjects. No differences in antifungal susceptibility to the six agents tested were observed between Candida isolates from diabetic and non-diabetic subjects. However, differences were observed between the two geographically different diabetes mellitus populations. Oral yeast isolates from diabetes mellitus patients in the UK more often displayed resistance or intermediate resistance to fluconazole (P=0.02), miconazole (P<0.0001), and ketoconazole (P=0.01) than did isolates from diabetes mellitus patients in Italy. In addition, more C. albicans isolates were found in diabetic and non-diabetic subjects that were susceptible to fluconazole (P=0.0008 and P=0.01, respectively) than non-albicans isolates. The difference in the antifungal resistance of isolates from the two populations of diabetes mellitus patients may be related to differences in the therapeutic management of candidal infections between the two centres.

Common drug-drug interactions in antifungal treatments for superficial fungal infections.

PubMed

Gupta, Aditya K; Versteeg, Sarah G; Shear, Neil H

2018-04-01

Antifungal agents can be co-administered alongside several other medications for a variety of reasons such as the presence of comorbidities. Pharmacodynamic interactions such as synergistic and antagonistic interactions could be the result of co-administered medications. Pharmacokinetic interactions could also transpire through the inhibition of metabolizing enzymes and drug transport systems, altering the absorption, metabolism and excretion of co-administered medications. Both pharmacodynamic and pharmacokinetic interactions can result in hospitalization due to serious adverse effects associated with antifungal agents, lower therapeutic doses required to achieve desired antifungal activity, and prevent antifungal resistance. Areas covered: The objective of this review is to summarize pharmacodynamic and pharmacokinetic interactions associated with common antifungal agents used to treat superficial fungal infections. Pharmacodynamic and pharmacokinetic interactions that impact the therapeutic effects of antifungal agents and drugs that are influenced by the presence of antifungal agents was the context to which these antifungal agents were addressed. Expert opinion: The potential for drug-drug interactions is minimal for topical antifungals as opposed to oral antifungals as they have minimal exposure to other co-administered medications. Developing non-lipophilic antifungals that have unique metabolizing pathways and are topical applied are suggested properties that could help limit drug-drug interactions associated with future treatments.

Oral candidiasis following steroid therapy for oral lichen planus.

PubMed

Marable, D R; Bowers, L M; Stout, T L; Stewart, C M; Berg, K M; Sankar, V; DeRossi, S S; Thoppay, J R; Brennan, M T

2016-03-01

The purpose of this multicentre study was to determine the incidence of oral candidiasis in patients treated with topical steroids for oral lichen planus (OLP) and to determine whether the application of a concurrent antifungal therapy prevented the development of an oral candidiasis in these patients. Records of 315 patients with OLP seen at four Oral Medicine practices treated for at least 2 weeks with steroids with and without the use of an antifungal regimen were retrospectively reviewed. The overall incidence of oral fungal infection in those treated with steroid therapy for OLP was 13.6%. There was no statistically significant difference in the rate of oral candidiasis development in those treated with an antifungal regimen vs those not treated prophylactically (14.3% vs 12.6%) (P = 0.68). Despite the use of various regimens, none of the preventive antifungal strategies used in this study resulted in a significant difference in the rate of development of an oral candidiasis in patients with OLP treated with steroids. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Virulence and antifungal therapy of murine disseminated infection by Rhodotorula mucilaginosa.

PubMed

Thomson, Pamela; López-Fernández, Loida; Guarro, Josep; Capilla, Javier

2017-09-01

Rhodotorula infections have emerged in recent years causing mainly fungemia associated to high mortality. We have evaluated the in vitro activity of nine antifungal drugs against four clinical strains of Rhodotorula mucilaginosa, being amphotericin B, voriconazole and posaconazole the most active compounds. The experimental virulence of this fungus and the efficacy of the three mentioned drugs were evaluated in disseminated infections in neutropenic mice. Infection resulted in a high fungal load in all the organs studied without evident particular tropism. All treated animals showed reduced burden respect to the control in a strain dependent manner being voriconazole slightly superior to posaconazole and amphotericin B. Copyright © 2017 Elsevier Inc. All rights reserved.

Antigenemia in Patients with Paracoccidioidomycosis: Detection of the 87-Kilodalton Determinant during and after Antifungal Therapy

PubMed Central

Gómez, B. L.; Figueroa, J. I.; Hamilton, A. J.; Diez, S.; Rojas, M.; Tobón, A. M.; Hay, R. J.; Restrepo, A.

1998-01-01

Serological diagnosis and follow-up of paracoccidioidomycosis (PCM) patients have relied mainly on the detection of antibody responses by using techniques such as complement fixation (CF) and immunodiffusion. We recently described a novel inhibition enzyme-linked immunosorbent assay (inh-ELISA) which proved to be useful in the diagnosis of PCM via the detection of an 87-kDa determinant in patient sera (B. L. Gomez, J. I. Figueroa, A. J. Hamilton, B. Ortiz, M. A. Robledo, R. J. Hay, and A. Restrepo, J. Clin. Microbiol. 35:3278–3283, 1997). This test has now been assessed as a means of following up PCM patients. A total of 24 PCM patients, classified according to their clinical presentation (6 with the acute form of the disease, of whom two had AIDS, 12 with the multifocal form of the disease, and 6 with the unifocal form of the disease), were studied. The four human immunodeficiency virus-negative patients with acute PCM showed a statistically significant decrease in circulating antigen levels after the start of antifungal therapy. Antigen levels in this group became negative by our criteria (≤2.3 μg/ml) before week 20 and remained so in three of four of these patients. In contrast, the two AIDS patients who also presented with the acute form of PCM showed no statistically significant decrease in circulating antigen levels even after 68 weeks of therapy. Taken together as a group, the patients with the multifocal form showed a statistically significant decrease in antigenemia after 28 weeks of therapy. In addition, five of six patients with the unifocal form became antigen negative by week 40. Antigen level decrease mirrored clinical cure in the majority of patients in all clinical groups; in contrast, measurement of anti-PCM antibodies via the CF test showed wide fluctuations in titers during the follow-up period. The inh-ELISA for the detection of the 87-kDa Paracoccidioides brasiliensis determinant would appear to be a valuable additional tool in the follow

Potato Dextrose Agar Antifungal Susceptibility Testing for Yeasts and Molds: Evaluation of Phosphate Effect on Antifungal Activity of CMT-3

PubMed Central

Liu, Yu; Tortora, George; Ryan, Maria E.; Lee, Hsi-Ming; Golub, Lorne M.

2002-01-01

The broth macrodilution method (BMM) for antifungal susceptibility testing, approved by the National Committee for Clinical Laboratory Standards (NCCLS), was found to have deficiencies in testing of the antifungal activity of a new type of antifungal agent, a nonantibacterial chemically modified tetracycline (CMT-3). The high content of phosphate in the medium was found to greatly increase the MICs of CMT-3. To avoid the interference of phosphate in the test, a new method using potato dextrose agar (PDA) as a culture medium was developed. Eight strains of fungi, including five American Type Culture Collection strains and three clinical isolates, were used to determine the MICs of amphotericin B and itraconazole with both the BMM and the PDA methods. The MICs of the two antifungal agents determined with the PDA method showed 99% agreement with those determined with the BMM method within 1 log2 dilution. Similarly, the overall reproducibility of the MICs with the PDA method was above 97%. Three other antifungal agents, fluconazole, ketoconazole, and CMT-3, were also tested in parallel against yeasts and molds with both the BMM and the PDA methods. The MICs of fluconazole and ketoconazole determined with the PDA method showed 100% agreement within 1 log2 dilution of those obtained with the BMM method. However, the MICs of CMT-3 determined with the BMM method were as high as 128 times those determined with the PDA method. The effect of phosphate on the antifungal activity of CMT-3 was evaluated by adding Na2HPO4 to PDA in the new method. It was found that the MIC of CMT-3 against a Penicillium sp. increased from 0.5 μg/ml (control) to 2.0 μg/ml when the added phosphate was used at a concentration of 0.8 mg/ml, indicating a strong interference of Na2HPO4 with the antifungal activity of CMT-3. Except for fluconazole, all the other antifungal agents demonstrated clear end points among the yeasts and molds tested. Nevertheless, with its high reproducibility, good

Enhancing Photodynamyc Therapy Efficacy by Combination Therapy: Dated, Current and Oncoming Strategies

PubMed Central

Postiglione, Ilaria; Chiaviello, Angela; Palumbo, Giuseppe

2011-01-01

Combination therapy is a common practice in many medical disciplines. It is defined as the use of more than one drug to treat the same disease. Sometimes this expression describes the simultaneous use of therapeutic approaches that target different cellular/molecular pathways, increasing the chances of killing the diseased cell. This short review is concerned with therapeutic combinations in which PDT (Photodynamyc Therapy) is the core therapeutic partner. Besides the description of the principal methods used to assess the efficacy attained by combinations in respect to monotherapy, this review describes experimental results in which PDT was combined with conventional drugs in different experimental conditions. This inventory is far from exhaustive, as the number of photosensitizers used in combination with different drugs is very large. Reports cited in this work have been selected because considered representative. The combinations we have reviewed include the association of PDT with anti-oxidants, chemotherapeutics, drugs targeting topoisomerases I and II, antimetabolites and others. Some paragraphs are dedicated to PDT and immuno-modulation, others to associations of PDT with angiogenesis inhibitors, receptor inhibitors, radiotherapy and more. Finally, a look is dedicated to combinations involving the use of natural compounds and, as new entries, drugs that act as proteasome inhibitors. PMID:24212824

[Adequacy of new systemic antifungal agents prescriptions in a teaching hospital].

PubMed

Pavese, P; Ouachi, Z; Vittoz, J-P; Lebeau, B; Foroni, L; Allenet, B; Stahl, J-P; François, P

2007-12-01

The aim of this study was to evaluate the adequacy and the conformity of prescriptions of new systemic antifungal drugs to guidelines and scientific data. Each prescription of liposomal amphotericin B (lip Amb), voriconazole, and caspofungin made between May 2003 and May 2004 in a teaching hospital were reviewed by an infectious diseases specialist. He used criteria based on marketing authorization, national recommendations, and scientific data. One hundred and fifteen files were studied during the 12-month period and 203 prescriptions analyzed. Most patients were immunodepressed. The indication of the treatment was appropriate for 127 prescriptions (62.6%). Dose and drug interactions were compliant with prescription rules for 158 prescriptions (77.8%). Among the causes of misuse, 16.3% concerned combinations of antifungals. Prescriptions of liposomal amphotericin B, voriconazole and caspofungin complied with guidelines respectively in 69.7, 60.6 and 36.8% of the cases. Among the 127 appropriate prescriptions, the use of cheaper molecules with an equivalent clinical effectiveness would have allowed saving 13.6% of the total cost of these prescriptions. This study will lead us to implement policies for new antifungal prescription.

Antifungal effect and action mechanism of antimicrobial peptide polybia-CP.

PubMed

Wang, Kairong; Jia, Fengjing; Dang, Wen; Zhao, Yanyan; Zhu, Ranran; Sun, Mengyang; Qiu, Shuai; An, Xiaoping; Ma, Zelin; Zhu, Yuanyuan; Yan, Jiexi; Kong, Ziqing; Yan, Wenjin; Wang, Rui

2016-01-01

The incidence of life-threatening invasive fungal infections increased significantly in recent years. However, the antifungal therapeutic options are very limited. Antimicrobial peptides are a class of potential lead chemical for the development of novel antifungal agents. Antimicrobial peptide polybia-CP was purified from the venom of the social wasp Polybia paulista. In this study, we synthesized polybia-CP and determined its antifungal effects against a series of Candidian species. Our results showed that polybia-CP has potent antifungal activity and fungicidal activity against the tested fungal cells with a proposed membrane-active action mode. In addition, polybia-CP could induce the increase of cellular reactive oxygen species production, which would attribute to its antifungal activity. In conclusion, the present study suggests that polybia-CP has potential as an antifungal agent or may offer a new strategy for antifungal therapeutic option. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd.

In vitro antifungal sensitivity of fluconazole, clotrimazole and nystatin against vaginal candidiasis in females of childbearing age.

PubMed

Khan, Fouzia; Baqai, Rakhshanda

2010-01-01

Vaginal candidiasis is the most common infection of females. A large variety of antifungal drugs are used for treatment. The objective of this study was isolation and identification of Candida from high vaginal swabs and in vitro antifungal activity of Clotrimazole, Fluconazole and Nystatin against Candida. Two hundred and fifty high vaginal swabs were collected from females reporting at different hospitals of Karachi. Wet mount was performed to observe the budding cells of Candida. Vaginal swabs were cultured on Sabouraud's dextrose agar with added antibiotics. Plates were incubated at room temperature for seven days. Chlamydospores of Candida albicans were identified on corn meal agar. Species of Candida were identified on Biggy agar. In vitro antifungal activity of Clotrimazole, Fluconazole and Nystatin was performed by MIC (Minimum inhibitory concentration), well diffusion method and disc diffusion method. Out of 250 high vaginal swabs, Candida species were isolated in 100 (40%) of cases. Out of 100, C. albican 30 (30%), C. tropicalis 21 (21%), C. parapsillosis 10 (10%), C. parakrusi 8 (8%), C. glabrata 8 (8%), C. krusei 3 (3%) were isolated. In vitro antifungal activity indicated Clotrimazole (MIC 16 and 8 microg/ml) effective against 68 (70%) of Candida SPP, Fluconazole (MIC 64 and 32 microg/ml) effective against 29 (36.2%) and Nystatin disc (100 units) was 51 (63.5%) effective. C. albicans was mainly isolated. Clotrimazole was more effective as compared to Fluconazole and Nystatin. Antifungal susceptibility testing should be determined before therapy to avoid treatment failures.

Oropharyngeal candidiasis in head and neck cancer patients in Iran: Species identification, antifungal susceptibility and pathogenic characterization.

PubMed

Jahanshiri, Z; Manifar, S; Moosa, H; Asghari-Paskiabi, F; Mahmoodzadeh, H; Shams-Ghahfarokhi, M; Razzaghi-Abyaneh, M

2018-06-01

Oropharyngeal candidiasis (OPC) is the most frequent opportunistic fungal infection in head and neck cancer patients. This study was done to identify the Candida species, which cause OPC, and to evaluate their antifungal susceptibility pattern and pathogenic characteristics in Iranian head and neck cancer patients treated by radiotherapy. The oral clinical samples were determined by culturing on CHROMagar, carbohydrate assimilation and ITS sequencing methods. Biofilm formation, phospholipase and proteinase activity and antifungal susceptibility were examined too. Among 54 patients with confirmed OPC, 39 (72.22%) patients were male and 15 (27.77%) were female. The most frequently Candida species from a total of 60 isolates was C. albicans (53.3%), followed by C. tropicalis (21.66%), C. glabrata (15%), C. kefyr (5%) and C. dubliniensis (1.66%). All the isolates were high-producers of biofilm. All of Candida isolates were proteinase positive and 47 isolates (81.04%) represented phospholipase activity. The maximum and minimum rates of antifungal resistance belonged to ketoconazole (93.75% of C. albicans and 89.28% of Candida non-albicans) and fluconazole (62.50% and 42.85% of C. albicans and Candida non-albicans), respectively. The most effective antifungal against all candida isolates was fluconazole. Our data can estimate abundance of OPC in male and female head and neck cancer patients and is helpful to use effective strategies for antifungal treatment, prophylaxis, and preventive therapies in these patients. Copyright © 2018. Published by Elsevier Masson SAS.

[Combination drug therapy in patients with BPH].

PubMed

Kuzmenko, A V; Kuzmenko, V V; Gyaurgiev, T A

2018-03-01

Introuction. One of the risk factors for LUTS is an infravesical obstruction, which is most often caused by benign prostatic hyperplasia (BPH). BPH symptoms are formed due to three components: static (mechanical), dynamic, and impaired functional capacity of the bladder. Medical treatment with 1-blockers decreases the outflow obstruction. 5-alpha reductase inhibitors are used to inhibit the static component of BPH. To investigate the effectiveness of various modifications of medical therapy of BPH using -blockers and 5-reductase inhibitors and combinations thereof. The study comprised 90 BPH patients who were divided into three groups, with each group containing 30 people. Patients of group I, II and III received monotherapy with -blockers, a combination of 5-reductase and -blockers, and fixed-dose combination drug Duodart, respectively. Evaluation of the treatment effectiveness included filling out voiding diaries, completing the I-PSS and QL questionnaires, uroflowmetry, transrectal ultrasonography of the prostate and estimation of the incidence of adverse effects. Also, compliance with the treatment was evaluated, and the number of patients who had episodes of acute urinary retention and required surgical treatment during the 12 month treatment course was registered. Compared to monotherapy, combination therapy with -blockers and 5-reductase inhibitors more effectively reduces the LUTS, increases Qmax and prevents the disease progression, which manifests in a lower incidence of AUR and fewer surgical interventions in groups II and III. However, the combination therapy can be associated with some side effects. Patients who received fixed-dose combination drug Duodart had a greater compliance rate than patients on the combination of drugs, which, in our opinion, is associated with fewer cases of AUR and surgical interventions. The use of Duodart in patients with BPH effectively alleviates LUTS and reduces the risk of the disease progression, which manifests itself

The application of prodrug-based nano-drug delivery strategy in cancer combination therapy.

PubMed

Ge, Yanxiu; Ma, Yakun; Li, Lingbing

2016-10-01

Single drug therapy that leads to the multidrug resistance of cancer cells and severe side-effect is a thing of the past. Combination therapies that affect multiple signaling pathways have been the focus of recent active research. Due to the successful development of prodrug-based nano-drug delivery systems (P-N-DDSs), their use has been extended to combination therapy as drug delivery platforms. In this review, we focus specifically on the P-N-DDSs in the field of combination therapy including the combinations of prodrugs with different chemotherapeutic agents, other therapeutic agents, nucleic acid or the combination of different types of therapy (e.g. chemotherapy and phototherapy). The relevant examples of prodrug-based nanoparticulate drug delivery strategy in combination cancer therapy from the recent literature are discussed to demonstrate the feasibilities of relevant technology. Copyright © 2016 Elsevier B.V. All rights reserved.

Pharmacokinetic drug interactions with clopidogrel: updated review and risk management in combination therapy

PubMed Central

Wang, Zhi-Yu; Chen, Meng; Zhu, Ling-Ling; Yu, Lu-Shan; Zeng, Su; Xiang, Mei-Xiang; Zhou, Quan

2015-01-01

Background Coprescribing of clopidogrel and other drugs is common. Available reviews have addressed the drug–drug interactions (DDIs) when clopidogrel is as an object drug, or focused on combination use of clopidogrel and a special class of drugs. Clinicians may still be ignorant of those DDIs when clopidogrel is a precipitant drug, the factors determining the degree of DDIs, and corresponding risk management. Methods A literature search was performed using PubMed, MEDLINE, Web of Science, and the Cochrane Library to analyze the pharmacokinetic DDIs of clopidogrel and new P2Y12 receptor inhibitors. Results Clopidogrel affects the pharmacokinetics of cerivastatin, repaglinide, ferulic acid, sibutramine, efavirenz, and omeprazole. Low efficacy of clopidogrel is anticipated in the presence of omeprazole, esomeprazole, morphine, grapefruit juice, scutellarin, fluoxetine, azole antifungals, calcium channel blockers, sulfonylureas, and ritonavir. Augmented antiplatelet effects are anticipated when clopidogrel is coprescribed with aspirin, curcumin, cyclosporin, St John’s wort, rifampicin, and angiotensin-converting enzyme inhibitors. The factors determining the degree of DDIs with clopidogrel include genetic status (eg, cytochrome P540 [CYP]2B6*6, CYP2C19 polymorphism, CYP3A5*3, CYP3A4*1G, and CYP1A2-163C.A), species differences, and dose strength. The DDI risk does not exhibit a class effect, eg, the effects of clopidogrel on cerivastatin versus other statins, the effects of proton pump inhibitors on clopidogrel (omeprazole, esomeprazole versus pantoprazole, rabeprazole), the effects of rifampicin on clopidogrel versus ticagrelor and prasugrel, and the effects of calcium channel blockers on clopidogrel (amlodipine versus P-glycoprotein-inhibiting calcium channel blockers). The mechanism of the DDIs with clopidogrel involves modulating CYP enzymes (eg, CYP2B6, CYP2C8, CYP2C19, and CYP3A4), paraoxonase-1, hepatic carboxylesterase 1, P-glycoprotein, and organic anion

Synergistic antifungal activity of statin-azole associations as witnessed by Saccharomyces cerevisiae- and Candida utilis-bioassays and ergosterol quantification.

PubMed

Cabral, María Eugenia; Figueroa, Lucía I C; Fariña, Julia I

2013-01-03

Frequent opportunist fungal infections and the resistance to available antifungal drugs promoted the development of new alternatives for treatment, like antifungal drug combinations. This work aimed to detect the antifungal synergism between statins and azoles by means of an agar-well diffusion bioassay with Saccharomyces cerevisiae ATCC 32051 and Candida utilis Pr(1-2) as test strains. Synergistic antifungal effects were tested by simultaneously adding a sub inhibitory concentration (SIC) of statin (atorvastatin, lovastatin, pravastatin, rosuvastatin or simvastatin) plus a minimal inhibitory concentration (MIC) of azole (clotrimazole, fluconazole, itraconazole, ketoconazole or miconazole) to yeast-embedded YNB agar plates, and a positive result corresponded to a yeast growth inhibition halo higher than that produced by the MIC of the azole alone. Yeast cell ergosterol quantification by RP-HPLC was used to confirm statin-azole synergism, and ergosterol rescue bioassays were performed for evaluating statin-induced ergosterol synthesis blockage. Growth inhibition was significantly increased when clotrimazole, fluconazole, itraconazole, ketoconazole and miconazole were combined with atorvastatin, lovastatin, rosuvastatin and simvastatin. Highest growth inhibition increments were observed on S. cerevisiae (77.5%) and C. utilis (43.2%) with a SIC of simvastatin plus a MIC of miconazole, i.e. 4 + 2.4 μg/ml or 20 + 4.8 μg/ml, respectively. Pravastatin showed almost no significant effects (0-7.6% inhibition increase). Highest interaction ratios between antifungal agents corresponded to simvastatin-miconazole combinations and were indicative of synergism. Synergism was also confirmed by the increased reduction in cellular ergosterol levels (S. cerevisiae, 40% and C. utilis, 22%). Statin-induced ergosterol synthesis blockage was corroborated by means of ergosterol rescue bioassays, pravastatin being the most easily abolished inhibition whilst rosuvastatin being the most

Candida infective endocarditis: an observational cohort study with a focus on therapy.

PubMed

Arnold, Christopher J; Johnson, Melissa; Bayer, Arnold S; Bradley, Suzanne; Giannitsioti, Efthymia; Miró, José M; Tornos, Pilar; Tattevin, Pierre; Strahilevitz, Jacob; Spelman, Denis; Athan, Eugene; Nacinovich, Francisco; Fortes, Claudio Q; Lamas, Cristiane; Barsic, Bruno; Fernández-Hidalgo, Nuria; Muñoz, Patricia; Chu, Vivian H

2015-04-01

Candida infective endocarditis is a rare disease with a high mortality rate. Our understanding of this infection is derived from case series, case reports, and small prospective cohorts. The purpose of this study was to evaluate the clinical features and use of different antifungal treatment regimens for Candida infective endocarditis. This prospective cohort study was based on 70 cases of Candida infective endocarditis from the International Collaboration on Endocarditis (ICE)-Prospective Cohort Study and ICE-Plus databases collected between 2000 and 2010. The majority of infections were acquired nosocomially (67%). Congestive heart failure (24%), prosthetic heart valve (46%), and previous infective endocarditis (26%) were common comorbidities. Overall mortality was high, with 36% mortality in the hospital and 59% at 1 year. On univariate analysis, older age, heart failure at baseline, persistent candidemia, nosocomial acquisition, heart failure as a complication, and intracardiac abscess were associated with higher mortality. Mortality was not affected by use of surgical therapy or choice of antifungal agent. A subgroup analysis was performed on 33 patients for whom specific antifungal therapy information was available. In this subgroup, 11 patients received amphotericin B-based therapy and 14 received echinocandin-based therapy. Despite a higher percentage of older patients and nosocomial infection in the echinocandin group, mortality rates were similar between the two groups. In conclusion, Candida infective endocarditis is associated with a high mortality rate that was not impacted by choice of antifungal therapy or by adjunctive surgical intervention. Additionally, echinocandin therapy was as effective as amphotericin B-based therapy in the small subgroup analysis. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Antifungal activity and cytotoxicity of extracts and triterpenoid saponins obtained from the aerial parts of Anagallis arvensis L.

PubMed

Soberón, José R; Sgariglia, Melina A; Pastoriza, Ana C; Soruco, Estela M; Jäger, Sebastián N; Labadie, Guillermo R; Sampietro, Diego A; Vattuone, Marta A

2017-05-05

Anagallis arvensis L. (Primulaceae) is used in argentinean northwestern traditional medicine to treat fungal infections. We are reporting the isolation and identification of compounds with antifungal activity against human pathogenic yeast Candida albicans, and toxicity evaluation. to study the antifungal activity of extracts and purified compounds obtained form A. arvensis aerial parts, alone and in combinations with fluconazole (FLU), and to study the toxicity of the active compounds. Disk diffusion assays were used to perform an activity-guided isolation of antifungal compounds from the aerial parts of A. arvensis. Broth dilution checkerboard and viable cell count assays were employed to determine the effects of samples and combinations of FLU + samples against Candida albicans. The chemical structures of active compounds were elucidated by spectroscopic analysis. Genotoxic and haemolytic effects of the isolated compounds were determined. Four triterpenoid saponins (1-4) were identified. Anagallisin C (AnC), exerted the highest inhibitory activity among the assayed compounds against C. albicans reference strain (ATCC 10231), with MIC-0 =1µg/mL. The Fractional Inhibitory Concentration Index (FICI=0.129) indicated a synergistic effect between AnC (0.125µg/mL) and FLU (0.031µg/mL) against C. albicans ATCC 10231. AnC inhibited C. albicans 12-99 FLU resistant strain (MIC-0 =1µg/mL), and the FICI=0.188 indicated a synergistic effect between AnC (0.125µg/mL) and fluconazole (16µg/mL). The combination AnC+ FLU exerted fungicidal activity against both C. albicans strains. AnC exerted inhibitory activity against C. albicans ATCC 10231 sessile cells (MIC 5 0=0.5µg/mL and MIC 80 =1µg/mL) and against C. albicans 12-99 sessile cells (MIC 5 0=0.75µg/mL and MIC 80 =1.25µg/mL). AnC exerted haemolytic effect against human red blood cells at 15µg/mL and did not exerted genotoxic effect on Bacillus subtilis rec strains. The antifungal activity and lack of genotoxic

Antifungal activity of eicosanoic acids isolated from the endophytic fungus Mycosphaerella sp. against Cryptococcus neoformans and C. gattii.

PubMed

Pereira, Cristiane Bigatti; Pereira de Sá, Nívea; Borelli, Beatriz Martins; Rosa, Carlos Augusto; Barbeira, Paulo Jorge Sanches; Cota, Betania Barros; Johann, Susana

2016-11-01

The antifungal effects of two eicosanoic acids, 2-amino-3,4-dihydroxy-2-25-(hydroxymethyl)-14-oxo-6,12-eicosenoic acid (compound 1) and myriocin (compound 2), isolated from Mycosphaerella sp. were evaluated against Cryptococcus neoformans and C. gattii. The compounds displayed antifungal activities against several isolates of C. neoformans and C. gattii, with minimal inhibitory concentration (MIC) values ranging from 0.49 to 7.82 μM for compound 1 and 0.48-1.95 μM for compound 2. In the checkerboard microtiter test, both compounds exhibited synergistic activity with amphotericin B against C. gattii. Ultrastructural analysis revealed several signs of damage in C. gattii and C. neoformans cells treated with compounds 1 and 2, including deformities in cell shape, depressions on the surface, and withered cells. The cells of C. gattii treated with compounds 1 and 2 showed less loss of cellular material in comparison to those treated with amphotericin B. The difference in cellular material loss increased in a test compound concentration-dependent manner. Consistent with this observation, compounds 1 and 2 were able to internalize propidium iodide (PI) in C. gattii cells. In addition, compound 2 induced the formation of several pseudohyphae, suggesting that it could reduce virulence in C. gattii cells. The study results show that these natural products led to membrane damage; however, this may not be the main target of action. These compounds have potential antifungal activity and could be useful in further studies for developing more effective combination therapies with amphotericin B and reducing side effects in patients. Copyright © 2016 Elsevier Ltd. All rights reserved.

Antifungal potential of marine natural products.

PubMed

El-Hossary, Ebaa M; Cheng, Cheng; Hamed, Mostafa M; El-Sayed Hamed, Ashraf Nageeb; Ohlsen, Knut; Hentschel, Ute; Abdelmohsen, Usama Ramadan

2017-01-27

Fungal diseases represent an increasing threat to human health worldwide which in some cases might be associated with substantial morbidity and mortality. However, only few antifungal drugs are currently available for the treatment of life-threatening fungal infections. Furthermore, plant diseases caused by fungal pathogens represent a worldwide economic problem for the agriculture industry. The marine environment continues to provide structurally diverse and biologically active secondary metabolites, several of which have inspired the development of new classes of therapeutic agents. Among these secondary metabolites, several compounds with noteworthy antifungal activities have been isolated from marine microorganisms, invertebrates, and algae. During the last fifteen years, around 65% of marine natural products possessing antifungal activities have been isolated from sponges and bacteria. This review gives an overview of natural products from diverse marine organisms that have shown in vitro and/or in vivo potential as antifungal agents, with their mechanism of action whenever applicable. The natural products literature is covered from January 2000 until June 2015, and we are reporting the chemical structures together with their biological activities, as well as the isolation source. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Cisplatin Cross-Linked Multifunctional Nanodrugplexes for Combination Therapy.

PubMed

Zhang, Weiqi; Tung, Ching-Hsuan

2017-03-15

Combination therapy efficiently tackles cancer by hitting multiple action mechanisms. However, drugs administered, simultaneously or sequentially, may not reach the targeted sites with the desired dose and ratio. The outcomes of combination therapy could be improved with a polymeric nanoparticle, which can simultaneously transport an optimal combination of drugs. We have demonstrated a simple one-pot strategy to formulate nanomedicines based on platinum coordination and the noncovalent interactions of the drugs. A naturally occurring polymer, hyaluronan (HA), was chosen as the building scaffold to form a nanodrugplex with cisplatin and aromatic-cationic drugs. The platinum coordination between cisplatin and HA induces the formation of a nanocomplex. The aromatic-cationic drugs are tightly packed by an electrostatic interaction and π-π stacking. The nanodrugplex bears excellent flexibility in drug combination and size control. It is stable in storage and has favorable release kinetics and targeting capabilities toward CD44, a receptor for HA that is highly expressed on many types of cancer cells.

The role of combination medical therapy in the treatment of acromegaly.

PubMed

Lim, Dawn Shao Ting; Fleseriu, Maria

2017-02-01

Uncontrolled acromegaly results in approximately 2-fold excess mortality. Pituitary surgery is first-line therapy, and medical treatment is indicated for persistent disease. While cabergoline and pegvisomant are used in select patients, somatostatin receptor ligands (SRLs) remain the cornerstone of medical treatment. Management of patients poorly responsive to SRLs is therefore, challenging. The purpose of this review is to highlight the options for combination medical therapy in the treatment of acromegaly, with an emphasis on efficacy and safety. All original articles/abstracts detailing combination medical therapy in acromegaly were identified from a PubMed search. Studies reviewed included retrospective and open-label prospective studies. While the combination of SRL and cabergoline was generally well tolerated, a lower baseline insulin-like growth factor-1 (IGF-1) level was the best predictor of efficacy; this combination may be most effective in patients with mildly elevated IGF-1. SRL-pegvisomant combination normalized IGF-1 in the majority of patients; continued efficacy despite individual drug dosing reduction was also reported. The risk of significant liver enzyme elevation was, however, higher than that reported with SRL monotherapy; close monitoring is recommended. Data on pegvisomant-cabergoline combination is limited, but this may be an option in the setting of SRL intolerance. Reports on temozolomide used in combination with other medical therapies in patients with aggressive GH-secreting tumors are also summarized. While more prospective, randomized controlled trials on long-term efficacy and safety are needed, combination medical therapy remains a treatment strategy that should be considered for acromegaly patients poorly responsive to SRLs.

Antifungal Treatment is Not Required for Immunocompetent Individuals With Asymptomatic Esophageal Candidiasis.

PubMed

Min, Yang Won; Kim, Eun; Son, Hee Jung; Kim, Jae J; Rhee, Poong-Lyul

2015-11-01

Although esophageal candidiasis (EC) is an opportunistic infection, asymptomatic EC (AEC) is occasionally encountered in otherwise healthy individuals. This study evaluates the impact of antifungal treatment in immunocompetent individuals with AEC and investigates risk factors for persistent or recurrent EC. The authors identified patients with biopsy-proven AEC from the database of individuals receiving screening endoscopy (n = 99,255). After excluding patients receiving immunosuppressive therapy, being positive for human immunodeficiency virus, receiving no follow-up endoscopy, or having no antifungal treatment data, a total of 142 patients were divided into remission and nonremission groups. Remission was defined when EC was not detectable on follow-up endoscopy. On baseline comparison, nonremission group was older (57.5 ± 10.3 versus 52.5 ± 10.5 years, P = 0.017) and more likely to have cardiovascular disease (12.9% versus 1.8%, P = 0.021) and history of pulmonary tuberculosis (PTB) (22.6% versus 4.5%, P = 0.004) and exhibited a lower triglyceride level (101.4 ± 37.4 versus 122.6 ± 79.6 mg/dL, P = 0.039) than remission group, whereas grade of EC and concomitant endoscopic findings did not differ between 2 groups. Antifungal treatment was also similarly performed between 2 groups. Multivariate analysis revealed that history of PTB is independently associated with nonremission (odds ratio 4.495, 95% confidence interval 1.023-19.762, P = 0.047). No patients demonstrated EC-related complications during a mean follow-up of 28.0 ± 12.0 months. In conclusion, our results suggested that antifungal treatment is not required for immunocompetent individuals with AEC and past history of PTB is an independent predictor for persistent or recurrent EC.

Is fixed combination therapy appropriate for initial hypertension treatment?

PubMed

Elliott, William J

2002-08-01

Recent clinical trials in hypertension prove how seldom single drug therapy achieves target blood pressure (BP) and reduces cardiovascular morbidity and mortality. A natural response is the testing and marketing of fixed-dose combination products for hypertension, of which 14 have been approved in the United States since 1993. Currently, only five products are indicated by the Food and Drug Administration for initial therapy of hypertension; all include a diuretic. To achieve such an indication, studies must show not only safety and efficacy of the combination, but also BP lowering that is at least additive compared with the two agents given separately, as well as a "synergy" not present when each agent is given alone. Some advantages to initial combination therapy include greater BP reduction, improved adherence to pill taking, fewer side effects, and lower cost. The most likely candidates for initial combination therapy are patients with initial BP higher than 160/100 mm Hg, or those with a BP goal lower than the customary 140/90 mm Hg. These include patients with target organ damage, clinical cardiovascular disease, proteinuria, renal impairment, or diabetes mellitus. In many of these circumstances, an angiotensin converting enzyme inhibitor or angiotensin II receptor antagonist is frequently recommended; adding a diuretic or calcium antagonist to it is much more likely to result in achievement of the BP goal. More research is being done to explore the combination of not only two representatives from classes of conventional agents, but also other drugs that may help address the multiple manifestations of the "metabolic syndrome" that often accompanies hypertension.

Systemic antifungal therapy for tinea capitis in children.

PubMed

Chen, Xiaomei; Jiang, Xia; Yang, Ming; González, Urbà; Lin, Xiufang; Hua, Xia; Xue, Siliang; Zhang, Min; Bennett, Cathy

2016-05-12

Tinea capitis is a common contagious fungal infection of the scalp in children. Systemic therapy is required for treatment and to prevent spread. This is an update of the original Cochrane review. To assess the effects of systemic antifungal drugs for tinea capitis in children. We updated our searches of the following databases to November 2015: the Cochrane Skin Group Specialised Register, CENTRAL (2015, Issue 10), MEDLINE (from 1946), EMBASE (from 1974), LILACS (from 1982), and CINAHL (from 1981). We searched five trial registers and checked the reference lists of studies for references to relevant randomised controlled trials (RCTs). We obtained unpublished, ongoing trials and grey literature via correspondence with experts in the field and from pharmaceutical companies. RCTs of systemic antifungal therapy in children with normal immunity under the age of 18 with tinea capitis confirmed by microscopy, growth of fungi (dermatophytes) in culture or both. We used standard methodological procedures expected by Cochrane. We included 25 studies (N = 4449); 4 studies (N = 2637) were new to this update.Terbinafine for four weeks and griseofulvin for eight weeks showed similar efficacy for the primary outcome of complete (i.e. clinical and mycological) cure in three studies involving 328 participants with Trichophyton species infections (84.2% versus 79.0%; risk ratio (RR) 1.06, 95% confidence interval (CI) 0.98 to 1.15; low quality evidence).Complete cure with itraconazole (two to six weeks) and griseofulvin (six weeks) was similar in two studies (83.6% versus 91.0%; RR 0.92, 95% CI 0.81 to 1.05; N = 134; very low quality evidence). In two studies, there was no difference between itraconazole and terbinafine for two to three weeks treatment (73.8% versus 78.8%; RR 0.93, 95% CI 0.72 to 1.19; N = 160; low quality evidence). In three studies, there was a similar proportion achieving complete cured with two to four weeks of fluconazole or six weeks of griseofulvin (41

Synergistic combination dry powders for inhaled antimicrobial therapy

NASA Astrophysics Data System (ADS)

Heng, Desmond; Lee, Sie Huey; Teo, Jeanette; Ng, Wai Kiong; Chan, Hak-Kim; Tan, Reginald B. H.

2013-06-01

Combination products play an important role in medicine as they offer improved clinical effectiveness, enhanced patient adherence, and reduced administrative costs. In combination antimicrobial therapy, the desired outcome is to extend the antimicrobial spectrum and to achieve a possible synergistic effect. However, adverse antagonistic species may sometimes emerge from such combinations, leading to treatment failure. Therefore, it is crucial to screen the drug candidates for compatibility and possible antagonistic interactions. This work aims to develop a novel synergistic dry powder inhaler (DPI) formulation for antimicrobial combination therapy via the pulmonary route. Binary and ternary combinations were prepared via spray drying on a BUCHI® Nano Spray Dryer B-90. All powders were within the respirable size range, and were consisted of spherical particles that were slightly corrugated. The powers yielded fine particle fractions (of the loaded dose) of over 40% when dispersed using an Aerolizer® DPI at 60 L/min. Time-kill studies carried out against common respiratory tract pathogenic bacteria Pseudomonas aeruginosa, Staphylococcus aureus, Klebsiella pneumonia and Acinetobacter baumannii at 1x the minimum inhibitory concentration (MIC) over 24 hours revealed no antagonistic behavior for both combinations. While the interactions were generally found to be indifferent, a favorable synergistic effect was detected in the binary combination when it was tested against Pseudomonas aeruginosa bacteria.

Sedaxicenes: potential new antifungal ferrocene-based agents?

PubMed

Rubbiani, R; Blacque, O; Gasser, G

2016-04-21

Fungal infections are a group of diseases spread all over the world with an extremely high morbidity. Worryingly, although several pathogenic fungi were found to develop resistance towards traditional therapy, research towards the discovery of novel antimycotic agents is very limited. Considering the promising results obtained with the ferrocene-based drug candidates Ferroquine and Ferrocifen as antimalarial and anticancer drug candidates, respectively, we envisaged derivatizing the organic scaffold of a new broad-spectrum fungicide, namely sedaxane, with a ferrocenyl moiety in order to obtain new metal-based antifungal agents. The new ferrocenyl sedaxane derivatives called herein Sedaxicenes (, and ) were characterized using different analytical techniques and the structures were confirmed by X-ray crystallography. As expected for antimycotic agents, , and were found to have a low or even no toxicity towards human cells (IC50 > 100 μM). Interestingly, while the parent drug did not display any mycotoxicity (EC50 > 100 μM), complex was found to have some antifungal activity with an IC50 value of 43 μM under the same experimental conditions. In order to investigate the possible redox-mediated mode of action of , we synthesized the ruthenocene analogue of , namely . Ruthenocene is known to have a completely different electrochemical behaviour from ferrocene although both the compounds are isostructural. As anticipated, complex was found to induce an increase of the reactive oxygen species level in S. cerevisiae, contrary to its analogue and to the parent compound sedaxane.

Challenges, solutions, and recommendations for Alzheimer's disease combination therapy.

PubMed

Hendrix, James A; Bateman, Randall J; Brashear, H Robert; Duggan, Cynthia; Carrillo, Maria C; Bain, Lisa J; DeMattos, Ronald; Katz, Russell G; Ostrowitzki, Susanne; Siemers, Eric; Sperling, Reisa; Vitolo, Ottavio V

2016-05-01

Given the complex neuropathology Alzheimer's disease (AD), combination therapy may be necessary for effective treatment. However, scientific, pragmatic, regulatory, and business challenges need to be addressed before combination therapy for AD can become a reality. Leaders from academia and industry, along with a former member of the Food and Drug Administration and the Alzheimer's Association, have explored these challenges and here propose a strategy to facilitate proof-of-concept combination therapy trials in the near future. First, a more integrated understanding of the complex pathophysiology and progression of AD is needed to identify the appropriate pathways and the disease stage to target. Once drug candidates are identified, novel clinical trial designs and selection of appropriate outcome assessments will be needed to enable definition and evaluation of the appropriate dose and dosing regimen and determination of efficacy. Success in addressing this urgent problem will only be achieved through collaboration among multiple stakeholders. Copyright © 2016 Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Invasive Aspergillus terreus morphological transitions and immunoadaptations mediating antifungal resistance.

PubMed

Bengyella, Louis; Yekwa, Elsie Laban; Subhani, Muhammad Nasir; Tambo, Ernest; Nawaz, Kiran; Hetsa, Bakoena Ashton; Iftikhar, Sehrish; Waikhom, Sayanika Devi; Roy, Pranab

2017-01-01

Aspergillus terreus Thom is a pathogen of public health and agricultural importance for its seamless abilities to expand its ecological niche. The aim of this study was holistically to investigate A. terreus morphological and immunoadaptations and their implication in antifungal resistance and proliferation during infection. In-depth unstructured mining of relevant peer-reviewed literature was performed for A. terreus morphological, immune, resistance, and genetic diversity based on the sequenced calmodulin-like gene. Accessory conidia and phialidic conidia produced by A. terreus confer discrete anti-fungal resistance that ensures survivability during therapies. Interestingly, by producing unique metabolites such as Asp-melanin and terretonin, A. terreus is capable of hijacking macrophages and scavenging iron, respectively. As such, A. terreus has established a rare mechanism to mitigate phagocytosis and swing the interaction dynamics in favor of its proliferation and survival in hosts. It is further unraveled that besides A. terreus genetic diversity, morphological, biochemical, and immunologic adaptations associated with conidia germination and discharge of chemical signals during infection enable masking of the host defense as an integral part of its strategy to survive and rapidly colonize hosts.

Optimal control of malaria: combining vector interventions and drug therapies.

PubMed

Khamis, Doran; El Mouden, Claire; Kura, Klodeta; Bonsall, Michael B

2018-04-24

The sterile insect technique and transgenic equivalents are considered promising tools for controlling vector-borne disease in an age of increasing insecticide and drug-resistance. Combining vector interventions with artemisinin-based therapies may achieve the twin goals of suppressing malaria endemicity while managing artemisinin resistance. While the cost-effectiveness of these controls has been investigated independently, their combined usage has not been dynamically optimized in response to ecological and epidemiological processes. An optimal control framework based on coupled models of mosquito population dynamics and malaria epidemiology is used to investigate the cost-effectiveness of combining vector control with drug therapies in homogeneous environments with and without vector migration. The costs of endemic malaria are weighed against the costs of administering artemisinin therapies and releasing modified mosquitoes using various cost structures. Larval density dependence is shown to reduce the cost-effectiveness of conventional sterile insect releases compared with transgenic mosquitoes with a late-acting lethal gene. Using drug treatments can reduce the critical vector control release ratio necessary to cause disease fadeout. Combining vector control and drug therapies is the most effective and efficient use of resources, and using optimized implementation strategies can substantially reduce costs.

Antifungal Compounds against Candida Infections from Traditional Chinese Medicine

PubMed Central

2017-01-01

Infections caused by Candida albicans, often refractory and with high morbidity and mortality, cause a heavy burden on the public health while the current antifungal drugs are limited and are associated with toxicity and resistance. Many plant-derived molecules including compounds isolated from traditional Chinese medicine (TCM) are reported to have antifungal activity through different targets such as cell membrane, cell wall, mitochondria, and virulence factors. Here, we review the recent progress in the anti-Candida compounds from TCM, as well as their antifungal mechanisms. Considering the diverse targets and structures, compounds from TCM might be a potential library for antifungal drug development. PMID:29445739

Ambroxol Hydrochloride Combined with Fluconazole Reverses the Resistance of Candida albicans to Fluconazole.

PubMed

Li, Xiuyun; Zhao, Yuanhao; Huang, Xin; Yu, Cuixiang; Yang, Yilei; Sun, Shujuan

2017-01-01

In this study, we found that ambroxol hydrochloride (128 μg/mL) exhibits synergistic antifungal effects in combination with fluconazole (2 μg/mL) against resistant planktonic Candida albicans ( C. albicans ) cells. This combination also exhibited synergistic effects against resistant C. albicans biofilms in different stages (4, 8, and 12 h) according to the microdilution method. In vitro data were further confirmed by the success of this combination in treating Galleria mellonella infected by resistant C. albicans . With respect to the synergistic mechanism, our result revealed that ambroxol hydrochloride has an effect on the drug transporters of resistant C. albicans , increasing the uptake and decreasing the efflux of rhodamine 6G, a fluorescent alternate of fluconazole. This is the first study to investigate the in vitro and in vivo antifungal effects, as well as the possible synergistic mechanism of ambroxol hydrochloride in combination with fluconazole against resistant C. albicans . The results show the potential role for this drug combination as a therapeutic alternative to treat resistant C. albicans and provide insights into the development of antifungal targets and new antifungal agents.

Rapamycin exerts antifungal activity in vitro and in vivo against Mucor circinelloides via FKBP12-dependent inhibition of Tor.

PubMed

Bastidas, Robert J; Shertz, Cecelia A; Lee, Soo Chan; Heitman, Joseph; Cardenas, Maria E

2012-03-01

The zygomycete Mucor circinelloides is an opportunistic fungal pathogen that commonly infects patients with malignancies, diabetes mellitus, and solid organ transplants. Despite the widespread use of antifungal therapy in the management of zygomycosis, the incidence of infections continues to rise among immunocompromised individuals. In this study, we established that the target and mechanism of antifungal action of the immunosuppressant rapamycin in M. circinelloides are mediated via conserved complexes with FKBP12 and a Tor homolog. We found that spontaneous mutations that disrupted conserved residues in FKBP12 conferred rapamycin and FK506 resistance. Disruption of the FKBP12-encoding gene, fkbA, also conferred rapamycin and FK506 resistance. Expression of M. circinelloides FKBP12 (McFKBP12) complemented a Saccharomyces cerevisiae mutant strain lacking FKBP12 to restore rapamycin sensitivity. Expression of the McTor FKBP12-rapamycin binding (FRB) domain conferred rapamycin resistance in S. cerevisiae, and McFKBP12 interacted in a rapamycin-dependent fashion with the McTor FRB domain in a yeast two-hybrid assay, validating McFKBP12 and McTor as conserved targets of rapamycin. We showed that in vitro, rapamycin exhibited potent growth inhibitory activity against M. circinelloides. In a Galleria mellonella model of systemic mucormycosis, rapamycin improved survival by 50%, suggesting that rapamycin and nonimmunosuppressive analogs have the potential to be developed as novel antifungal therapies for treatment of patients with mucormycosis.

The combination therapy of Ephedra herb and Loxoprofen caused gastric lesions in mice.

PubMed

Cho, Shigefumi; Hong, Tie; Jin, Guang-Bi; Yoshino, Gen; Miura, Myota; Aikawa, Yoshihiro; Yasuno, Fumiko; Cyong, Jong-Chol

2002-01-01

The combination therapy of a Kampo formula and an analgesic-antipyretic agent is often used for the common cold in Japan. We investigated the effect of such a combination therapy, using the Ephedra herb, which is a common ingredient of Kakkon-to and Mao-to, and Loxoprofen, a nonsteroidal anti-inflammatory drug (NSAID), on fever induced in an experimental model of mice under strong stress. The combination therapy of Ephedra herb and Loxoprofen caused gastric mucosal lesions and loss of body weight. It is considered that this combination therapy should be avoided because of its adverse effects.

NLLSS: Predicting Synergistic Drug Combinations Based on Semi-supervised Learning

PubMed Central

Chen, Ming; Wang, Quanxin; Zhang, Lixin; Yan, Guiying

2016-01-01

Fungal infection has become one of the leading causes of hospital-acquired infections with high mortality rates. Furthermore, drug resistance is common for fungus-causing diseases. Synergistic drug combinations could provide an effective strategy to overcome drug resistance. Meanwhile, synergistic drug combinations can increase treatment efficacy and decrease drug dosage to avoid toxicity. Therefore, computational prediction of synergistic drug combinations for fungus-causing diseases becomes attractive. In this study, we proposed similar nature of drug combinations: principal drugs which obtain synergistic effect with similar adjuvant drugs are often similar and vice versa. Furthermore, we developed a novel algorithm termed Network-based Laplacian regularized Least Square Synergistic drug combination prediction (NLLSS) to predict potential synergistic drug combinations by integrating different kinds of information such as known synergistic drug combinations, drug-target interactions, and drug chemical structures. We applied NLLSS to predict antifungal synergistic drug combinations and showed that it achieved excellent performance both in terms of cross validation and independent prediction. Finally, we performed biological experiments for fungal pathogen Candida albicans to confirm 7 out of 13 predicted antifungal synergistic drug combinations. NLLSS provides an efficient strategy to identify potential synergistic antifungal combinations. PMID:27415801

Azilsartan/chlorthalidone combination therapy for blood pressure control.

PubMed

Cheng, Judy Wm

2013-01-01

Edarbyclor(®) is a combined angiotensin receptor blocker (ARB) and thiazide-like diuretic (azilsartan and chlorthalidone), and was approved on December 20, 2011 by the US Food and Drug Administration (FDA) for hypertension management. To review the pharmacology, pharmacokinetics, efficacy, safety, tolerability, and role of azilsartan plus chlorthalidone for hypertension management. Peer-reviewed clinical trials, review articles, and relevant treatment guidelines, were identified from the databases MEDLINE and Current Contents (both 1966 to February 15, 2013, inclusive) using search terms "azilsartan", "chlorthalidone", "pharmacology", "pharmacokinetics", "pharmacodynamics", "pharmacoeconomics", and "cost-effectiveness". The FDA website, as well as manufacturer prescribing information, was also reviewed to identify other relevant information. Azilsartan is a new ARB with high affinity for the angiotensin 1 receptor, approved by the FDA for hypertension management. Unlike other ARBs, azilsartan has no clinical data supporting improvement in cardiovascular outcomes, and is not approved for indications other than hypertension, which a select few other ARBs may be used for (eg, diabetic nephropathy and heart failure). Chlorthalidone is a longer acting thiazide-like diuretic that has been demonstrated to improve cardiovascular outcomes. Combination treatment with azilsartan/chlorthalidone is effective for reducing blood pressure. Compared to olmesartan/hydrochlorothiazide and azilsartan/hydrochlorothiazide combinations, azilsartan/chlorthalidone appears to be more efficacious for reducing blood pressure. Azilsartan/chlorthalidone can be considered an antihypertensive therapy option in patients for whom combination therapy is required (blood pressure >20 mmHg systolic or >10 mmHg diastolic above goal). Cost to patients and insurance coverage will probably determine whether azilsartan/chlorthalidone will be the most appropriate combination therapy for an individual

Is there a decline in cognitive functions after combined electroconvulsive therapy and antipsychotic therapy in treatment-refractory schizophrenia?

PubMed

Pawełczyk, Agnieszka; Kołodziej-Kowalska, Emilia; Pawełczyk, Tomasz; Rabe-Jabłońska, Jolanta

2015-03-01

An analysis of literature shows that there is still little evidence concerning the efficacy of electroconvulsive therapy (ECT) combined with antipsychotic therapy in a group of treatment-resistant schizophrenia patients. More precisely, its influence on cognitive functions is still equivocal. The aim of this study was to assess the influence of ECT combined with antipsychotic therapy on working memory, attention, and executive functions in a group of treatment-refractory schizophrenia patients. Twenty-seven patients completed the study: 14 men and 13 women, aged 21 to 55 years (mean age, 32.8 years), diagnosed with treatment-resistant schizophrenia. Each patient underwent a course of ECT sessions and was treated with antipsychotic medications. Before the ECT and within 3 days after the last ECT session, the participants were assessed with the following neuropsychological tests: Trail Making Test (TMT) and Wisconsin Cart Sorting Test (WCST). There were no significant differences in the TMT and WCST results after combined ECT and antipsychotic therapy in treatment-refractory schizophrenia patients. According to the results of the neuropsychological tests, there was no decline in attention, executive functions, or working memory. The current study shows no significant difference in attention, working memory, or executive functions after treatment with a combination of electroconvulsive and antipsychotic therapy. This suggests that combined electroconvulsive therapy may not have a negative influence on the neuropsychological functioning of patients with treatment resistant schizophrenia.

Antifungal Drug Susceptibility of Candida Species Isolated from HIV-Positive Patients Recruited at a Public Hospital in São Luís, Maranhão, Brazil.

PubMed

Terças, Ana L G; Marques, Sirlei G; Moffa, Eduardo B; Alves, Márcia B; de Azevedo, Conceição M P S; Siqueira, Walter L; Monteiro, Cristina A

2017-01-01

Oropharyngeal candidiasis is the most common fungal infection in hospitalized patients with acquired immune deficiency syndrome (AIDS). Its progression results in invasive infections, which are a significant cause of morbidity and mortality. This study aimed to quickly and accurately identify Candida spp. from oral mucosa of AIDS patients recruited at Presidente Vargas Hospital, in São Luís city, Brazil and to evaluate the sensitivity profile of these fungi to antifungals by using an automated system. Isolates were collected from oropharyngeal mucosa of 52 hospitalized AIDS patients, under anti-viral and antifungal therapies. Patients were included in research if they were HIV-positive, above 18 years of age and after obtaining their written consent. CHROMagar ® Candida and the automated ViteK-2 ® system were used to isolate and identify Candida spp., respectively. Antifungal susceptibility testing was performed using the ViteK-2 ® system, complemented with the Etest ® , using the drugs amphotericin B, fluconazole, flucytosine, and voriconazole. Oropharyngeal candidiasis had a high prevalence in these hospitalized AIDS patients (83%), and the most prevalent species was Candida albicans (56%). Antifungal susceptibility test showed that 64.7% of the Candida spp. were susceptible, 11.8% were dose-dependent sensitive, and 23.5% were resistant. All the Candida krusei and Candida famata isolates and two of Candida glabrata were resistant to fluconazole. Most of AIDS patients presented oropharyngeal candidiasis and C. albicans was the most frequently isolated species. The results showed high variability in resistance among isolated species and indicates the need to identify the Candida spp. involved in the infection and the need to test antifungal susceptibility as a guide in drug therapy in patients hospitalized with AIDS. This is the first relate about AIDS patients monitoring in a public hospital in São Luís concerning the precise identification and

Fungal and Bacterial Infection Mitigation with Antibiotic and Antifungal Loaded Biopolymer Sponges

NASA Astrophysics Data System (ADS)

Parker, Ashley Cox

Musculoskeletal injuries are some of the most prevalent injuries in both civilian and military populations and their infections can be difficult to treat, often resulting in multiple surgeries and increased costs. In both previous and recent military operations, extremity injuries have been the most common battlefield injuries and many involve complex, open fractures. These extremity injuries are especially susceptible to multiple pathogenic, and sometimes drug resistant, bacteria and fungi. Fungal infections have recently become increasingly problematic in both military and civilian populations and have significantly higher amputation rates than those from bacterial infections. Many of these bacterial and fungal strains adhere to tissue and implanted orthopaedic hardware within wounds, forming biofilms. These problematic, often polymicrobial, infections threaten the health of the patient, but the risk also exists of spreading within hospitals to become prominent resistant infections. Local antimicrobial delivery releases high levels of antimicrobials directly to injured wound tissue, overcoming sub-bactericidal or subfungicidal antimicrobial levels present in the avascular wound zones. This research will determine the ability of modified chitosan sponges, buffered with sodium acetate or blended with polyethylene glycol (PEG), to act as short term adjunctive therapies to initial surgical treatment for delivering both antibiotics and/or antifungals for early abatement of infection. The objective of this work was to evaluate both types of modified sponges for in vitro and in vivo material characteristics and device functionality. In vitro analysis demonstrated both the buffered and PEG modified chitosan sponges exhibited increased degradation and functional cytocompatibility. The chitosan/PEG sponges were able to be loaded with hydrophobic antifungals and the sponges released in vitro biologically active concentrations, alone or in combination with the antibiotic

EUCAST breakpoints for antifungals.

PubMed

Rodríguez-Tudela, Juan L; Arendrup, Maiken C; Cuenca-Estrella, Manuel; Donnelly, J Peter; Lass-Flörl, Cornelia

2010-03-01

Susceptibility testing of fungi and development of interpretative breakpoints has become increasingly important due to the growing incidence of invasive fungal infections, the number and classes of antifungals, and the emerging reports of acquired resistance. The subcommittee on antifungal susceptibility testing of the European Committee on Antibiotic Susceptibility Testing (EUCAST) has developed standards for susceptibility testing of fermentative yeasts and molds as well as proposing breakpoints for fluconazole and voriconazole against Candida. The aim of this work is to describe the EUCAST process of setting breakpoints for antifungals. Five aspects are evaluated during the process of developing breakpoints: 1) the most common dosage used in each European country, 2) the definition of the wild-type population for each target microorganism at the species level and the determination of epidemiological cutoffs, 3) the drug's pharmacokinetics and 4) pharmacodynamics, including Monte Carlo simulations, and 5) the correlation of MICs with clinical outcome of patients treated with the compound. When insufficient data are available (e.g., due to lack of information on the clinical outcome of infections caused by isolates with an elevated MIC), epidemiological cutoff values, rather than breakpoints, are recommended until the necessary information becomes available. Copyright 2010 Prous Science, S.A.U. or its licensors. All rights reserved.

Posaconazole: an extended-spectrum triazole antifungal agent.

PubMed

Schiller, Daryl S; Fung, Horatio B

2007-09-01

those receiving fluconazole or itraconazole (>2% vs >8%, respectively; P = 0.001). An additional 2 trials have investigated posaconazole for the treatment of oropharyngeal candidiasis (OPC) in patients with HIV infection. A randomized, controlled, evaluator-blinded study in 350 HIV-infected patients with OPC found similar 14-day clinical success rates with posaconazole and fluconazole (91.7% and 92.5%, respectively; 95% CI, -6.6l to 5.04), whereas an open-label study in 176 HIV-infected patients with a history of refractory OPC reported a 28-day clinical success rate of 75%. Numerous small studies and case reports have described successful posaconazole treatment of zygomycosis, aspergillosis, fusariosis, endemic dimorphic fungal infection, and superficial and subcutaneous fungal infections that were refractory to conventional antifungal agents or in patients who were unable to tolerate these agents. Posaconazole has been well tolerated. The most common complaints have been gastrointestinal in nature, including nausea (7%-8%) and diarrhea (3%-11%), although these have rarely led to permanent discontinuation of therapy. Other common adverse effects have included vomiting (4%-7%), headache (2%-8%), and liver enzyme elevations (2%-3%). Posaconazole suspension administered at up to 800 mg/d is a reasonable alternative to conventional antifungal agents for the prevention and treatment of IFIs in high-risk populations. It may also be suitable in patients with infections caused by rare or relatively resistant fungi, and those who are unable to tolerate long-term therapy with other antifungal agents.

Targeting Metabolic Survival Pathways in Lung Cancer via Combination Therapy

DTIC Science & Technology

2014-06-01

B1, non-small cell lung cancer, glutamine metabolism, biguanides 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18 . NUMBER OF...combination therapy (months 15-16) Task 5. In vivo testing of biguanide and glutamine metabolism inhibitors in xenograft models of LKB1-proficient and...combination therapies in xenograft mice (months 12-15) IACUC and ACURO approval have been granted for in vivo xenograft studies, which will commence in

Combination therapy in hypertension: an Asia-Pacific consensus viewpoint.

PubMed

Abdul Rahman, Abdul Rashid; Reyes, Eugenio B; Sritara, Piyamitr; Pancholia, Arvind; Van Phuoc, Dang; Tomlinson, Brian

2015-05-01

Hypertension incurs a significant healthcare burden in Asia-Pacific countries, which have suboptimal rates of blood pressure (BP) treatment and control. A consensus meeting of hypertension experts from the Asia-Pacific region convened in Hanoi, Vietnam, in April 2013. The principal objectives were to discuss the growing problem of hypertension in the Asia-Pacific region, and to develop consensus recommendations to promote standards of care across the region. A particular focus was recommendations for combination therapy, since it is known that most patients with hypertension will require two or more antihypertensive drugs to achieve BP control, and also that combinations of drugs with complementary mechanisms of action achieve BP targets more effectively than monotherapy. The expert panel reviewed guidelines for hypertension management from the USA and Europe, as well as individual Asia-Pacific countries, and devised a treatment matrix/guide, in which they propose the preferred combination therapy regimens for patients with hypertension, both with and without compelling indications. This report summarizes key recommendations from the group, including recommended antihypertensive combinations for specific patient populations. These strategies generally entail initiating therapy with free drug combinations, starting with the lowest available dosage, followed by treatment with single-pill combinations once the BP target has been achieved. A single reference for the whole Asia-Pacific region may contribute to increased consistency of treatment and greater proportions of patients achieving BP control, and hence reducing hypertension-related morbidity and mortality.

Triple combination antibiotic therapy for carbapenemase-producing Klebsiella pneumoniae: a systematic review.

PubMed

Jacobs, David M; Safir, M Courtney; Huang, Dennis; Minhaj, Faisal; Parker, Adam; Rao, Gauri G

2017-11-25

The spread of carbapenemase-producing K. pneumoniae (CPKP) has become a significant problem worldwide. Combination therapy for CPKP is encouraging, but polymyxin resistance to many antibiotics is hampering effective treatment. Combination therapy with three or more antibiotics is being increasingly reported, therefore we performed a systematic review of triple combination cases in an effort to evaluate their clinical effectiveness for CPKP infections. The PubMed database was searched to identify all published clinical outcomes of CPKP infections treated with triple combination therapy. Articles were stratified into two tiers depending on the level of clinical detail provided. A tier 1 study included: antibiotic regimen, regimen-specific outcome, patient status at onset of infection, and source of infection. Articles not reaching these criteria were considered tier 2. Thirty-three studies were eligible, 23 tier 1 and ten tier 2. Among tier 1 studies, 53 cases were included in this analysis. The most common infection was pneumonia (31%) followed by primary or catheter-related bacteremia (21%) and urinary tract infection (17%). Different combinations of antibiotic classes were utilized in triple combinations, the most common being a polymyxin (colistin or polymyxin B, 86.8%), tigecycline (73.6%), aminoglycoside (43.4%), or carbapenem (43.4%). Clinical and microbiological failure occurred in 14/39 patients (35.9%) and 22/42 patients (52.4%), respectively. Overall mortality for patients treated with triple combination therapy was 35.8% (19/53 patients). Triple combination therapy is being considered as a treatment option for CPKP. Polymyxin-based therapy is the backbone antibiotic in these regimens, but its effectiveness needs establishing in prospective clinical trials.

Anti-rotavirus effects by combination therapy of stevioside and Sophora flavescens extract.

PubMed

Alfajaro, Mia Madel; Rho, Mun-Chual; Kim, Hyun-Jeong; Park, Jun-Gyu; Kim, Deok-Song; Hosmillo, Myra; Son, Kyu-Yeol; Lee, Ju-Hwan; Park, Sang-Ik; Kang, Mun-Il; Ryu, Young Bae; Park, Ki Hun; Oh, Hyun-Mee; Lee, Seung Woong; Park, Su-Jin; Lee, Woo Song; Cho, Kyoung-Oh

2014-06-01

Anti-rotaviral activities of Sophora flavescens extract (SFE) and stevioside (SV) from Stevia rebaudiana Bertoni either singly or in various combinations were examined in vitro and in vivo using a porcine rotavirus G5[P7] strain. Combination of SFE and SV inhibited in vitro virus replication more efficiently than each single treatment. In the piglet model, SV had no effect on rotavirus enteritis, whereas SFE improved but did not completely cure rotaviral enteritis. Interestingly, combination therapy of SFE and SV alleviated diarrhea, and markedly improved small intestinal lesion score and fecal virus shedding. Acute toxicity tests including the piglet lethal dose 50, and body weight, organ weight and pathological changes for the combination therapy did not show any adverse effect on the piglets. These preliminary data suggest that the combination therapy of SV and SFE is a potential curative medication for rotaviral diarrhea in pigs. Determination of the efficacy of this combination therapy in other species including humans needs to be addressed in the future. Copyright © 2014 Elsevier Ltd. All rights reserved.

Antifungal activity of secondary plant metabolites from potatoes (Solanum tuberosum L.): Glycoalkaloids and phenolic acids show synergistic effects.

PubMed

Sánchez-Maldonado, A F; Schieber, A; Gänzle, M G

2016-04-01

To study the antifungal effects of the potato secondary metabolites α-solanine, α-chaconine, solanidine and caffeic acid, alone or combined. Resistance to glycoalkaloids varied among the fungal species tested, as derived from minimum inhibitory concentrations assays. Synergistic antifungal activity between glycoalkaloids and phenolic compounds was found. Changes in the fluidity of fungal membranes caused by potato secondary plant metabolites were determined by calculation of the generalized polarization values. The results partially explained the synergistic effect between caffeic acid and α-chaconine and supported findings on membrane disruption mechanisms from previous studies on artificial membranes. LC/MS analysis was used to determine variability and relative amounts of sterols in the different fungal species. Results suggested that the sterol pattern of fungi is related to their resistance to potato glycoalkaloids and to their taxonomy. Fungal resistance to α-chaconine and possibly other glycoalkaloids is species dependent. α-Chaconine and caffeic acid show synergistic antifungal activity. The taxonomic classification and the sterol pattern play a role in fungal resistance to glycoalkaloids. Results improve the understanding of the antifungal mode of action of potato secondary metabolites, which is essential for their potential utilization as antifungal agents in nonfood systems. © 2016 The Society for Applied Microbiology.

Antifungal modes of action of Saccharomyces and other biocontrol yeasts against fungi isolated from sour and grey rots.

PubMed

Nally, M C; Pesce, V M; Maturano, Y P; Rodriguez Assaf, L A; Toro, M E; Castellanos de Figueroa, L I; Vazquez, F

2015-07-02

The aim of this study was to determine the putative modes of action of 59 viticultural yeasts (31 Saccharomyces and 28 non-Saccharomyces) that inhibited fungi isolated from sour and grey rot in grapes. Inhibition of fungal mycelial growth by metabolites, enzyme activities (laminarinases, chitinases), antifungal volatiles, competition for nutrients (siderophores, Niche Overlap Index (NOI)), inhibition of fungal spore germination and decreased germinal tube length and induction of resistance were assayed. Biofungicide yeasts were classified into "antifungal patterns", according to their mechanisms of action. Thirty isolates presented at least two of the mechanisms assayed. We propose that inhibition of fungal mycelial growth by metabolites, laminarinases, competition for nutrients, inhibition of fungal spore germination and decreased germinal tube length, and antifungal volatiles by Saccharomyces and non-Saccharomyces viticultural yeasts is used as putative biocontrol mechanisms against phytopathogenic fungi. Twenty-four different antifungal patterns were identified. Siderophore production (N)and a combination of siderophore production and NOI>0.92 (M)were the most frequent antifungal patterns observed in the biofungicide yeasts assayed. Elucidation of these mechanisms could be useful for optimization of an inoculum formulation, resulting in a more consistent control of grey and sour rot with Saccharomyces and non-Saccharomyces biocontrol yeasts. Copyright © 2015 Elsevier B.V. All rights reserved.

Isolating antifungals from fungus-growing ant symbionts using a genome-guided chemistry approach.

PubMed

Seipke, Ryan F; Grüschow, Sabine; Goss, Rebecca J M; Hutchings, Matthew I

2012-01-01

We describe methods used to isolate and identify antifungal compounds from actinomycete strains associated with the leaf-cutter ant Acromyrmex octospinosus. These ants use antibiotics produced by symbiotic actinomycete bacteria to protect themselves and their fungal cultivar against bacterial and fungal infections. The fungal cultivar serves as the sole food source for the ant colony, which can number up to tens of thousands of individuals. We describe how we isolate bacteria from leaf-cutter ants collected in Trinidad and analyze the antifungal compounds made by two of these strains (Pseudonocardia and Streptomyces spp.), using a combination of genome analysis, mutagenesis, and chemical isolation. These methods should be generalizable to a wide variety of insect-symbiont situations. Although more time consuming than traditional activity-guided fractionation methods, this approach provides a powerful technique for unlocking the complete biosynthetic potential of individual strains and for avoiding the problems of rediscovery of known compounds. We describe the discovery of a novel nystatin compound, named nystatin P1, and identification of the biosynthetic pathway for antimycins, compounds that were first described more than 60 years ago. We also report that disruption of two known antifungal pathways in a single Streptomyces strain has revealed a third, and likely novel, antifungal plus four more pathways with unknown products. This validates our approach, which clearly has the potential to identify numerous new compounds, even from well-characterized actinomycete strains. Copyright © 2012 Elsevier Inc. All rights reserved.

Synthesis and quantitative structure-antifungal activity relationships of clovane derivatives against Botrytis cinerea.

PubMed

Saiz-Urra, Liane; Racero, Juan C; Macías-Sáchez, Antonio J; Hernández-Galán, Rosario; Hanson, James R; Perez-Gonzalez, Maykel; Collado, Isidro G

2009-03-25

Twenty-three clovane derivatives, nine described here for the first time, bearing substituents on carbon C-2, have been synthesized and evaluated for their in vitro antifungal activity against the phytopathogenic fungus Botrytis cinerea. The results showed that compounds 9, 14, 16, and 18 bearing nitrogen atoms in the chain attached at C-2 displayed potent antifungal activity, whereas mercapto derivatives 13, 19, and 22 displayed low activity. The antifungal activity showed a clear structure-activity relationship (SAR) trend, which confirmed the importance of the nature of the C-2 chain on the antifungal activity. On the basis of these observations, the metabolism of compounds 8 and 14 by the fungus B. cinerea, and the metabolism of other clovanes by this fungus, described previously, a pro-drug action mechanism for 2-alkoxyclovane compounds is proposed. Quantitative structure-activity relationship (QSAR) studies were performed to rationalize the results and to suggest further optimization, using a topological sub-structural molecular design (TOPS-MODE) approach. The model displayed good fit and predictive capability, describing 85.5% of the experimental variance, with a standard deviation of 9.502 and yielding high values of cross-validation determination coefficients (q2CV-LOO = 0.784 and q2boot = 0.673). The most significant variables were the spectral moments weighted by bond dipole moment (Dip), hydrophobicity (Hyd), and the combined dipolarity/polarizability Abraham molecular descriptor (Ab-pi2H).

Antifungal activity and mode of action of thymol and its synergism with nystatin against Candida species involved with infections in the oral cavity: an in vitro study.

PubMed

de Castro, Ricardo Dias; de Souza, Trícia Murielly Pereira Andrade; Bezerra, Louise Morais Dornelas; Ferreira, Gabriela Lacet Silva; Costa, Edja Maria Melo de Brito; Cavalcanti, Alessandro Leite

2015-11-24

Limitations of antifungal agents used in the treatment of oral candidiasis, as the development of resistant strains, are known by the scientific community. In this context, the aim of this study was to evaluate the antifungal activity of thymol against Candida albicans, Candida tropicalis and Candida krusei strains and to determine its mode of action and synergistic effect when combined with the synthetic antifungal nystatin. The minimum inhibitory concentration (MIC) was determined using a microdilution technique, and the minimum fungicidal concentration (MFC) was determined via subculture sowing. The mode of action of thymol was established by verifying fungal growth in the presence of sorbitol or ergosterol. The fractional inhibitory concentration index (FIC) was determined using the checkerboard method. Thymol presented an antifungal effect, with MICs of 39 μg/mL for C. albicans and C. krusei and 78 μg/mL for C. tropicalis. The results of the antifungal test remained unchanged in the presence of sorbitol; however, the MIC value of thymol against C. albicans increased eight times (from 39.0 to 312.5 μg/mL) in presence of exogenous ergosterol. The combination of thymol and nystatin reduced the MIC values of both products by 87.4%, generating an FIC index of 0.25. Thymol was found to have a fungicidal effect on Candida species and a synergistic effect when combined with nystatin.

Azilsartan/chlorthalidone combination therapy for blood pressure control

PubMed Central

Cheng, Judy WM

2013-01-01

Background Edarbyclor® is a combined angiotensin receptor blocker (ARB) and thiazide-like diuretic (azilsartan and chlorthalidone), and was approved on December 20, 2011 by the US Food and Drug Administration (FDA) for hypertension management. Objective To review the pharmacology, pharmacokinetics, efficacy, safety, tolerability, and role of azilsartan plus chlorthalidone for hypertension management. Methods Peer-reviewed clinical trials, review articles, and relevant treatment guidelines, were identified from the databases MEDLINE and Current Contents (both 1966 to February 15, 2013, inclusive) using search terms “azilsartan”, “chlorthalidone”, “pharmacology”, “pharmacokinetics”, “pharmacodynamics”, “pharmacoeconomics”, and “cost-effectiveness”. The FDA website, as well as manufacturer prescribing information, was also reviewed to identify other relevant information. Results Azilsartan is a new ARB with high affinity for the angiotensin 1 receptor, approved by the FDA for hypertension management. Unlike other ARBs, azilsartan has no clinical data supporting improvement in cardiovascular outcomes, and is not approved for indications other than hypertension, which a select few other ARBs may be used for (eg, diabetic nephropathy and heart failure). Chlorthalidone is a longer acting thiazide-like diuretic that has been demonstrated to improve cardiovascular outcomes. Combination treatment with azilsartan/chlorthalidone is effective for reducing blood pressure. Compared to olmesartan/hydrochlorothiazide and azilsartan/hydrochlorothiazide combinations, azilsartan/chlorthalidone appears to be more efficacious for reducing blood pressure. Conclusions Azilsartan/chlorthalidone can be considered an antihypertensive therapy option in patients for whom combination therapy is required (blood pressure >20 mmHg systolic or >10 mmHg diastolic above goal). Cost to patients and insurance coverage will probably determine whether azilsartan

Curcumin in combined cancer therapy.

PubMed

Troselj, Koraljka Gall; Kujundzic, Renata Novak

2014-01-01

The mechanisms of beneficial preventive and therapeutic effects achieved by traditional and complementary medicine are currently being deciphered in molecular medicine. Curcumin, a yellow-colored polyphenol derived from the rhizome of turmeric (Curcuma longa), influences a wide variety of cellular processes through the reshaping of many molecular targets. One of them, nuclear factor kappa B (NF-κB), represents a strong mediator of inflammation and, in a majority of systems, supports the pro-proliferative features of cancer cells. The application of various anticancer drugs, cytostatics, triggers signals which lead to an increase in cellular NF-κB activity. As a consequence, cancer cells often reshape their survival signaling pathways and, over time, become resistant to applied therapy. Curcumin was shown to be a strong inhibitor of NF-κB activity and its inhibitory effect on NF-κB related pathways often leads to cellular apoptotic response. All these facts, tested and confirmed in many different biological systems, have paved the way for research aimed to elucidate the potential beneficial effects of combining curcumin and various anti-cancer drugs in order to establish more efficient and less toxic cancer treatment modalities. This review addresses certain aspects of NF-κB-related inflammatory response, its role in carcinogenesis and therapy benefits that may be gained through silencing NF-κB by selectively combining curcumin and various anticancer drugs.

Luliconazole, an alternative antifungal agent against Aspergillus terreus.

PubMed

Zargaran, M; Taghipour, S; Kiasat, N; Aboualigalehdari, E; Rezaei-Matehkolaei, A; Zarei Mahmoudabadi, A; Shamsizadeh, F

2017-09-01

Aspergillus terreus is the fourth leading cause of invasive and non-invasive aspergillosis and one of the causative agents of morbidity and mortality among immunocompromised and high-risk patients. A. terreus appears to have increased as a cause of opportunistic fungal infections from superficial to serious invasive infections. Although, invasive aspergillosis is often treated empirically with amphotericin B, most A. terreus isolates are resistant both in vivo and in vitro to some antifungal drugs. In this study, we aimed to evaluate antifungals susceptibility profiles of the different strains of A. terreus against amphotericin B, caspofungin, fluconazole, voriconazole, posaconazole and luliconazole. Forty A. terreus strains originating from environmental sources (air and soil) were identified using by macroscopic and microscopic features. Six antifungals including, amphotericin B, caspofungin, fluconazole, voriconazole, posaconazole and luliconazole were applied for susceptibility tests. Our results show that tested isolates had different susceptibility to antifungals. The lowest MIC GM related to luliconazole (0.00236μg/ml), followed by posaconazole (0.18621μg/ml), voriconazole (0.22925μg/ml), caspofungin (0.86μg/ml), fluconazole (8μg/ml) and amphotericin B (11.12μg/ml). This study demonstrated that luliconazole had an excellent in vitro activity against all tested isolates of A. terreus, with MIC GM 0.00236μg/mL than other tested antifungals. As a result, luliconazole could be a possible alternative antifungal for the treatment of aspergillosis due to A. terreus. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Rechargeable Infection-responsive Antifungal Denture Materials

PubMed Central

Cao, Z.; Sun, X.; Yeh, C.-K.; Sun, Y.

2010-01-01

Candida-associated denture stomatitis (CADS) is a significant clinical concern. We developed rechargeable infection-responsive antifungal denture materials for potentially managing the disease. Polymethacrylic acid (PMAA) was covalently bound onto diurethane dimethacrylate denture resins in the curing step. The PMAA resins bound cationic antifungal drugs such as miconazole and chlorhexidine digluconate (CG) through ionic interactions. The anticandidal activities of the drug-containing PMAA-resin discs were sustained for a prolonged period of time (weeks and months). Drug release was much faster at acidic conditions (pH 5) than at pH 7. Drugs bound to the denture materials could be “washed out” by treatment with EDTA, and the drug-depleted resins could be recharged with the same or a different class of anticandidal drugs. These results suggest clinical potential of the newly developed antifungal denture materials in the management of CADS and other infectious conditions. PMID:20940361

Rechargeable infection-responsive antifungal denture materials.

PubMed

Cao, Z; Sun, X; Yeh, C-K; Sun, Y

2010-12-01

Candida-associated denture stomatitis (CADS) is a significant clinical concern. We developed rechargeable infection-responsive antifungal denture materials for potentially managing the disease. Polymethacrylic acid (PMAA) was covalently bound onto diurethane dimethacrylate denture resins in the curing step. The PMAA resins bound cationic antifungal drugs such as miconazole and chlorhexidine digluconate (CG) through ionic interactions. The anticandidal activities of the drug-containing PMAA-resin discs were sustained for a prolonged period of time (weeks and months). Drug release was much faster at acidic conditions (pH 5) than at pH 7. Drugs bound to the denture materials could be "washed out" by treatment with EDTA, and the drug-depleted resins could be recharged with the same or a different class of anticandidal drugs. These results suggest clinical potential of the newly developed antifungal denture materials in the management of CADS and other infectious conditions.

Gene Therapy for Brain Cancer: Combination Therapies Provide Enhanced Efficacy and Safety

PubMed Central

Candolfi, Marianela; Kroeger, Kurt M.; Muhammad, A.K.M.G.; Yagiz, Kader; Farrokhi, Catherine; Pechnick, Robert N.; Lowenstein, Pedro R.; Castro, Maria G.

2009-01-01

Glioblastoma multiforme (GBM) is the most common primary brain cancer in adults. Despite significant advances in treatment and intensive research, the prognosis for patients with GBM remains poor. Therapeutic challenges for GBM include its invasive nature, the proximity of the tumor to vital brain structures often preventing total resection, and the resistance of recurrent GBM to conventional radiotherapy and chemotherapy. Gene therapy has been proposed as a useful adjuvant for GBM, to be used in conjunction with current treatment. Work from our laboratory has shown that combination of conditional cytotoxic with immunotherapeutic approaches for the treatment of GBM elicits regression of large intracranial tumor masses and anti-tumor immunological memory in syngeneic rodent models of GBM. In this review we examined the currently available animal models for GBM, including rodent transplantable models, endogenous rodent tumor models and spontaneous GBM in dogs. We discuss non-invasive surrogate end points to assess tumor progression and therapeutic efficacy, such as behavioral tests and circulating biomarkers. Growing preclinical and clinical data contradict the old dogma that cytotoxic anti-cancer therapy would lead to an immune-suppression that would impair the ability of the immune system to mount an anti-tumor response. The implications of the findings reviewed indicate that combination of cytotoxic therapy with immunotherapy will lead to synergistic antitumor efficacy with reduced neurotoxicity and supports the clinical implementation of combined cytotoxic-immunotherapeutic strategies for the treatment of patients with GBM. PMID:19860655

Combinatorial effect of mutagenesis and medium component optimization on Bacillus amyloliquefaciens antifungal activity and efficacy in eradicating Botrytis cinerea.

PubMed

Masmoudi, Fatma; Ben Khedher, Saoussen; Kamoun, Amel; Zouari, Nabil; Tounsi, Slim; Trigui, Mohamed

2017-04-01

This work is directed towards Bacillus amyloliquefaciens strain BLB371 metabolite production for biocontrol of fungal phytopathogens. In order to maximise antifungal metabolite production by this strain, two approaches were combined: random mutagenesis and medium component optimization. After three rounds of mutagenesis, a hyper active mutant, named M3-7, was obtained. It produces 7 fold more antifungal metabolites (1800AU/mL) than the wild strain in MC medium. A hybrid design was applied to optimise a new medium to enhance antifungal metabolite production by M3-7. The new optimized medium (35g/L of peptone, 32.5g/L of sucrose, 10.5g/L of yeast extract, 2.4g/L of KH 2 PO 4 , 1.3g/L of MgSO 4 and 23mg/L of MnSO 4 ) achieved 1.62 fold enhancement in antifungal compound production (3000AU/mL) by this mutant, compared to that achieved in MC medium. Therefore, combinatory effect of these two approaches (mutagenesis and medium component optimization) allowed 12 fold improvement in antifungal activity (from 250UA/mL to 3000UA/mL). This improvement was confirmed against several phytopathogenic fungi with an increase of MIC and MFC over than 50%. More interestingly, a total eradication of gray mold was obtained on tomato fruits infected by Botrytis cinerea and treated by M3-7, compared to those treated by BLB371. From the practical point of view, combining random mutagenesis and medium optimization could be considered as an excellent tool for obtaining promising biological products useful against phytopathogenic fungi. Copyright © 2017 Elsevier GmbH. All rights reserved.

Determination of antifungal susceptibility patterns among the environmental isolates of Aspergillus fumigatus in Iran

PubMed Central

Mohammadi, Faezeh; Dehghan, Parvin; Nekoeian, Shahram; Hashemi, Seyed Jamal

2016-01-01

Background: In recent years, triazole-resistant environmental isolates of Aspergillus fumigatus have emerged in Europe and Asia. Azole resistance has been reported in patients who are treated with long-term azole therapy or exposure of the fungus spores to the azole fungicides used in agriculture. To date, a wide range of mutations in A. fumigatus have been described conferring azole-resistance, which commonly involves modifications in the cyp51A gene. We investigated antifungal susceptibility pattern of environmental isolates of A. fumigatus. Materials and Methods: In this study, 170 environmental samples collected from indoors surfaces of three hospitals in Iran. It was used β-tubulin gene to confirm the all of A. fumigatus isolates, which was identified by conventional methods. Furthermore, the antifungal susceptibility of itraconazole, voriconazole, and posaconazole was investigated using broth microdilution test, according to European Committee on Antimicrobial Susceptibility testing reference method. Results: From a total of 158 environmental molds fungi obtained from the hospitals, 58 isolates were identified as A. fumigatus by amplification of expected size of β-tubulin gene (~500 bp). In this study, in vitro antifungal susceptibility testing has shown that there were not high minimum inhibitory concentration values of triazole antifungals in all of the 58 environmental isolates of A. fumigatus. Conclusion: Our findings demonstrated that there was not azole-resistant among environmental isolates of A. fumigatus. Medical triazoles compounds have structural similarity with triazole fungicide compounds in agriculture, therefore, resistance development through exposure to triazole fungicide compounds in the environment is important but it sounds there is not a serious health problem in drug resistance in environmental isolates in Iran. PMID:27656605

[Antifungals cellular targets and mechanisms of resistance].

PubMed

Accoceberry, Isabelle; Noël, Thierry

2006-01-01

Antifungals of systemic use for the treatment of invasive fungal infections belong to four main chemical families which have globally three cellular targets in fungal cells: fluorinated pyrimidines act on deoxyribonucleic acid (DNA) replication and protein synthesis; polyenes and azoles are toxic for ergosterol and its biosynthetic pathway; lipopeptides inhibit the synthesis of cell wall beta glucans. The resistance mechanisms that are developed by some fungi begin to be well understood particularly in Candida yeasts. The underlying bases of these mechanisms are either mutations that modify the antifungal target, or that block access to the target, and, on the other hand, the overexpression of genes encoding the target, or some membrane proteins involved in the active efflux of antifungal drugs.

Combined immunomodulator and antimicrobial therapy eliminates polymicrobial sepsis and modulates cytokine production in combined injured mice

PubMed Central

Elliott, Thomas B.; Bolduc, David L.; Ledney, G. David; Kiang, Juliann G.; Fatanmi, Oluseyi O.; Wise, Stephen Y.; Romaine, Patricia L. P.; Newman, Victoria L.; Singh, Vijay K.

2015-01-01

Purpose: A combination therapy for combined injury (CI) using a non-specific immunomodulator, synthetic trehalose dicorynomycolate and monophosphoryl lipid A (STDCM-MPL), was evaluated to augment oral antimicrobial agents, levofloxacin (LVX) and amoxicillin (AMX), to eliminate endogenous sepsis and modulate cytokine production. Materials and methods: Female B6D2F1/J mice received 9.75 Gy cobalt-60 gamma-radiation and wound. Bacteria were isolated and identified in three tissues. Incidence of bacteria and cytokines were compared between treatment groups. Results: Results demonstrated that the lethal dose for 50% at 30 days (LD50/30) of B6D2F1/J mice was 9.42 Gy. Antimicrobial therapy increased survival in radiation-injured (RI) mice. Combination therapy increased survival after RI and extended survival time but did not increase survival after CI. Sepsis began five days earlier in CI mice than RI mice with Gram-negative species predominating early and Gram-positive species increasing later. LVX plus AMX eliminated sepsis in CI and RI mice. STDCM-MPL eliminated Gram-positive bacteria in CI and most RI mice but not Gram-negative. Treatments significantly modulated 12 cytokines tested, which pertain to wound healing or elimination of infection. Conclusions: Combination therapy eliminates infection and prolongs survival time but does not assure CI mouse survival, suggesting that additional treatment for proliferative-cell recovery is required. PMID:25994812

Combined immunomodulator and antimicrobial therapy eliminates polymicrobial sepsis and modulates cytokine production in combined injured mice.

PubMed

Elliott, Thomas B; Bolduc, David L; Ledney, G David; Kiang, Juliann G; Fatanmi, Oluseyi O; Wise, Stephen Y; Romaine, Patricia L P; Newman, Victoria L; Singh, Vijay K

2015-01-01

A combination therapy for combined injury (CI) using a non-specific immunomodulator, synthetic trehalose dicorynomycolate and monophosphoryl lipid A (STDCM-MPL), was evaluated to augment oral antimicrobial agents, levofloxacin (LVX) and amoxicillin (AMX), to eliminate endogenous sepsis and modulate cytokine production. Female B6D2F(1)/J mice received 9.75 Gy cobalt-60 gamma-radiation and wound. Bacteria were isolated and identified in three tissues. Incidence of bacteria and cytokines were compared between treatment groups. Results demonstrated that the lethal dose for 50% at 30 days (LD(50/30)) of B6D2F(1)/J mice was 9.42 Gy. Antimicrobial therapy increased survival in radiation-injured (RI) mice. Combination therapy increased survival after RI and extended survival time but did not increase survival after CI. Sepsis began five days earlier in CI mice than RI mice with Gram-negative species predominating early and Gram-positive species increasing later. LVX plus AMX eliminated sepsis in CI and RI mice. STDCM-MPL eliminated Gram-positive bacteria in CI and most RI mice but not Gram-negative. Treatments significantly modulated 12 cytokines tested, which pertain to wound healing or elimination of infection. Combination therapy eliminates infection and prolongs survival time but does not assure CI mouse survival, suggesting that additional treatment for proliferative-cell recovery is required.

Antifungal activity directed toward the Cell wall by 2-cyclohexylidenhydrazo-4-phenyl-thiazole against Candida albicans.

PubMed

de Sa, Nivea Pereira; Possa, Ana Paula; Perez, Pilar; Ferreira, Jaqueline Maria Siqueira; Fonseca, Nayara Cristina; Lino, Cleudiomar Inacio; Cruz, Lana Barreto; de Oliveira, Renata Barbosa; Rosa, Carlos Augusto; Borelli, Beatriz Martins; Mylonakis, Eleftherios; Fuchs, Beth Burgwyn; Johann, Susana

2018-05-30

Background The increasing incidence of invasive forms of candidiasis and resistance to antifungal therapy leads us to seek new and more effective antifungal compounds. Objectives Investigate the antifungal activity and toxicity as well as to evaluate the potential targets of 2-cyclohexylidenhydrazo-4-phenyl-thiazole (CPT) in Candida albicans. Methods The antifungal activity of CPT against the survival of C. albicans was investigated in Caenorhabditis elegans. Additionally, we determined the effect of CPT on the inhibition of C. albicans adhesion capacity to buccal epithelial cells (BECs), the toxicity of CPT in mammalian cells, and the potential targets of CPT in C. albicans. Results CPT exhibited a minimum inhibitory concentration (MIC) value of 0.4-1.9 µg/mL. Furthermore, CPT at high concentrations (>60 x MIC) showed no or low toxicity in HepG2 cells and <1% haemolysis in human erythrocytes. In addition, CPT decreased the adhesion capacity of yeasts to the BECs and prolonged the survival of C. elegans infected with C. albicans. Analysis of CPT-treated the cells showed that their cell wall was thinner than that of untreated cells, especially the glucan layer. We found that there was a significantly lower quantity of 1,3-β-D-glucan present in CPT-treated cells than that in untreated cells. Assays performed on several mutant strains showed that the MIC value of CPT was high for its antifungal activity on yeasts with defective 1,3-β-glucan synthase. Conclusions In conclusion, CPT appears to target the cell wall of C. albicans, exhibits low toxicity in mammalian cells, and prolongs the survival of C. elegans infected with C. albicans. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Combination nicotine replacement therapy: strategies for initiation and tapering.

PubMed

Hsia, Stephanie L; Myers, Mark G; Chen, Timothy C

2017-04-01

Several studies and meta-analyses have demonstrated the efficacy of combination nicotine replacement therapy (NRT) for patients who wish to quit smoking. However, there is limited guidance with respect to initiation and tapering of combination NRT. We attempt to review the evidence and rationale behind combination NRT, present the dosing used in combination NRT studies, and propose a step-down approach for tapering of combination NRT with integration of behavioral strategies. Copyright © 2017. Published by Elsevier Inc.

Combinational chelation therapy abrogates lead-induced neurodegeneration in rats.

PubMed

Pachauri, Vidhu; Saxena, Geetu; Mehta, Ashish; Mishra, Deepshikha; Flora, Swaran J S

2009-10-15

Lead, a ubiquitous and potent neurotoxicant causes oxidative stress which leads to numerous neurobehavioral and physiological alterations. The ability of lead to bind sulfhydryl groups or compete with calcium could be one of the reasons for its debilitating effects. In the present study, we addressed: i) if chelation therapy could circumvent the altered oxidative stress and prevent neuronal apoptosis in chronic lead-intoxicated rats, ii) whether chelation therapy could reverse biochemical and behavioral changes, and iii) if mono or combinational therapy with captopril (an antioxidant) and thiol chelating agents (DMSA/MiADMSA) is more effective than individual thiol chelator in lead-exposed rats. Results indicated that lead caused a significant increase in reactive oxygen species, nitric oxide, and intracellular free calcium levels along with altered behavioral abnormalities in locomotor activity, exploratory behavior, learning, and memory that were supported by changes in neurotransmitter levels. A fall in membrane potential, release of cytochrome c, and DNA damage indicated mitochondrial-dependent apoptosis. Most of these alterations showed significant recovery following combined therapy with captopril with MiADMSA and to a smaller extend with captopril+DMSA over monotherapy with these chelators. It could be concluded from our present results that co-administration of a potent antioxidant (like captopril) might be a better treatment protocol than monotherapy to counter lead-induced oxidative stress. The major highlight of the work is an interesting experimental evidence of the efficacy of combinational therapy using an antioxidant with a thiol chelator in reversing neurological dystrophy caused due to chronic lead exposure in rats.

Novel fluconazole derivatives with promising antifungal activity.

PubMed

Thamban Chandrika, Nishad; Shrestha, Sanjib K; Ngo, Huy X; Howard, Kaitlind C; Garneau-Tsodikova, Sylvie

2018-02-01

The fungistatic nature and toxicity concern associated with the azole drugs currently on the market have resulted in an increased demand for new azole antifungal agents for which these problematic characteristics do not exist. The extensive use of azoles has resulted in fungal strains capable of resisting the action of these drugs. Herein, we report the synthesis and antifungal activity of novel fluconazole (FLC) analogues with alkyl-, aryl-, cycloalkyl-, and dialkyl-amino substituents. We evaluated their antifungal activity by MIC determination and time-kill assay as well as their safety profile by hemolytic activity against murine erythrocytes as well as cytotoxicity against mammalian cells. The best compounds from our study exhibited broad-spectrum activity against most of the fungal strains tested, with excellent MIC values against a number of clinical isolates. The most promising compounds were found to be less hemolytic than the least hemolytic FDA-approved azole antifungal agent voriconazole (VOR). Finally, we demonstrated that the synthetic alkyl-amino FLC analogues displayed chain-dependent fungal membrane disruption as well as inhibition of ergosterol biosynthesis as possible mechanisms of action. Copyright © 2017 Elsevier Ltd. All rights reserved.

Comparative study on antifungal activities of chitosan nanoparticles and chitosan silver nano composites against Fusarium oxysporum species complex.

PubMed

Dananjaya, S H S; Erandani, W K C U; Kim, Cheol-Hee; Nikapitiya, Chamilani; Lee, Jehee; De Zoysa, Mahanama

2017-12-01

Though the metal nanoparticles (NPs) have been shown favorable results against fungal diseases, erratic environmental toxicity of NPs have raised serious concerns against their applications. Hence, it is vital to modify antifungal compounds into safe substitutes over synthetic chemicals. In this study, antifungal effects of chitosan nanoparticles (CNPs) and chitosan silver nanocomposites (CAgNCs) were compared against Fusarium oxysporum species complex. CNPs and CAgNCs were synthesized, characterized and compared based on the transmission electron microscope, X-ray diffraction, UV-vis absorbance spectra, particle size distribution, zeta potential and thermal stability analysis. Ultra-structural analysis on mycelium membrane of treated F. oxysporum showed that CNPs and CAgNCs could induce a pronounced membrane damage and disruption of the mycelium surface, increase the membrane permeability, and even cell disintegration. CAgNCs showed a significantly higher radial growth inhibition than CNPs in all the tested concentrations. Both CNPs and CAgNCs were not only effective in reducing the fungal growth, but also caused morphological and ultrastructural changes in the pathogen, thereby suggesting its usage as an antifungal dispersion system to control F. oxysporum. Additionally, CNPs and CAgNCs therapy reduced the F. oxysporum infection in zebrafish. Data demonstrates biologically active CNPs and CAgNCs are promising antifungal agents against F. oxysporum. Copyright © 2017 Elsevier B.V. All rights reserved.

Antifungal study of the resinous exudate and of meroterpenoids isolated from Psoralea glandulosa (Fabaceae).

PubMed

Madrid, Alejandro; Espinoza, Luis; González, Cesar; Mellado, Marco; Villena, Joan; Santander, Rocío; Silva, Viviana; Montenegro, Iván

2012-12-18

Psoralea glandulosa L. (Fabaceae) is a medicinal resinous shrub used in Chilean folk medicine as antiseptic in treatment of infections and skin diseases caused by bacteria and fungus. To evaluate the in vitro antifungal activity of the resin and the active components from P. glandulosa against clinical yeast isolates. Active compounds were obtained of the resinous exudate from aerial parts of P. glandulosa. Eight species of yeast were exposed to the resin and two major compounds. Minimum inhibitory concentration (MIC(80)) was determined according to the standard broth microdilution method. Bakuchiol and 3-hydroxy-bakuchiol demonstrated potent activity with the MIC(80) ranging from 4 to >16 and 0.125 to 16 μg/mL, respectively. The resin had some degree of antifungal activity. The overall results provided important information for the potential application of the 3-hydroxy-bakuchiol from P. glandulosa in the therapy of serious infection and skin diseases caused by clinical yeast. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Screening of selected single and polyherbal Ayurvedic medicines for Antibacterial and Antifungal activity

PubMed Central

Kekuda, T.R Prashith; Kavya, R; Shrungashree, R.M; Suchitra, S.V

2010-01-01

The present study deals with antimicrobial activity of ayurvedic drugs containing single herb (Amalaki Choorna and Yastimadhu Choorna) and combination of herbs (DN-90 and Asanadi Kwatha Choorna). Disc diffusion method was used to assess antibacterial activity and antifungal activity was tested using Poison food technique. Absence of bacterial growth around the discs impregnated with the aqueous extracts of drugs and reduction of fungal growth in poisoned plates indicated antimicrobial activity. Further, the results of antibacterial activity of Amalaki choorna were comparable with standard drug Streptomycin. Asanadi Kwatha Choorna inhibited bacteria to more extent than Yastimadhu choorna and DN-90. Among fungi tested, more antifungal activity was observed against Mucor sp. The antimicrobial activity of drugs tested could be due to active principles present in them. PMID:22557355

A Systematic Review of Clinical Practice Guidelines' Recommendations on Levothyroxine Therapy Alone versus Combination Therapy (LT4 plus LT3) for Hypothyroidism.

PubMed

Kraut, Eyal; Farahani, Pendar

2015-12-04

Patients with hypothyroidism are increasingly enquiring about the benefit of using combination therapy of levothyroxine (LT4) and liothyronine (LT3) as a potential treatment for hypothyroidism. Combination therapy, however, remains controversial. The purpose of this study was to systematically review available hypothyroidism treatment recommendations from clinical practice guidelines from around the world to identify the consensus regarding combination therapy. Clinical practice guidelines were obtained from searches of PubMed, EMBASE, and MEDLINE, using several combinations of MeSH terms. The search was limited to clinical guidelines in English-language publications, published between January 1, 1990 and May 1, 2015. A quantitative approach was utilized for data synthesis. Thirteen guidelines were identified, including three regarding pregnancy, two regarding pediatric populations and eight regarding adult populations. There were six guidelines from North America, four guidelines from Europe and three guidelines from South America. Twelve of the guidelines were published after 2010. Nine guidelines addressed combination therapy of LT4 plus LT3, and all nine concluded that LT4 therapy alone is the standard of care, with insufficient evidence to recommend widespread combination therapy. Only the 2012 ETA Guidelines and the 2015 BTA Guidelines concluded that combination therapy could be used, although only in certain circumstances and as an experimental treatment. This systematic review illustrates that clinical practice guidelines worldwide do not recommend and do not support routine use of combination LT4 and LT3 therapy to treat hypothyroidism.

Oral combination therapy: repaglinide plus metformin for treatment of type 2 diabetes.

PubMed

Raskin, P

2008-12-01

Type 2 diabetes is characterized by decreases in insulin secretion and insulin sensitivity. Several classes of oral antidiabetic medications are currently approved for the treatment of type 2 diabetes. A stepwise treatment approach from monotherapy to combination therapy is traditionally used; however, the frequency of treatment failure with monotherapy has resulted in a move towards earlier treatment with combination therapies that target the two principal defects in glycaemic control. One such combination regimen is repaglinide (a prandial glucose regulator that increases insulin release) plus metformin (an insulin sensitizer that inhibits hepatic glucose output, increases peripheral glucose uptake and utilization and minimizes weight gain). Findings from several clinical trials have shown that combination therapy with repaglinide plus metformin is well tolerated and results in greater reductions of haemoglobin A(1c) and fasting plasma glucose values compared with either monotherapy. Repaglinide may also provide a more suitable alternative to combination therapy with sulphonylureas and metformin because of its reduced propensity for hypoglycaemia. The combination regimen of repaglinide plus metformin should therefore be considered as a valuable option in the management of patients with type 2 diabetes when monotherapy is no longer adequate.

Gastrointestinal Toxicities With Combined Antiangiogenic and Stereotactic Body Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pollom, Erqi L.; Deng, Lei; Pai, Reetesh K.

2015-07-01

Combining the latest targeted biologic agents with the most advanced radiation technologies has been an exciting development in the treatment of cancer patients. Stereotactic body radiation therapy (SBRT) is an ablative radiation approach that has become established for the treatment of a variety of malignancies, and it has been increasingly used in combination with biologic agents, including those targeting angiogenesis-specific pathways. Multiple reports have emerged describing unanticipated toxicities arising from the combination of SBRT and angiogenesis-targeting agents, particularly of late luminal gastrointestinal toxicities. In this review, we summarize the literature describing these toxicities, explore the biological mechanism of action ofmore » toxicity with the combined use of antiangiogenic therapies, and discuss areas of future research, so that this combination of treatment modalities can continue to be used in broader clinical contexts.« less

Rapamycin Exerts Antifungal Activity In Vitro and In Vivo against Mucor circinelloides via FKBP12-Dependent Inhibition of Tor

PubMed Central

Bastidas, Robert J.; Shertz, Cecelia A.; Lee, Soo Chan; Heitman, Joseph

2012-01-01

The zygomycete Mucor circinelloides is an opportunistic fungal pathogen that commonly infects patients with malignancies, diabetes mellitus, and solid organ transplants. Despite the widespread use of antifungal therapy in the management of zygomycosis, the incidence of infections continues to rise among immunocompromised individuals. In this study, we established that the target and mechanism of antifungal action of the immunosuppressant rapamycin in M. circinelloides are mediated via conserved complexes with FKBP12 and a Tor homolog. We found that spontaneous mutations that disrupted conserved residues in FKBP12 conferred rapamycin and FK506 resistance. Disruption of the FKBP12-encoding gene, fkbA, also conferred rapamycin and FK506 resistance. Expression of M. circinelloides FKBP12 (McFKBP12) complemented a Saccharomyces cerevisiae mutant strain lacking FKBP12 to restore rapamycin sensitivity. Expression of the McTor FKBP12-rapamycin binding (FRB) domain conferred rapamycin resistance in S. cerevisiae, and McFKBP12 interacted in a rapamycin-dependent fashion with the McTor FRB domain in a yeast two-hybrid assay, validating McFKBP12 and McTor as conserved targets of rapamycin. We showed that in vitro, rapamycin exhibited potent growth inhibitory activity against M. circinelloides. In a Galleria mellonella model of systemic mucormycosis, rapamycin improved survival by 50%, suggesting that rapamycin and nonimmunosuppressive analogs have the potential to be developed as novel antifungal therapies for treatment of patients with mucormycosis. PMID:22210828

Repaglinide/troglitazone combination therapy: improved glycemic control in type 2 diabetes.

PubMed

Raskin, P; Jovanovic, L; Berger, S; Schwartz, S; Woo, V; Ratner, R

2000-07-01

This multicenter open-label clinical trial compared the efficacy and safety of repaglinide/troglitazone combination therapy, repaglinide monotherapy, and troglitazone monotherapy in type 2 diabetes that had been inadequately controlled by sulfonylureas, acarbose, or metformin alone. Patients with type 2 diabetes (n = 256) who had inadequate glycemic control (HbA1c > or =7.0%) during previous monotherapy were randomly assigned to receive repaglinide (0.5-4.0 mg at meals), troglitazone (200-600 mg once daily), or a combination of repaglinide (1-4 mg at meals) and troglitazone (200-600 mg once daily). After a 4-6 week washout period, the trial assessed 22 weeks of treatment: 3 weeks (weeks 0-2) of forced titration, 11 weeks of fixed-dose treatment (weeks 3-13), and 8 weeks (weeks 14-21) of titration to maximum dose. Changes in HbA1c and fasting plasma glucose (FPG) values were measured. The combination therapy showed a significant reduction in mean HbA1c values (-1.7%) that was greater than with either type of monotherapy Repaglinide monotherapy resulted in a reduction of HbA1c values that was significantly greater than troglitazone (-0.8 vs. -0.4%) (P < 0.05). Combination therapy was more effective in reducing FPG values (-80 mg/dl) than either repaglinide (-43 mg/dl) or troglitazone (-46 mg/dl) monotherapies. Adverse events were similar in all groups. Combination therapy with repaglinide and troglitazone leads to better glycemic control than monotherapy with either agent alone. Repaglinide monotherapy was more effective in lowering HbA1c levels than troglitazone monotherapy Repaglinide/troglitazone combination therapy was effective and did not show unexpected adverse events.

Combined therapy using acupressure therapy, hypnotherapy, and transcendental meditation versus placebo in type 2 diabetes.

PubMed

Bay, Roohallah; Bay, Fatemeh

2011-09-01

Type 2 diabetes is one of the most widespread diseases in the world. The main aim of this research was to evaluate the effect of combined therapy using acupressure therapy, hypnotherapy, and transcendental meditation (TM) on the blood sugar (BS) level in comparison with placebo in type 2 diabetic patients. We used "convenience sampling" for selection of patients with type 2 diabetes; 20 patients were recruited. For collection of data, we used an identical quasi-experimental design called "nonequivalent control group." Therapy sessions each lasting 60-90 min were carried out on 10 successive days. We prescribed 2 capsules (containing 3g of wheat flour each) for each member of the placebo group (one for evening and one for morning). Pre-tests, post-tests, and follow-up tests were conducted in a medical laboratory recognized by the Ministry of Health and Medical Education of Iran. Mean BS level in the post-tests and follow-up tests for the experimental group was reduced significantly in comparison with the pre-tests whereas in the placebo group no changes were observed. Combined therapy including acupressure therapy, hypnotherapy, and TM reduced BS of type 2 diabetic patients and was more effective than placebo therapy on this parameter. Copyright © 2011. Published by Elsevier B.V.

Evaluation of the antifungal activity and modulation between Cajanus cajan (L.) Millsp. leaves and roots ethanolic extracts and conventional antifungals

PubMed Central

Brito, Samara A.; Rodrigues, Fabíola F. G.; Campos, Adriana R.; da Costa, José G. M.

2012-01-01

Background: The use and investigation of natural products with antimicrobial activity from vegeral source have been reported by several researchers. Cajanus cajan (Fabaceae) is a multiple use specie mainly as human food. In popular medicine, diverse parts of the plant are used as sedative and to treat cough, hepatitis, and diabetes. Materials and Methods: This study shows the characterization of secondary metabolites present in ehtanolic extracts from leaves and roots of Cajanus cajan by phytochemical prospection. The evaluation of the antifungal activity was performed by the microdilution method, and from the subinhibitory concentrations (MIC 1/8) the modulatory activity of antifungical (fluconazole and ketoconazole) was analyzed by the direct contact assay against C. albicans ATCC40006, Candida krusei ATCC 6538 and Candida tropicalis ATCC 40042. Results: The results showed the presence of tannins, flavonoids, and alkaloids in both extracts as the clinically relevant antifungal activity. The modulatory potential is presented by the antifungal tested against yeasts. Conclusion: The extracts studied here have demonstrated to be a new therapeutic source to treat these microorganism-associated diseases. PMID:22701281

Evaluation of the antifungal activity and modulation between Cajanus cajan (L.) Millsp. leaves and roots ethanolic extracts and conventional antifungals.

PubMed

Brito, Samara A; Rodrigues, Fabíola F G; Campos, Adriana R; da Costa, José G M

2012-04-01

The use and investigation of natural products with antimicrobial activity from vegeral source have been reported by several researchers. Cajanus cajan (Fabaceae) is a multiple use specie mainly as human food. In popular medicine, diverse parts of the plant are used as sedative and to treat cough, hepatitis, and diabetes. This study shows the characterization of secondary metabolites present in ehtanolic extracts from leaves and roots of Cajanus cajan by phytochemical prospection. The evaluation of the antifungal activity was performed by the microdilution method, and from the subinhibitory concentrations (MIC 1/8) the modulatory activity of antifungical (fluconazole and ketoconazole) was analyzed by the direct contact assay against C. albicans ATCC40006, Candida krusei ATCC 6538 and Candida tropicalis ATCC 40042. The results showed the presence of tannins, flavonoids, and alkaloids in both extracts as the clinically relevant antifungal activity. The modulatory potential is presented by the antifungal tested against yeasts. The extracts studied here have demonstrated to be a new therapeutic source to treat these microorganism-associated diseases.

Recent Advances in Upconversion Nanoparticles-Based Multifunctional Nanocomposites for Combined Cancer Therapy.

PubMed

Tian, Gan; Zhang, Xiao; Gu, Zhanjun; Zhao, Yuliang

2015-12-16

Lanthanide-doped upconversion nanoparticles (UCNPs) have the ability to generate ultraviolet or visible emissions under continuous-wave near-infrared (NIR) excitation. Utilizing this special luminescence property, UCNPs are approved as a new generation of contrast agents in optical imaging with deep tissue-penetration ability and high signal-to-noise ratio. The integration of UCNPs with other functional moieties can endow them with highly enriched functionalities for imaging-guided cancer therapy, which makes composites based on UCNPs emerge as a new class of theranostic agents in biomedicine. Here, recent progress in combined cancer therapy using functional nanocomposites based on UCNPs is reviewed. Combined therapy referring to the co-delivery of two or more therapeutic agents or a combination of different treatments is becoming more popular in clinical treatment of cancer because it generates synergistic anti-cancer effects, reduces individual drug-related toxicity and suppresses multi-drug resistance through different mechanisms of action. Here, the recent advances of combined therapy contributed by UCNPs-based nanocomposites on two main branches are reviewed: i) photodynamic therapy and ii) chemotherapy, which are the two most widely adopted therapies of UCNPs-based composites. The future prospects and challenges in this emerging field will be also discussed. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Cost-effectiveness analysis of combination antifungal therapy with voriconazole and anidulafungin versus voriconazole monotherapy for primary treatment of invasive aspergillosis in Spain

PubMed Central

Grau, Santiago; Azanza, Jose Ramon; Ruiz, Isabel; Vallejo, Carlos; Mensa, Josep; Maertens, Johan; Heinz, Werner J; Barrueta, Jon Andoni; Peral, Carmen; Mesa, Francisco Jesús; Barrado, Miguel; Charbonneau, Claudie; Rubio-Rodríguez, Darío; Rubio-Terrés, Carlos

2017-01-01

Objective According to a recent randomized, double-blind clinical trial comparing the combination of voriconazole and anidulafungin (VOR+ANI) with VOR monotherapy for invasive aspergillosis (IA) in patients with hematologic disease or with hematopoietic stem cell transplant, mortality was lower after 6 weeks with VOR+ANI than with VOR monotherapy in a post hoc analysis of patients with galactomannan-based IA. The objective of this study was to compare the cost-effectiveness of VOR+ANI with VOR, from the perspective of hospitals in the Spanish National Health System. Methods An economic model with deterministic and probabilistic analyses was used to determine costs per life-year gained (LYG) for VOR+ANI versus VOR in patients with galactomannan-based IA. Mortality, adverse event rates, and life expectancy were obtained from clinical trial data. The costs (in 2015 euros [€]) of the drugs and the adverse event-related costs were obtained from Spanish sources. A Tornado plot and a Monte Carlo simulation (1,000 iterations) were used to assess uncertainty of all model variables. Results According to the deterministic analysis, for each patient treated with VOR+ANI compared with VOR monotherapy, there would be a total of 0.348 LYG (2.529 vs 2.181 years, respectively) at an incremental cost of €5,493 (€17,902 vs €12,409, respectively). Consequently, the additional cost per LYG with VOR+ANI compared with VOR would be €15,785. Deterministic sensitivity analyses confirmed the robustness of these findings. In the probabilistic analysis, the cost per LYG with VOR+ANI was €15,774 (95% confidence interval: €15,763–16,692). The probability of VOR+ANI being cost-effective compared with VOR was estimated at 82.5% and 91.9%, based on local cost-effectiveness thresholds of €30,000 and €45,000, respectively. Conclusion According to the present economic study, combination therapy with VOR+ANI is cost-effective as primary therapy of IA in galactomannan

Increased chitin biosynthesis contributes to the resistance of Penicillium polonicum against the antifungal protein PgAFP.

PubMed

Delgado, Josué; Owens, Rebecca A; Doyle, Sean; Asensio, Miguel A; Núñez, Félix

2016-01-01

Antifungal proteins from molds have been proposed as a valuable tool against unwanted molds, but the resistance of some fungi limits their use. Resistance to antimicrobial peptides has been suggested to be due to lack of interaction with the mold or to a successful response. The antifungal protein PgAFP produced by Penicillium chrysogenum inhibits the growth of various ascomycetes, but not Penicillium polonicum. To study the basis for resistance to this antifungal protein, localization of PgAFP and metabolic, structural, and morphological changes were investigated in P. polonicum. PgAFP bound the outer layer of P. polonicum but not regenerated chitin, suggesting an interaction with specific molecules. Comparative two-dimensional gel electrophoresis (2D-PAGE) and comparative quantitative proteomics revealed changes in the relative abundance of several proteins from ribosome, spliceosome, metabolic, and biosynthesis of secondary metabolite pathways. The proteome changes and an altered permeability reveal an active reaction of P. polonicum to PgAFP. The successful response of the resistant mold seems to be based on the higher abundance of protein Rho GTPase Rho1 that would lead to the increased chitin deposition via cell wall integrity (CWI) signaling pathway. Thus, combined treatment with chitinases could provide a complementary means to combat resistance to antifungal proteins.

A hematology consensus agreement on antifungal strategies for neutropenic patients with hematological malignancies and stem cell transplant recipients. Gruppo Italiano Malattie Ematologiche dell'Adulto, Gruppo Italiano Trapianto di Midollo Osseo, Associazione Italiana Ematologia ed Oncologia Pediatrica, Invasive Fungal Infections Cooperative Group of the European Organization for Research and Treatment of Cancer and Sorveglianza Epidemiologica delle Infezioni Fungine nelle Emopatie Maligne.

PubMed

Girmenia, Corrado; Aversa, Franco; Busca, Alessandro; Candoni, Anna; Cesaro, Simone; Luppi, Mario; Pagano, Livio; Rossi, Giuseppe; Venditti, Adriano; Nosari, Anna Maria

2013-09-01

In the attempt to establish key therapy definitions and provide shared approaches to invasive fungal diseases in neutropenic patients, trials of empiric, preeemptive and targeted antifungal therapy (EAT, PAT and TAT) were reviewed, and a Consensus Development Conference Project was convened. The Expert-Panel concurred that all antifungal treatments, including EAT, should always follow an adequate diagnostic strategy and that the standard definition of PAT may be misleading: being PAT guided by the results of a diagnostic work-up, it should better be termed diagnostic-driven antifungal therapy (DDAT). The Expert-Panel agreed that radiological findings alone are insufficient for the choice of a TAT and that the identification of the etiologic pathogen is needed. The Consensus Agreement proceeded identifying which clinical and microbiological findings were sufficient to start a DDAT and which were not. Finally, an algorithm to rationalize the choice of antifungal drugs on the basis of clinical manifestations, antifungal prophylaxis, instrumental and laboratory findings was drawn up. Copyright © 2012 John Wiley & Sons, Ltd.

Stimulation with lysates of Aspergillus terreus, Candida krusei and Rhizopus oryzae maximizes cross-reactivity of anti-fungal T cells.

PubMed

Deo, Shivashni S; Virassamy, Balaji; Halliday, Catriona; Clancy, Leighton; Chen, Sharon; Meyer, Wieland; Sorrell, Tania C; Gottlieb, David J

2016-01-01

Invasive fungal diseases caused by filamentous fungi and yeasts are significant causes of morbidity and mortality in immunosuppressed hematology patients. We previously published a method to expand Aspergillus fumigatus-specific T cells for clinical cell therapy. In the present study, we investigated expansion of T cells specific for other fungal pathogens and creation of a broadly reactive panfungal T-cell product. Fungal strains selected were those frequently observed in the clinical hematology setting and included Aspergillus, Candida, Fusarium, Rhizopus and Lomentospora/Scedosporium. Four T-cell cultures specific to each fungus were established. We selected lysates of Aspergillus terreus, Candida krusei and Rhizopus oryzae to expand panfungal T cells. Allelic restriction of anti-fungal activity was determined through the use of specific major histocompatibility complex class II-blocking antibodies. Individual T-cell cultures specific to each fungus could be expanded in vitro, generating predominantly CD4(+) T cells of which 8% to 20% were fungus-specific. We successfully expanded panfungal T cells from the peripheral blood (n = 8) and granulocyte-colony-stimulating factor-primed stem cell products (n = 3) of normal donors by using a combination of lysates from Aspergillus terreus, Candida krusei and Rhizopus oryzae. Anti-fungal activity was mediated through human leukocyte antigen (HLA)-DR alleles and was maintained when antigen-presenting cells from partially HLA-DRB1-matched donors were used to stimulate T cells. We demonstrate a method to manufacture panfungal T-cell products with specificity against a range of clinical fungal pathogens by use of the blood and stem cells of healthy donors as the starting material. The safety and efficacy of these products will need to be tested clinically. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Clinical effectiveness of rivastigmine monotherapy and combination therapy in Alzheimer's patients.

PubMed

Sonali, Nirmal; Tripathi, Manjari; Sagar, Rajesh; Velpandian, Thirumurthy; Subbiah, Vivekanandhan

2013-02-01

Rivastigmine is an acetylcholinesterase inhibitor; the genotype data seen alongside the phenotype data explain the mutation or the molecular genetics involved and also help to relate the phenotype of an individual with their genotype. To determine the clinical effectiveness of CYP2D6, CYP3A4, CYP2C9/19, and UGT polymorphism on the steady-state plasma concentrations and therapeutic outcome of rivastigmine monotherapy and combination therapy in patients with Alzheimer's disease. In this study, a significant allele frequency was observed for CYP2D6*3 polymorphism in patients under rivastigmine combination therapy (A>del = 0.50 [patients] and A>del = 0.20 [controls]), UGT2B7 (T = 0.17 [patients] and 0.33 [Controls], and UGT1A9*5 A = 0.58 [patients] and 0.26 [Controls]). The drug levels and P value of responders/nonresponders were found to be 0.17 ± 0.08/0.22 ± 0.16 and 0.574 for rivastigmine and 0.18 ± 0.11/0.66 ± 0.63 and 0.009 for rivastigmine in combination therapy and 1.40 ± 0.65/0.59 ± 0.84 and 0.05 for memantine in combination therapy. Poor metabolizer subjects of UGT2B7 polymorphism in patients under rivastigmine combination therapy have higher drug levels with a poor response to the drug treatments. © 2012 Blackwell Publishing Ltd.

An antifungal protein from the pea Pisum sativum var. arvense Poir.

PubMed

Wang, H X; Ng, T B

2006-07-01

An antifungal protein with a molecular mass of 11 kDa and a lysine-rich N-terminal sequence was isolated from the seeds of the pea Pisum sativum var. arvense Poir. The antifungal protein was unadsorbed on DEAE-cellulose but adsorbed on Affi-gel blue gel and CM-cellulose. It exerted antifungal activity against Physalospora piricola with an IC50 of 0.62 microM, and also antifungal activity against Fusarium oxysporum and Mycosphaerella arachidicola. It inhibited human immunodeficiency virus type 1 reverse transcriptase with an IC50 of 4.7 microM.

Effects of sugar and amino acid supplementation on Aureobasidium pullulans NRRL 58536 antifungal activity against four Aspergillus species.

PubMed

Prasongsuk, Sehanat; Ployngam, Saowaluck; Wacharasindhu, Sumrit; Lotrakul, Pongtharin; Punnapayak, Hunsa

2013-09-01

Cultured cell extracts from ten tropical strains of Aureobasidium pullulans were screened for antifungal activity against four pathogenic Aspergillus species (Aspergillus flavus, Aspergillus niger, Aspergillus fumigatus, and Aspergillus terreus) using the well diffusion and conidial germination inhibition assays. The crude cell extract from A. pullulans NRRL 58536 resulted in the greatest fungicidal activity against all four Aspergillus species and so was selected for further investigation into enhancing the production of antifungal activity through optimization of the culture medium, carbon source (sucrose and glucose) and amino acid (phenylalanine, proline, and leucine) supplementation. Sucrose did not support the production of any detectable antifungal activity, while glucose did with the greatest antifungal activity against all four Aspergillus species being produced in cells grown in medium containing 2.5 % (w/v) glucose. With respect to the amino acid supplements, variable trends between the different Aspergillus species and amino acid combinations were observed, with the greatest antifungal activities being obtained when grown with phenylalanine plus leucine supplementation for activity against A. flavus, proline plus leucine for A. terreus, and phenylalanine plus proline and leucine for A. niger and A. fumigatus. Thin layer chromatography, spectrophotometry, high-performance liquid chromatography, (1)H-nuclear magnetic resonance, and MALDI-TOF mass spectrometry analyses were all consistent with the main component of the A. pullulans NRRL 58536 extracts being aureobasidins.

Antifungal-protein production in maize (Zea mays) suspension cultures.

PubMed

Perri, Fabio; Della Penna, Serena; Rufini, Francesca; Patamia, Maria; Bonito, Mariantonietta; Angiolella, Letizia; Vitali, Alberto

2009-04-01

The growing emergency due to the phenomenon of drug resistance to micro-organisms has pushed forward the search for new potential drug alternatives to those already in use. Plants represent a suitable source of new antifungal molecules, as they produce a series of defensive proteins. Among them are the PRPs (pathogenesis-related proteins), shown to be effective in vitro against human pathogens. An optimized and established cell-suspension culture of maize (Zea mays) was shown to constitutively secrete in the medium a series of PRPs comprising the antifungal protein zeamatin (P33679) with a final yield of approx. 3 mg/litre. The in-vitro-produced zeamatin possessed antifungal activity towards a clinical strain of the human pathogenic yeast Candida albicans, an activity comparable with the one reported for the same protein extracted from maize seeds. Along with zeamatin, other PRPs were expressed: a 9 kDa lipid-transfer protein, a 26 kDa xylanase inhibitor and a new antifungal protein, PR-5. A fast, two-step chromatographic procedure was set up allowing the complete purification of the proteins considered, making this cell line a valuable system for the production of potential antifungal agents in a reliable and easy way.

Natural compounds and combination therapy in colorectal cancer treatment.

PubMed

Rejhová, A; Opattová, A; Čumová, A; Slíva, D; Vodička, P

2018-01-20

Colorectal cancer (CRC) therapy using conventional chemotherapeutics represents a considerable burden for the patient's organism because of high toxicity while the response is relatively low. Our review summarizes the findings about natural compounds as chemoprotective agents for decreasing risk of CRC. It also identifies natural compounds which possess anti-tumor effects of various characteristics, mainly in vitro on colorectal cell lines or in vivo studies on experimental models, but also in a few clinical trials. Many of natural compounds suppress proliferation by inducing cell cycle arrest or induce apoptosis of CRC cells resulting in the inhibition of tumor growth. A novel employment of natural substances is a so-called combination therapy - administration of two or more substances - conventional chemotherapeutics and a natural compound or more natural compounds at a time. Some natural compounds may sensitize to conventional cytotoxic therapy, reinforce the drug effective concentration, intensify the combined effect of both administered therapeutics or exert cytotoxic effects specifically on tumor cells. Moreover, combined therapy by targeting multiple signaling pathways, uses various mechanisms to reduce the development of resistance to antitumor drugs. The desired effect could be to diminish burden on the patient's organism by replacing part of the dose of a conventional chemotherapeutic with a natural substance with a defined effect. Many natural compounds are well tolerated by the patients and do not cause toxic effects even at high doses. Interaction of conventional chemotherapeutics with natural compounds introduces a new aspect in the research and therapy of cancer. It could be a promising approach to potentially achieve improvements, while minimizing of adverse effects associated with conventional chemotherapy. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Monotherapy versus combination therapy against carbapenem-resistant Gram-negative bacteria: A retrospective observational study.

PubMed

Ghafur, A; Devarajan, V; Raja, T; Easow, J; Raja, M A; Sreenivas, S; Ramakrishnan, B; Raman, S G; Devaprasad, D; Venkatachalam, B; Nimmagadda, R

2016-01-01

Colistin-based combination therapy (CCT) is extensively used to treat infections due to carbapenem-resistant Gram-negative bacteria (CRGNB). There are no data available from India on the usefulness of combination therapy, especially in the oncology setup. The aim of this study was to analyze the clinical effectiveness of CCT over monotherapy in patients with CRGNB. We conducted a retrospective, observational study of patients with CRGNB bloodstream infections in our oncology and bone marrow transplant center. Over a 3-year study period (2011-2014), we could identify 91 patients satisfying study criteria. There was no statistically significant difference in the 28-day mortality between monotherapy and combination therapy arms (mono n = 26, mortality 10 (38.5%); combination n = 65, mortality 28 (40%); P = 0.886). Neutropenic patients with Enterobacteriaceae bloodstream infections performed better with combination therapy (mono n = 7, mortality 6 (85.7%); combination therapy n = 22, mortality 8 (36.4%); P = 0.035). There was no significant difference in the 28-day mortality between the two treatment arms in other subgroups. Our study did not find CCT superior to colistin monotherapy in patients with CRGNB blood stream infections; except in the subgroup of neutropenic patients with Enterobacteriaceae bloodstream infections, where combination therapy performed better.

Antifungal Activity of Plasmacytoid Dendritic Cells and the Impact of Chronic HIV Infection.

PubMed

Maldonado, Samuel; Fitzgerald-Bocarsly, Patricia

2017-01-01

Due to the effectiveness of combined antiretroviral therapy, people living with HIV can control viral replication and live longer lifespans than ever. However, HIV-positive individuals still face challenges to their health and well-being, including dysregulation of the immune system resulting from years of chronic immune activation, as well as opportunistic infections from pathogenic fungi. This review focuses on one of the key players in HIV immunology, the plasmacytoid dendritic cell (pDC), which links the innate and adaptive immune response and is notable for being the body's most potent producer of type-I interferons (IFNs). During chronic HIV infection, the pDC compartment is greatly dysregulated, experiencing a substantial depletion in number and compromise in function. This immune dysregulation may leave patients further susceptible to opportunistic infections. This is especially important when considering a new role for pDCs currently emerging in the literature: in addition to their role in antiviral immunity, recent studies suggest that pDCs also play an important role in antifungal immunity. Supporting this new role, pDCs express C-type lectin receptors including dectin-1, dectin-2, dectin-3, and mannose receptor, and toll-like receptors-4 and -9 that are involved in recognition, signaling, and response to a wide variety of fungal pathogens, including Aspergillus fumigatus, Cryptococcus neoformans, Candida albicans , and Pneumocystis jirovecii . Accordingly, pDCs have been demonstrated to recognize and respond to certain pathogenic fungi, measured via activation, cytokine production, and fungistatic activity in vitro , while in vivo mouse models indicated a strikingly vital role for pDCs in survival against pulmonary Aspergillus challenge. Here, we discuss the role of the pDC compartment and the dysregulation it undergoes during chronic HIV infection, as well as what is known so far about the role and mechanisms of pDC antifungal activity.

Upfront triple combination therapy in pulmonary arterial hypertension: a pilot study.

PubMed

Sitbon, Olivier; Jaïs, Xavier; Savale, Laurent; Cottin, Vincent; Bergot, Emmanuel; Macari, Elise Artaud; Bouvaist, Hélène; Dauphin, Claire; Picard, François; Bulifon, Sophie; Montani, David; Humbert, Marc; Simonneau, Gérald

2014-06-01

Patients with severe pulmonary arterial hypertension (PAH) in New York Heart Association (NYHA) functional class (FC) III/IV have a poor prognosis, despite survival benefits being demonstrated with intravenous epoprostenol. In this pilot study, the efficacy and safety of a triple combination therapy regimen in patients with severe PAH was investigated. Data from newly diagnosed NYHA FC III/IV PAH patients (n=19) initiated on upfront triple combination therapy (intravenous epoprostenol, bosentan and sildenafil) were collected retrospectively from a prospective registry. Significant improvements in 6-min walk distance and haemodynamics were observed after 4 months' triple combination therapy in 18 patients (p<0.01); 17 patients had improved to NYHA FC I or II. One patient was not included in the month 4 assessment (due to an emergency lung transplant in month 3). At the final evaluation (mean ± sd 32 ± 19 months), all 18 patients had sustained clinical and haemodynamic improvement. Overall survival estimates for the triple combination cohort were 100% at 1, 2 and 3 years. Expected survival calculated from the French equation was 75% (95% CI 68-82%), 60% (95% CI 50-70%) and 49% (95% CI 38-60%) at 1, 2 and 3 years, respectively. This pilot study provides preliminary evidence of the long-term benefits of upfront triple combination therapy in patients with severe PAH. ©ERS 2014.

[Combination therapy of chronic bacterial prostatitis].

PubMed

Khryanin, A A; Reshetnikov, O V

2016-08-01

The article discusses the possible etiological factors in the development of chronic bacterial prostatitis. The authors presented a comparative long-term analysis of morbidity from non-viral sexually transmitted infections (STIs) in Russia. Against the background of general decline in STIs incidence, a significant percentage of them is made up by urogenital trichomoniasis. The findings substantiated the advantages of combination therapy (ornidazole and ofloxacin) for bacterial urinary tract infections.

Combination Therapy Strategies Against Multiple-Resistant Streptococcus Suis.

PubMed

Yu, Yang; Fang, Jin-Tao; Zheng, Mei; Zhang, Qing; Walsh, Timothy R; Liao, Xiao-Ping; Sun, Jian; Liu, Ya-Hong

2018-01-01

Streptococcus suis is a major swine pathogen, an emerging zoonotic agent responsible for meningitis, endocarditis and septicaemia followed by deafness in humans. The development of antimicrobial resistance in S. suis increases the risk for therapeutic failure in both animals and humans. In this study, we report the synergism of combination therapy against multi-resistant S. suis isolates from swine. Twelve antibiotic profiles were determined against 11 S. suis strains. To investigate their synergistic/antagonistic activity, checkerboard assay was performed for all the possible combinations. In-vitro killing curves and in-vivo treatment trials were used to confirm the synergistic activity of special combinations against S. suis dominant clones. In this study, 11 S. suis isolates were highly resistant to erythromycin, clindamycin, trimethoprim/sulfamethoxazole, and tetracycline with ratios of 80-100%, and the resistance percentages to enrofloxacin, florfenicol, and spectinomycin were ~50%. The checkerboard data identified two combination regimens, ampicillin plus apramycin and tiamulin plus spectinomycin which gave the greatest level of synergism against the S. suis strains. In-vitro kill-curves showed a bacterial reduction of over 3-logCFU with the use of combination treatments, whilst the application of mono-therapies achieve less than a 2-logCFU cell killing. In-vivo models confirm that administration of these two combinations significantly reduced the number of bacterial cells after 24 h of treatment. In conclusions, the combinations of ampicillin plus apramycin and tiamulin plus spectinomycin showed the greatest synergism and may be potential strategies for treatment of multi-resistant S. suis in animal.

Antifungal cyclic peptides from the marine sponge Microscleroderma herdmani

USDA-ARS?s Scientific Manuscript database

Screening natural product extracts from National Cancer Institute Open Repository for antifungal discovery afforded hits for bioassay-guided fractionation. Upon LC-MS analysis of column fractions with antifungal activities to generate information on chemical structure, two new cyclic hexapeptides, m...

Strong synergism of dexamethasone in combination with fluconazole against resistant Candida albicans mediated by inhibiting drug efflux and reducing virulence.

PubMed

Sun, Wenwen; Wang, Decai; Yu, Cuixiang; Huang, Xin; Li, Xiuyun; Sun, Shujuan

2017-09-01

Candida albicans is the most commonly isolated Candida spp. in the clinic and its resistance to fluconazole (FLC) has been emerging rapidly. Combination therapy may be a potentially effective approach to combat drug resistance. In this study, the combination antifungal effects of dexamethasone (DXM) and FLC against resistant C. albicans in vitro were assayed using minimum inhibitory concentrations (MICs), sessile MICs and time-kill curves. The in vivo efficacy of this drug combination was evaluated using a Galleria mellonella model by determining survival rate, fungal burden and histological damage. In addition, the impact of DXM on efflux pump activity was investigated using a rhodamine 6G assay. Expression of CDR1, CDR2 and MDR1 was determined by real-time quantitative PCR, and extracellular phospholipase activity was detected by the egg yolk agar method to reveal the potential synergistic mechanism. The results showed that DXM potentiates the antifungal effect of FLC against resistant C. albicans strains both in vitro and in vivo, and the synergistic mechanism is related to inhibiting the efflux of drugs and reducing the virulence of C. albicans. Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Effectiveness of cognitive behavioral therapy integrated with systematic desensitization, cognitive behavioral therapy combined with eye movement desensitization and reprocessing therapy, and cognitive behavioral therapy combined with virtual reality exposure therapy methods in the treatment of flight anxiety: a randomized trial.

PubMed

Triscari, Maria Teresa; Faraci, Palmira; Catalisano, Dario; D'Angelo, Valerio; Urso, Viviana

2015-01-01

The purpose of the research was to compare the effectiveness of the following treatment methods for fear of flying: cognitive behavioral therapy (CBT) integrated with systematic desensitization, CBT combined with eye movement desensitization and reprocessing therapy, and CBT combined with virtual reality exposure therapy. Overall, our findings have proven the efficacy of all interventions in reducing fear of flying in a pre- to post-treatment comparison. All groups showed a decrease in flight anxiety, suggesting the efficiency of all three treatments in reducing self-report measures of fear of flying. In particular, our results indicated significant improvements for the treated patients using all the treatment programs, as shown not only by test scores but also by participation in the post-treatment flight. Nevertheless, outcome measures maintained a significant effect at a 1-year follow-up. In conclusion, combining CBT with both the application of eye movement desensitization and reprocessing treatment and the virtual stimuli used to expose patients with aerophobia seemed as efficient as traditional cognitive behavioral treatments integrated with systematic desensitization.

Effectiveness of cognitive behavioral therapy integrated with systematic desensitization, cognitive behavioral therapy combined with eye movement desensitization and reprocessing therapy, and cognitive behavioral therapy combined with virtual reality exposure therapy methods in the treatment of flight anxiety: a randomized trial

PubMed Central

Triscari, Maria Teresa; Faraci, Palmira; Catalisano, Dario; D’Angelo, Valerio; Urso, Viviana

2015-01-01

The purpose of the research was to compare the effectiveness of the following treatment methods for fear of flying: cognitive behavioral therapy (CBT) integrated with systematic desensitization, CBT combined with eye movement desensitization and reprocessing therapy, and CBT combined with virtual reality exposure therapy. Overall, our findings have proven the efficacy of all interventions in reducing fear of flying in a pre- to post-treatment comparison. All groups showed a decrease in flight anxiety, suggesting the efficiency of all three treatments in reducing self-report measures of fear of flying. In particular, our results indicated significant improvements for the treated patients using all the treatment programs, as shown not only by test scores but also by participation in the post-treatment flight. Nevertheless, outcome measures maintained a significant effect at a 1-year follow-up. In conclusion, combining CBT with both the application of eye movement desensitization and reprocessing treatment and the virtual stimuli used to expose patients with aerophobia seemed as efficient as traditional cognitive behavioral treatments integrated with systematic desensitization. PMID:26504391

Combination Therapies for Traumatic Brain Injury: Retrospective Considerations

PubMed Central

Anderson, Gail; Atif, Fahim; Badaut, Jerome; Clark, Robert; Empey, Philip; Guseva, Maria; Hoane, Michael; Huh, Jimmy; Pauly, Jim; Raghupathi, Ramesh; Scheff, Stephen; Stein, Donald; Tang, Huiling; Hicks, Mona

2016-01-01

Abstract Patients enrolled in clinical trials for traumatic brain injury (TBI) may present with heterogeneous features over a range of injury severity, such as diffuse axonal injury, ischemia, edema, hemorrhage, oxidative damage, mitochondrial and metabolic dysfunction, excitotoxicity, inflammation, and other pathophysiological processes. To determine whether combination therapies might be more effective than monotherapy at attenuating moderate TBI or promoting recovery, the National Institutes of Health funded six preclinical studies in adult and immature male rats to evaluate promising acute treatments alone and in combination. Each of the studies had a solid rationale for its approach based on previous research, but only one reported significant improvements in long-term outcomes across a battery of behavioral tests. Four studies had equivocal results because of a lack of sensitivity of the outcome assessments. One study demonstrated worse results with the combination in comparison with monotherapies. While specific research findings are reported elsewhere, this article provides an overview of the study designs, insights, and recommendations for future research aimed at therapy development for TBI. PMID:25970337

Clinical translation of polymyxin-based combination therapy: Facts, challenges and future opportunities.

PubMed

Zhang, Xueli; Guo, Fengmei; Shao, Hua; Zheng, Xiao

2017-02-01

The emergence and spread of multidrug resistant Gram-negative bacteria has led to a resurgence in the clinical use of polymyxin antibiotics. However, the prevalence of polymyxin resistance is on the rise at an alarming rate, motivating the idea of combination therapy to sustain the revival of these "old" antibiotics. Although ample evidence in favor of combination therapy has emerged, it seems impracticable and confusing to find a promising combination from the diverse reports or gain adequate information on the efficacy and safety profile. With a stagnating discovery pipeline of novel antimicrobials, there is a clear need to fill the knowledge gaps in translating these basic research data to beneficial clinical practice. In this review, we examined the factors and ambiguities that stand as major hurdles in bringing polymyxin combination therapy to bedside care, highlighting the importance and urgency of incorporating translational research insights into areas of difficulty. We also discussed future research priorities that are essential to gather the necessary evidence and insights for promoting the best possible use of polymyxins in combination therapy. Copyright © 2016 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Steroid acne vs. Pityrosporum folliculitis: the incidence of Pityrosporum ovale and the effect of antifungal drugs in steroid acne.

PubMed

Yu, H J; Lee, S K; Son, S J; Kim, Y S; Yang, H Y; Kim, J H

1998-10-01

Steroid acne is a folliculitis that can result from systemic or topical administration of steroid, and has been described as showing a similar clinical picture to Pityrosporum folliculitis, but there have been few reports about the incidence of Pityrosporum ovale and the effect of antimycotic drugs in steroid acne and other acneiform eruptions. Our purpose was to describe the association between steroid acne and P. ovale, and to confirm the superior efficacy of oral antifungal drugs over anti-acne drugs in the treatment of steroid acne. The history, clinical features direct microscopy, histopathologic analysis, and therapeutic results of 125 cases with steroid acne or other acneiform eruptions were described and compared. Over 80% of patients with acneiform eruption receiving systemic steroid revealed significant numbers of P. ovale in the lesional follicle. Furthermore, oral antifungal drug (itraconazole) showed significantly better clinical and mycologic effects than any other group of medications used in this study. Steroid acne and other acneiform eruptions showing discrete follicular papules and/or pustules localized to the upper trunk and acneiform facial skin lesions associated with multiple acneiform lesions on the body in the summer period should be suspected as Pityrosporum folliculitis. In addition, oral antifungal drugs recommended for Pityrosporum folliculitis; however, it will require a larger case-control study to confirm the superiority of antifungal therapy over anti-acne treatment.

Aspergillus--classification and antifungal susceptibilities.

PubMed

Buzina, Walter

2013-01-01

Aspergillus is one of the most important fungal genera for the man, for its industrial use, its ability to spoil food and not least its medical impact as cause of a variety of diseases. Currently hundreds of species of Aspergillus are known; nearly fifty of them are able to cause infections in humans and animals. Recently, the genus Aspergillus is subdivided into 8 subgenera and 22 sections. The spectrum of diseases caused by Aspergillus species varies from superficial cutaneous to invasive and systemic infections. All species of Aspergillus investigated so far are resistant against the antifungals fluconazole and 5-fluorocytosine, the range of susceptibilities to currently available antifungals is discussed in this paper.

Fixed-dose combination therapy for the prevention of cardiovascular disease

PubMed Central

de Cates, Angharad N; Farr, Matthew RB; Rees, Karen; Casas, Juan P; Huffman, Mark

2014-01-01

This is the protocol for a review and there is no abstract. The objectives are as follows: To determine the effectiveness of fixed-dose combination therapy on optimising CVD risk factors and reducing CVD fatal and non-fatal events for both primary and secondary prevention of CVD. Details of CVD events and risk factors included are listed in the methods. We will also determine any adverse events associated with taking fixed-dose combination therapy. This will include studies conducted in both developed and developing regions of the world. PMID:25267903

Terbinafine in Combination with Other Antifungal Agents for Treatment of Resistant or Refractory Mycoses: Investigating Optimal Dosing Regimens Using a Physiologically Based Pharmacokinetic Model

PubMed Central

Dolton, Michael J.; Perera, Vidya; Pont, Lisa G.

2014-01-01

Terbinafine is increasingly used in combination with other antifungal agents to treat resistant or refractory mycoses due to synergistic in vitro antifungal activity; high doses are commonly used, but limited data are available on systemic exposure, and no assessment of pharmacodynamic target attainment has been made. Using a physiologically based pharmacokinetic (PBPK) model for terbinafine, this study aimed to predict total and unbound terbinafine concentrations in plasma with a range of high-dose regimens and also calculate predicted pharmacodynamic parameters for terbinafine. Predicted terbinafine concentrations accumulated significantly during the first 28 days of treatment; the area under the concentration-time curve (AUC)/MIC ratios and AUC for the free, unbound fraction (fAUC)/MIC ratios increased by 54 to 62% on day 7 of treatment and by 80 to 92% on day 28 compared to day 1, depending on the dose regimen. Of the high-dose regimens investigated, 500 mg of terbinafine taken every 12 h provided the highest systemic exposure; on day 7 of treatment, the predicted AUC, maximum concentration (Cmax), and minimum concentration (Cmin) were approximately 4-fold, 1.9-fold, and 4.4-fold higher than with a standard-dose regimen of 250 mg once daily. Close agreement was seen between the concentrations predicted by the PBPK model and the observed concentrations, indicating good predictive performance. This study provides the first report of predicted terbinafine exposure in plasma with a range of high-dose regimens. PMID:24126579

Terbinafine in combination with other antifungal agents for treatment of resistant or refractory mycoses: investigating optimal dosing regimens using a physiologically based pharmacokinetic model.

PubMed

Dolton, Michael J; Perera, Vidya; Pont, Lisa G; McLachlan, Andrew J

2014-01-01

Terbinafine is increasingly used in combination with other antifungal agents to treat resistant or refractory mycoses due to synergistic in vitro antifungal activity; high doses are commonly used, but limited data are available on systemic exposure, and no assessment of pharmacodynamic target attainment has been made. Using a physiologically based pharmacokinetic (PBPK) model for terbinafine, this study aimed to predict total and unbound terbinafine concentrations in plasma with a range of high-dose regimens and also calculate predicted pharmacodynamic parameters for terbinafine. Predicted terbinafine concentrations accumulated significantly during the first 28 days of treatment; the area under the concentration-time curve (AUC)/MIC ratios and AUC for the free, unbound fraction (fAUC)/MIC ratios increased by 54 to 62% on day 7 of treatment and by 80 to 92% on day 28 compared to day 1, depending on the dose regimen. Of the high-dose regimens investigated, 500 mg of terbinafine taken every 12 h provided the highest systemic exposure; on day 7 of treatment, the predicted AUC, maximum concentration (Cmax), and minimum concentration (Cmin) were approximately 4-fold, 1.9-fold, and 4.4-fold higher than with a standard-dose regimen of 250 mg once daily. Close agreement was seen between the concentrations predicted by the PBPK model and the observed concentrations, indicating good predictive performance. This study provides the first report of predicted terbinafine exposure in plasma with a range of high-dose regimens.

Orthodontics-surgical combination therapy for Class III skeletal malocclusion

PubMed Central

Ravi, M. S.; Shetty, Nillan K.; Prasad, Rajendra B.

2012-01-01

The correction of skeletal Class III malocclusion with severe mandibular prognathism in an adult individual requires surgical and Othodontic combination therapy. The inter disciplinary approach is the treatment of choice in most of the skeletal malocclusions. A case report of an adult individual with Class III malocclusion, having mandibular excess in sagittal and vertical plane and treated with orthodontics,, bilateral sagittal split osteotomy and Le – Forte I osteotomy for the correction of skeletal, dental and soft tissue discrepancies is herewith presented. The surgical–orthodontic combination therapy has resulted in near–normal skeletal, dental and soft tissue relationship, with marked improvement in the facial esthetics in turn, has helped the patient to improve the self-confidence level. PMID:22557903

Functionalised isocoumarins as antifungal compounds: Synthesis and biological studies.

PubMed

Simic, Milena; Paunovic, Nikola; Boric, Ivan; Randjelovic, Jelena; Vojnovic, Sandra; Nikodinovic-Runic, Jasmina; Pekmezovic, Marina; Savic, Vladimir

2016-01-01

A series of novel 3-substituted isocoumarins was prepared via Pd-catalysed coupling processes and screened in vitro for antifungal activity against Candida species. The study revealed antifungal potential of isocoumarins possessing the azole substituents, which, in some cases, showed biological properties equal to those of clinically used voriconazole. Selected compounds were also screened against voriconazole resistant Candida krusei 6258 and a clinical isolate Candida parapsilosis CA-27. Although the activity against these targets needs to be improved further, the results emphasise additional potential of this new class of antifungal compounds. Copyright © 2015 Elsevier Ltd. All rights reserved.

Keratitis-associated fungi form biofilms with reduced antifungal drug susceptibility.

PubMed

Zhang, Xiaoyan; Sun, Xuguang; Wang, Zhiqun; Zhang, Yang; Hou, Wenbo

2012-11-21

To investigate the biofilm-forming capacity of Fusarium solani, Cladosporium sphaerospermum, and Acremonium implicatum, and the activities of antifungal agents against the three keratitis-associated fungi. The architecture of biofilms was analyzed using scanning electron microscopy and confocal scanning laser microscopy (CSLM). Susceptibility against six antifungal drugs was measured using the CLSI M38-A method and XTT reduction assay. Time course analyses of CSLM revealed that biofilm formation occurred in an organized fashion through four distinct developmental phases: adhesion, germling formation, microcolony formation, and biofilm maturation. Scanning electron microscopy revealed that mature biofilms displayed a complex three-dimensional structure, consisting of coordinated network of hyphal structures glued by the extracellular matrix (ECM). The antifungal susceptibility testing demonstrated a time-dependent decrease in efficacy for all six antifungal agents as the complexity of fungal hyphal structures developed. Natamycin (NAT), amphotericin B (AMB), and NAT were the most effective against F. solani, C. sphaerospermum, and A. implicatum biofilm, respectively. Corneal isolates of F. solani, C. sphaerospermum, and A. implicatum could produce biofilms that were resistant to antifungal agents in vitro.

Immune Effects of Chemotherapy, Radiation, and Targeted Therapy and Opportunities for Combination With Immunotherapy.

PubMed

Wargo, Jennifer A; Reuben, Alexandre; Cooper, Zachary A; Oh, Kevin S; Sullivan, Ryan J

2015-08-01

There have been significant advances in cancer treatment over the past several years through the use of chemotherapy, radiation therapy, molecularly targeted therapy, and immunotherapy. Despite these advances, treatments such as monotherapy or monomodality have significant limitations. There is increasing interest in using these strategies in combination; however, it is not completely clear how best to incorporate molecularly targeted and immune-targeted therapies into combination regimens. This is particularly pertinent when considering combinations with immunotherapy, as other types of therapy may have significant impact on host immunity, the tumor microenvironment, or both. Thus, the influence of chemotherapy, radiation therapy, and molecularly targeted therapy on the host anti-tumor immune response and the host anti-host response (ie, autoimmune toxicity) must be taken into consideration when designing immunotherapy-based combination regimens. We present data related to many of these combination approaches in the context of investigations in patients with melanoma and discuss their potential relationship to management of patients with other tumor types. Importantly, we also highlight challenges of these approaches and emphasize the need for continued translational research. Copyright © 2015 Elsevier Inc. All rights reserved.

Complications of hematopoietic stem transplantation: Fungal infections.

PubMed

Omrani, Ali S; Almaghrabi, Reem S

2017-12-01

Patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) are at increased risk of invasive fungal infections, especially during the early neutropenic phase and severe graft-versus-host disease. Mold-active prophylaxis should be limited to the highest risk groups. Empiric antifungal therapy for HSCT with persistent febrile neutropenia is associated with unacceptable response rates, unnecessary antifungal therapy, increased risk of toxicity, and inflated costs. Empiric therapy should not be a substitute for detailed work up to identify the cause of fever in such patients. The improved diagnostic performance of serum biomarkers such as galactomannan and β-D-glucan, as well as polymerase chain reaction assays has allowed the development of diagnostic-driven antifungal therapy strategies for high risk patients. Diagnostic-driven approaches have resulted in reduced unnecessary antifungal exposure, improved diagnosis of invasive fungal disease, and reduced costs without increased risk of mortality. The appropriateness of diagnostic-driven antifungal strategy for individual HSCT centers depends on the availability and turnaround times for diagnostics, multidisciplinary expertise, and the local epidemiology of invasive fungal infections. Echinocandins are the treatment of choice for invasive candidiasis in most HSCT recipients. Fluconazole may be used for the treatment of invasive candidiasis in hemodynamically stable patients with no prior azole exposure. The primary treatment of choice for invasive aspergillosis is voriconazole. Alternatives include isavuconazole and lipid formulations of amphotericin. Currently available evidence does not support routine primary combination antifungal therapy for invasive aspergillosis. However, combination salvage antifungal therapy may be considered in selected patients. Therapeutic drug monitoring is recommended for the majority of HSCT recipients on itraconazole, posaconazole, or voriconazole. Copyright © 2017

Nicotiana alata Defensin Chimeras Reveal Differences in the Mechanism of Fungal and Tumor Cell Killing and an Enhanced Antifungal Variant

PubMed Central

Payne, Jennifer A. E.; Hayes, Brigitte M. E.; Durek, Thomas; Craik, David J.; Shafee, Thomas M. A.; Poon, Ivan K. H.; Hulett, Mark D.; van der Weerden, Nicole L.

2016-01-01

The plant defensin NaD1 is a potent antifungal molecule that also targets tumor cells with a high efficiency. We examined the features of NaD1 that contribute to these two activities by producing a series of chimeras with NaD2, a defensin that has relatively poor activity against fungi and no activity against tumor cells. All plant defensins have a common tertiary structure known as a cysteine-stabilized α-β motif which consists of an α helix and a triple-stranded β-sheet stabilized by four disulfide bonds. The chimeras were produced by replacing loops 1 to 7, the sequences between each of the conserved cysteine residues on NaD1, with the corresponding loops from NaD2. The loop 5 swap replaced the sequence motif (SKILRR) that mediates tight binding with phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] and is essential for the potent cytotoxic effect of NaD1 on tumor cells. Consistent with previous reports, there was a strong correlation between PI(4,5)P2 binding and the tumor cell killing activity of all of the chimeras. However, this correlation did not extend to antifungal activity. Some of the loop swap chimeras were efficient antifungal molecules, even though they bound poorly to PI(4,5)P2, suggesting that additional mechanisms operate against fungal cells. Unexpectedly, the loop 1B swap chimera was 10 times more active than NaD1 against filamentous fungi. This led to the conclusion that defensin loops have evolved as modular components that combine to make antifungal molecules with variable mechanisms of action and that artificial combinations of loops can increase antifungal activity compared to that of the natural variants. PMID:27503651

Cryptic antifungal compounds active by synergism with polyene antibiotics.

PubMed

Kinoshita, Hiroshi; Yoshioka, Mariko; Ihara, Fumio; Nihira, Takuya

2016-04-01

The majority of antifungal compounds reported so far target the cell wall or cell membrane of fungi, suggesting that other types of antibiotics cannot exert their activity because they cannot penetrate into the cells. Therefore, if the permeability of the cell membrane could be enhanced, many antibiotics might be found to have antifungal activity. We here used the polyene antibiotic nystatin, which binds to ergosterol and forms pores at the cell membrane, to enhance the cellular permeability. In the presence of nystatin, many culture extracts from entomopathogenic fungi displayed antifungal activity. Among all the active extracts, two active components were purified and identified as helvolic acid and terramide A. Because the minimum inhibitory concentration of either compound was reduced four-fold in the presence of nystatin, it can be concluded that this screening method is useful for detecting novel antifungal activity. Copyright © 2015 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

Evaluation of the Efficacy of Combined Therapy of Methotrexate and Etanercept versus Methotrexate as a Mono-Therapy.

PubMed

Rexhepi, Sylejman; Rexhepi, Mjellma; Rexhepi, Blerta; Sahatçiu-Meka, Vjollca; Mahmutaj, Vigan

2018-05-20

This study aims to evaluate the efficacy of Methotrexate (MTX) alone and combined therapy with Etanercept (ETN) and Methotrexate in patients with active rheumatoid arthritis (RA). In the randomised control study, conducted in the period from March 2014 until March 2016, we evaluated the efficacy of the treatment of patients with RA with MTX as monotherapy and combination treatment with MTX and ETN. In the Clinic of Rheumatology in Prishtina, 90 adult patients with RA were treated in combination with ETN (doses of 50 mg subcutaneously/weekly), with oral MTX (doses up to 20 mg weekly), and MTX alone (doses up to 20 mg weekly) during this period of two years. Clinical response was assessed using European League against Rheumatism (EULAR)/American College of Rheumatology (ACR) Criteria and the Disease Activity Score (DAS28). Radiographic changes were measured in the beginning and at the end of the study using Larsen's method. Of the cohort groups of 90 patients, mean age of 55.63, 15 patients, (16.6 %) were treated with combined therapy (ETN plus MTX) and 75 patients (83.3%) with monotherapy (MTX). After two years of treatment the group with combined therapy resulted with improvement of acute phase reactants as erythrocyte sedimentation rate (ESR) for the first hour (41.1 vs. 10.3 mm/hour) and C - reactive protein (CRP) (40.8 vs. 6 mg/liter), and compared to the group treated with monotherapy, there were no significant changes (ESR: 45.7 vs 34.3 mm/hour; CRP: 48 vs 24 mg/liter). Before the treatment, the severity of the disease was high, wherein the group with combined therapy DAS28 was 5.32, compared to the monotherapy group whom DAS28 was 5.90. After 2 years of treatment, we had significant changes in the results of DAS28, wherein the group treated with ETN plus MTX DAS28 was 2.12 ± 0.15, while in the group of patients treated with MTX DAS28 were 3.75 ± 0.39 (t = 13.03; df = 58; p < 0.0001). The group with combined therapy showed no evidence of radiographic

Nanoparticle-mediated combination chemotherapy and photodynamic therapy overcomes tumor drug resistance.

PubMed

Khdair, Ayman; Chen, Di; Patil, Yogesh; Ma, Linan; Dou, Q Ping; Shekhar, Malathy P V; Panyam, Jayanth

2010-01-25

Tumor drug resistance significantly limits the success of chemotherapy in the clinic. Tumor cells utilize multiple mechanisms to prevent the accumulation of anticancer drugs at their intracellular site of action. In this study, we investigated the anticancer efficacy of doxorubicin in combination with photodynamic therapy using methylene blue in a drug-resistant mouse tumor model. Surfactant-polymer hybrid nanoparticles formulated using an anionic surfactant, Aerosol-OT (AOT), and a naturally occurring polysaccharide polymer, sodium alginate, were used for synchronized delivery of the two drugs. Balb/c mice bearing syngeneic JC tumors (mammary adenocarcinoma) were used as a drug-resistant tumor model. Nanoparticle-mediated combination therapy significantly inhibited tumor growth and improved animal survival. Nanoparticle-mediated combination treatment resulted in enhanced tumor accumulation of both doxorubicin and methylene blue, significant inhibition of tumor cell proliferation, and increased induction of apoptosis. These data suggest that nanoparticle-mediated combination chemotherapy and photodynamic therapy using doxorubicin and methylene blue has significant therapeutic potential against drug-resistant tumors. Copyright 2009 Elsevier B.V. All rights reserved.

High-throughput synergy screening identifies microbial metabolites as combination agents for the treatment of fungal infections

PubMed Central

Zhang, Lixin; Yan, Kezhi; Zhang, Yu; Huang, Ren; Bian, Jiang; Zheng, Chuansen; Sun, Haixiang; Chen, Zhihui; Sun, Nuo; An, Rong; Min, Fangui; Zhao, Weibo; Zhuo, Ying; You, Jianlan; Song, Yongjie; Yu, Zhenyan; Liu, Zhiheng; Yang, Keqian; Gao, Hong; Dai, Huanqin; Zhang, Xiaoli; Wang, Jian; Fu, Chengzhang; Pei, Gang; Liu, Jintao; Zhang, Si; Goodfellow, Michael; Jiang, Yuanying; Kuai, Jun; Zhou, Guochun; Chen, Xiaoping

2007-01-01

The high mortality rate of immunocompromised patients with fungal infections and the limited availability of highly efficacious and safe agents demand the development of new antifungal therapeutics. To rapidly discover such agents, we developed a high-throughput synergy screening (HTSS) strategy for novel microbial natural products. Specifically, a microbial natural product library was screened for hits that synergize the effect of a low dosage of ketoconazole (KTC) that alone shows little detectable fungicidal activity. Through screening of ≈20,000 microbial extracts, 12 hits were identified with broad-spectrum antifungal activity. Seven of them showed little cytotoxicity against human hepatoma cells. Fractionation of the active extracts revealed beauvericin (BEA) as the most potent component, because it dramatically synergized KTC activity against diverse fungal pathogens by a checkerboard assay. Significantly, in our immunocompromised mouse model, combinations of BEA (0.5 mg/kg) and KTC (0.5 mg/kg) prolonged survival of the host infected with Candida parapsilosis and reduced fungal colony counts in animal organs including kidneys, lungs, and brains. Such an effect was not achieved even with the high dose of 50 mg/kg KTC. These data support synergism between BEA and KTC and thereby a prospective strategy for antifungal therapy. PMID:17360571

Using photodynamic therapy to estimate effectiveness of innovative combined diclofenac and tazaroten therapy of disseminated actinic keratosis.

PubMed

Osiecka, Beata J; Jurczyszyn, Kamil; Nockowski, Piotr; Lipinski, Artur; Sieja, Agnieszka; Ziółkowski, Piotr

2015-01-01

Early diagnosis and therapy of precancerous lesions and malignant tumors belong to the most challenging tasks in modern medicine. Photodynamic diagnosis can help diagnose both precancerous lesions and early carcinoma. Actinic keratosis (AK) is the most common precancerous lesion of the skin. The available data show a high effectiveness of diclofenac in treating multifocal AK. We report a case of a 52-year-old woman who complained of multiple disseminated AK lesions predominantly on the lower limbs and trunk with a significant exacerbation within the last 6 months. Due to the spreading of disease and a high number of AK foci, as well as technical problems with visiting the hospital (PDT Laboratory), photodynamic therapy was not applied. The patient was treated for 2 months with a combination of local administration of 3% diclofenac and 0.1% tazaroten and 3% diclofenac only as a half side (left-right) comparison. The effects of therapy were later clinically evaluated and verified by means of photodynamic diagnosis (PDD) directly after therapy and at a follow-up examination 3 months later. The evaluation of treatment was blinded. Treatment with diclofenac only on the right side of the body resulted in clearing of 55% of all treated lesions, which increased to 60% three months after finishing therapy. On the left side of the body, where combined therapy (diclofenac 2 times daily on uneven dates and diclofenac once a day + tazaroten once a day on even dates) was used, 77.5% pathologic lesions disappeared, but this did not increase at follow up. The treatment of multifocal, disseminated AK is a difficult task and also burdensome for the patient due to side effects like scarring or burning and itching which occur during most therapies. Combined therapy with diclofenac and tazaroten supported by PDD may improve the effects of routine treatment of AK.

Use of a modified hair strand test to assess the antifungal activity kinetics of dog hair after a 2% climbazole shampoo application.

PubMed

Petit, Jean Yanique; Cavana, Paola; Thoumire, Sandra; Guillot, Jacques; Perrot, Sébastien

2016-06-01

The "hair strand test" was first developed as a model to evaluate the antifungal activity of antidandruff shampoos. To assess the residual activity of an antifungal shampoo on the hair shafts of dogs after a single application, followed by bathing with a physiological shampoo one month later. Six beagles (two males and four females) from a research colony. Dogs were bathed with a 2% climbazole shampoo. Hairs were collected before application of the shampoo and at scheduled intervals for 30 days after treatment. A physiological shampoo was then applied to all dogs and hairs were collected following the same schedule. The inhibition zone around the hair shafts was measured after incubation on Sabouraud's dextrose agar plates streaked with three Malassezia pachydermatis strains. Inhibition zones around hairs collected from dogs bathed with 2% climbazole shampoo were significantly larger than those around hairs collected before shampooing at all time points (P = 0.003). An increase in the width of the inhibition zones around climbazole treated hairs was observed following physiological shampoo on Day 30 (P = 0.005). No significant differences were observed between Malassezia pachydermatis isolates (P = 0.571). No inhibition zones were seen around the hairs of dogs bathed with physiological shampoo only. The modified hair strand test is useful for the assessment of residual antifungal activity on animal hairs. Use of a physiological shampoo following antifungal shampoo therapy may increase the efficacy of the antifungal product for the control of Malassezia overgrowth. © 2016 ESVD and ACVD.

Sensitivity of Candida albicans to essential oils: are they an alternative to antifungal agents?

PubMed

Bona, E; Cantamessa, S; Pavan, M; Novello, G; Massa, N; Rocchetti, A; Berta, G; Gamalero, E

2016-12-01

Candida albicans is an important opportunistic pathogen, responsible for the majority of yeast infections in humans. Essential oils, extracted from aromatic plants, are well-known antimicrobial agents, characterized by a broad spectrum of activities, including antifungal properties. The aim of this work was to assess the sensitivity of 30 different vaginal isolated strains of C. albicans to 12 essential oils, compared to the three main used drugs (clotrimazole, fluconazole and itraconazole). Thirty strains of C. albicans were isolated from vaginal swab on CHROMagar ™ Candida. The agar disc diffusion method was employed to determine the sensitivity to the essential oils. The antifungal activity of the essential oils and antifungal drugs (clotrimazole, itraconazole and fluconazole) were investigated using a microdilution method. Transmission and scanning electron microscopy analyses were performed to get a deep inside on cellular damages. Mint, basil, lavender, tea tree oil, winter savory and oregano essential oils inhibited both the growth and the activity of C. albicans more efficiently than clotrimazole. Damages induced by essential oils at the cellular level were stronger than those caused by clotrimazole. Candida albicans is more sensitive to different essential oils compared to the main used drugs. Moreover, the essential oil affected mainly the cell wall and the membranes of the yeast. The results of this work support the research for new alternatives or complementary therapies against vaginal candidiasis. © 2016 The Society for Applied Microbiology.

An in vitro study of antifungal drug susceptibility of Candida species isolated from human immunodeficiency virus seropositive and human immunodeficiency virus seronegative individuals in Lucknow population Uttar Pradesh.

PubMed

Dar, Mohammad Shafi; Sreedar, Gadiputi; Shukla, Abhilasha; Gupta, Prashant; Rehan, Ahmad Danish; George, Jiji

2015-01-01

Candidiasis is the most common opportunistic infection in human immunodeficiency virus (HIV) seropositive patients, starting from asymptomatic colonization to pathogenic forms and gradual colonization of non-albicans in patients with advanced immunosuppression leads to resistance for azole group of antifungal drugs with high rate of morbidity and mortality. To isolate the Candida species and determine of antifungal drug susceptibility against fluconazole, itraconazole, nystatin, amphotericin B, and clotrimazolein HIV seropositive and control individuals, with or without clinical oropharyngeal candidiasis (OPC). Includes samples from faucial region of 70 subjects with and without clinical candidiasis in HIV seropositive and controls were aseptically inoculated onto Sabaraud's Dextrose Agar media and yeasts were identified for the specific species by Corn Meal Agar, sugar fermentation and heat tolerance tests. Antifungal drug susceptibility of the isolated species was done against above-mentioned drugs by E-test and disc diffusion method. The commonly isolated species in HIV seropositive and controls were Candida albicans, Candida glabrata and Candida tropicalis Candida guilliermondii and Candida dubliniensis isolated only in HIV seropositive patients. Susceptibility against selected antifungal drugs was observed more in HIV-negative individuals whereas susceptible dose-dependent and resistance were predominant in HIV-positive patients. Resistance is the major problem in the therapy of OPC, especially in HIV seropositive patients due to aggressive and prolonged use of antifungal agents, therefore, our study emphasizes the need for antifungal drug susceptibility testing whenever antifungal treatment is desired, especially in HIV-infected subjects.

Management of pulmonary arterial hypertension with a focus on combination therapies.

PubMed

Benza, Raymond L; Park, Myung H; Keogh, Anne; Girgis, Reda E

2007-05-01

Pulmonary arterial hypertension (PAH) is a rare but frequently fatal condition marked by vasoconstriction and vascular remodeling within small pulmonary arteries. The pathobiology of PAH involves imbalances in a multitude of endogenous mediators, which promote aberrant cellular growth, vasoconstriction and hemostasis within the pulmonary vascular tree. The mechanisms promoting these pathologic effects are complex. This complexity is highlighted by the many overlapping secondary messenger systems through which these mediators work. In light of this natural redundancy, it is not surprising that many of the drugs used to treat PAH, which have shown short-term efficacy, fall "short of the mark" in reversing or halting the progression of this disease in the long run. This very redundancy in pathways makes the case for the use of combination of drugs with differing mechanisms of action to treat PAH. Similar to what is now accepted as the standard of care for the treatment of cancer and left ventricular dysfunction, combination therapy has the greatest promise for inducing the most complete vascular remodeling of the pulmonary vasculature by "shutting down" as many of these pathologic pathways as possible. Combination therapies involving existing therapies or new agents with improved pharmacokinetic and/or pharmacodynamic properties represent an emerging clinical paradigm for patients with sub-optimally managed disease. As emerging data in this field of therapy comes to fruition, further reductions in the morbidity and mortality associated with PAH will manifest. The goal of this report is to review the philosophy of combination therapy and present the available data in this area of study.

LC-MS and 1H NMR as an improved dereplication tool to identify antifungal diterpenoids from Sagittaria latifolia

USDA-ARS?s Scientific Manuscript database

A dereplication strategy using a combination of liquid chromatography-mass spectrometry (LC-MS) and proton nuclear magnetic resonance spectroscopy (1H NMR) to facilitate compound identification towards antifungal natural product discovery is presented. This analytical approach takes advantage of th...

[Clinical study of cervical spondylotic radiculopathy treated with massage therapy combined with Magnetic sticking therapy at the auricular points and the cost comparison].

PubMed

Wang, Saina; Sheng, Feng; Pan, Yunhua; Xu, Feng; Wang, Zhichao; Cheng, Lei

2015-08-01

To compare the clinical efficacy on cervical spondylotic radiculopathy between the combined therapy of massage and magnetic-sticking at the auricular points and the simple massage therapy, and conduct the health economics evaluation. Seventy-two patients of cervical spondylotic radiculopathy were randomized into a combined therapy group, and a simple massage group, 36 cases in each one. Finally, 35 cases and 34 cases were met the inclusive criteria in the corresponding groups separately. In the combined therapy group, the massage therapy and the magnetic sticking therapy at auricular points were combined in the treatment. Massage therapy was mainly applied to Fengchi (GB 20), Jianjing (GB 21), Jianwaishu (SI 14), Jianyu (LI 15) and Quchi (LI 11). The main auricular points for magnetic sticking pressure were Jingzhui (AH13), Gan (On12) Shen (CO10), Shenmen (TF4), Pizhixia (AT4). In the simple massage group, the simple massage therapy was given, the massage parts and methods were the same as those in the combined therapy group. The treatment was given once every two days, three times a week, for 4 weeks totally. The cervical spondylosis effect scale and the simplified McGill pain questionnaire were adopted to observe the improvements in the clinical symptoms, clinical examination, daily life movement, superficial muscular pain in the neck and the health economics cost in the patients of the two groups. The effect was evaluated in the two groups. The effective rate and the clinical curative rate in the combined therapy group were better than those in the control group [100. 0% (35/35) vs 85. 3% (29/34), 42. 9% (15/35) vs 17. 6% (6/34), both P<0. 05]. The scores of the spontaneous symptoms, clinical examnation, daily life movement and superficialmuscular pain in the neck were improved apparently after treatment as compared with those before treatment in the patients of the two groups (all P<0. 001). In terms of the improvements in the spontaneous symptoms, clinical

Biotechnologically relevant enzymes and proteins. Antifungal mechanism of the Aspergillus giganteus AFP against the rice blast fungus Magnaporthe grisea.

PubMed

Moreno, Ana Beatriz; Martínez Del Pozo, Alvaro; San Segundo, Blanca

2006-10-01

The mold Aspergillus giganteus produces a basic, low molecular weight protein showing antifungal properties against economically important plant pathogens, the AFP (Antifungal Protein). In this study, we investigated the mechanisms by which AFP exerts its antifungal activity against Magnaporthe grisea. M. grisea is the causal agent of rice blast, one of the most devastating diseases of cultivated rice worldwide. AFP was purified from the extracellular medium of A. giganteus cultures. The AFP protein was found to induce membrane permeabilization in M. grisea cells. Electron microscopy studies revealed severe cellular degradation and damage of plasma membranes in AFP-treated fungal cells. AFP however failed to induce membrane permeabilization on rice or human HeLa cells. Furthermore, AFP enters the fungal cell and targets to the nucleus, as revealed by co-localization experiments of Alexa-labeled AFP with the SYTOX Green dye. Finally, AFP binds to nucleic acids, including M. grisea DNA. Our results suggest that the combination of fungal cell permeabilization, cell-penetrating ability and nucleic acid-binding activity of AFP determines its potent antifungal activity against M. grisea. These results are discussed in relation to the potential of the AFP protein to enhance crop protection against fungal diseases.

Ethical hot spots of combined individual and group therapy: applying four ethical systems.

PubMed

Brabender, Virginia M; Fallon, April

2009-01-01

Abstract Combined therapy presents ethical quandaries that occur in individual psychotherapy and group psychotherapy, and dilemmas specifically associated with their integration. This paper examines two types of ethical frameworks (a classical principle-based framework and a set of context-based frameworks) for addressing the ethical hot spots of combined therapy: self-referral, transfer of information, and termination. The principle-based approach enables the practitioner to see what core values may be served or violated by different courses of action in combined therapy dilemmas. Yet, the therapist is more likely to do justice to the complexity and richness of the combined therapy situation by supplementing a principle analysis with three additional ethical frameworks. These approaches are: virtue ethics, feminist ethics, and casuistry. An analysis of three vignettes illustrates how these contrasting ethical models not only expand the range of features to which the therapist attends but also the array of solutions the therapist generates.

Synthesis of natural acylphloroglucinol-based antifungal compounds against Cryptococcus species

USDA-ARS?s Scientific Manuscript database

Thirty-five analogs of naturally occurring acylphloroglucinols were designed and synthesized to identify antifungal compounds against Cryptococcus spp. that causes the life-threatening disseminated cryptococcosis. In vitro antifungal testing showed that 17 compounds were active against C. neoformans...

Alginate Oligosaccharides Inhibit Fungal Cell Growth and Potentiate the Activity of Antifungals against Candida and Aspergillus spp

PubMed Central

Tøndervik, Anne; Sletta, Håvard; Klinkenberg, Geir; Emanuel, Charlotte; Powell, Lydia C.; Pritchard, Manon F.; Khan, Saira; Craine, Kieron M.; Onsøyen, Edvar; Rye, Phil D.; Wright, Chris; Thomas, David W.; Hill, Katja E.

2014-01-01

The oligosaccharide OligoG, an alginate derived from seaweed, has been shown to have anti-bacterial and anti-biofilm properties and potentiates the activity of selected antibiotics against multi-drug resistant bacteria. The ability of OligoG to perturb fungal growth and potentiate conventional antifungal agents was evaluated using a range of pathogenic fungal strains. Candida (n = 11) and Aspergillus (n = 3) spp. were tested using germ tube assays, LIVE/DEAD staining, scanning electron microscopy (SEM), atomic force microscopy (AFM) and high-throughput minimum inhibition concentration assays (MICs). In general, the strains tested showed a significant dose-dependent reduction in cell growth at ≥6% OligoG as measured by optical density (OD600; P<0.05). OligoG (>0.5%) also showed a significant inhibitory effect on hyphal growth in germ tube assays, although strain-dependent variations in efficacy were observed (P<0.05). SEM and AFM both showed that OligoG (≥2%) markedly disrupted fungal biofilm formation, both alone, and in combination with fluconazole. Cell surface roughness was also significantly increased by the combination treatment (P<0.001). High-throughput robotic MIC screening demonstrated the potentiating effects of OligoG (2, 6, 10%) with nystatin, amphotericin B, fluconazole, miconazole, voriconazole or terbinafine with the test strains. Potentiating effects were observed for the Aspergillus strains with all six antifungal agents, with an up to 16-fold (nystatin) reduction in MIC. Similarly, all the Candida spp. showed potentiation with nystatin (up to 16-fold) and fluconazole (up to 8-fold). These findings demonstrate the antifungal properties of OligoG and suggest a potential role in the management of fungal infections and possible reduction of antifungal toxicity. PMID:25409186

Natural Killer Cells in Antifungal Immunity.

PubMed

Schmidt, Stanislaw; Tramsen, Lars; Lehrnbecher, Thomas

2017-01-01

Invasive fungal infections are still an important cause of morbidity and mortality in immunocompromised patients such as patients suffering from hematological malignancies or patients undergoing hematopoietic stem cell transplantion. In addition, other populations such as human immunodeficiency virus-patients are at higher risk for invasive fungal infection. Despite the availability of new antifungal compounds and better supportive care measures, the fatality rate of invasive fungal infection remained unacceptably high. It is therefore of major interest to improve our understanding of the host-pathogen interaction to develop new therapeutic approaches such as adoptive immunotherapy. As experimental methodologies have improved and we now better understand the complex network of the immune system, the insight in the interaction of the host with the fungus has significantly increased. It has become clear that host resistance to fungal infections is not only associated with strong innate immunity but that adaptive immunity (e.g., T cells) also plays an important role. The antifungal activity of natural killer (NK) cells has been underestimated for a long time. In vitro studies demonstrated that NK cells from murine and human origin are able to attack fungi of different genera and species. NK cells exhibit not only a direct antifungal activity via cytotoxic molecules but also an indirect antifungal activity via cytokines. However, it has been show that fungi exert immunosuppressive effects on NK cells. Whereas clinical data are scarce, animal models have clearly demonstrated that NK cells play an important role in the host response against invasive fungal infections. In this review, we summarize clinical data as well as results from in vitro and animal studies on the impact of NK cells on fungal pathogens.

Candidiasis and the impact of flow cytometry on antifungal drug discovery.

PubMed

Ku, Tsun Sheng N; Bernardo, Stella; Walraven, Carla J; Lee, Samuel A

2017-11-01

Invasive candidiasis continues to be associated with significant morbidity and mortality as well as substantial health care costs nationally and globally. One of the contributing factors is the development of resistance to antifungal agents that are already in clinical use. Moreover, there are known treatment limitations with all of the available antifungal agents. Since traditional techniques in novel drug discovery are time consuming, high-throughput screening using flow cytometry presents as a potential tool to identify new antifungal agents that would be useful in the management of these patients. Areas covered: In this review, the authors discuss the use of automated high-throughput screening assays based upon flow cytometry to identify potential antifungals from a library comprised of a large number of bioactive compounds. They also review studies that employed the use of this research methodology that has identified compounds with antifungal activity. Expert opinion: High-throughput screening using flow cytometry has substantially decreased the processing time necessary for screening thousands of compounds, and has helped enhance our understanding of fungal pathogenesis. Indeed, the authors see this technology as a powerful tool to help scientists identify new antifungal agents that can be added to the clinician's arsenal in their fight against invasive candidiasis.

[A case of lung metastasis from esophageal cancer resistant to fluorouracil and cisplatin combination therapy but responsive to radiation therapy].

PubMed

Ami, Katsunori; Seki, Ryouta; Takasaki, Jun; Amagasa, Hidetoshi; Kamikozuru, Hirotaka; Ganno, Hideaki; Kurokawa, Toshiaki; Fukuda, Akira; Nagahama, Takeshi; Ando, Masayuki; Yamada, Yosuke; Kodaka, Fumi; Arai, Kuniyoshi

2012-11-01

At present, fluorouracil and cisplatin combination therapy is the standard chemotherapy against esophageal cancer, but the choice of second-line chemotherapy is controversial. Furthermore, the effect of radiation therapy against lung metastasis from esophageal cancer is unclear. We report a case of lung metastasis from esophageal cancer resistant to fluorouracil and cisplatin combination therapy but responsive to radiation therapy. The patient was a 55-year-old woman who had undergone an operation for esophageal cancer at another hospital. A single right lung metastasis appeared 1 year after the operation. Combined fluorouracil and cisplatin therapy was administrated for 5 courses, but the lung metastasis increased in size. Afterwards, she was admitted to our hospital. We treated her with 14 courses of S-1 and docetaxel combination therapy administered over 13 months. The lung metastasis was decreased for a period. Furthermore, radiofrequency ablation under computed tomography was performed against the lung metastasis re-growth at another hospital. Although the lung metastasis increased in size, no further metastases were detected during the clinical course. The patient was treated with radiotherapy for the lung metastasis re-growth. The tumor had almost disappeared by 10 months after the completion of radiotherapy. Currently, she is receiving palliative care as an outpatient and the lung metastasis has not been evident for 2 years since the completion of radiotherapy.

Antifungal activity of Piper diospyrifolium Kunth (Piperaceae) essential oil

PubMed Central

Vieira, Silvia Cristina Heredia; de Paulo, Luis Fernando; Svidzinski, Terezinha Inez Estivaleti; Dias Filho, Benedito Prado; Nakamura, Celso Vataru; de Souza, Amanda; Young, Maria Cláudia Marx; Cortez, Diógenes Aparício Garcia

2011-01-01

In vitro activity of the essential oil from Piper diospyrifolium leaves was tested using disk diffusion techniques. The antifungal assay showed significant potencial antifungal activity: the oil was effective against several clinical fungal strains. The majority compounds in the essential oil were identified as sesquiterpenoids by GC-MS and GC-FID techniques. PMID:24031717

Drug Delivery Systems and Combination Therapy by Using Vinca Alkaloids

PubMed Central

Lee, Chun-Ting; Huang, Yen-Wei; Yang, Chih-Hui; Huang, Keng-Shiang

2015-01-01

Developing new methods for chemotherapy drug delivery has become a topic of great concern. Vinca alkaloids are among the most widely used chemotherapy reagents for tumor therapy; however, their side effects are particularly problematic for many medical doctors. To reduce the toxicity and enhance the therapeutic efficiency of vinca alkaloids, many researchers have developed strategies such as using liposome-entrapped drugs, chemical- or peptide-modified drugs, polymeric packaging drugs, and chemotherapy drug combinations. This review mainly focuses on the development of a vinca alkaloid drug delivery system and the combination therapy. Five vinca alkaloids (eg, vincristine, vinblastine, vinorelbine, vindesine, and vinflunine) are reviewed. PMID:25877096

Production and Characterization of Antifungal Compounds Produced by Lactobacillus plantarum IMAU10014

PubMed Central

Wang, HaiKuan; Yan, YanHua; Wang, JiaMing; Zhang, HePing; Qi, Wei

2012-01-01

Lactobacillus plantarum IMAU10014 was isolated from koumiss that produces a broad spectrum of antifungal compounds, all of which were active against plant pathogenic fungi in an agar plate assay. Two major antifungal compounds were extracted from the cell-free supernatant broth of L. plantarum IMAU10014. 3-phenyllactic acid and Benzeneacetic acid, 2-propenyl ester were carried out by HPLC, LC-MS, GC-MS, NMR analysis. It is the first report that lactic acid bacteria produce antifungal Benzeneacetic acid, 2-propenyl ester. Of these, the antifungal products also have a broad spectrum of antifungal activity, namely against Botrytis cinerea, Glomerella cingulate, Phytophthora drechsleri Tucker, Penicillium citrinum, Penicillium digitatum and Fusarium oxysporum, which was identified by the overlay and well-diffusion assay. F. oxysporum, P. citrinum and P. drechsleri Tucker were the most sensitive among molds. PMID:22276116

Selective BET bromodomain inhibition as an antifungal therapeutic strategy

PubMed Central

Mietton, Flore; Ferri, Elena; Champleboux, Morgane; Zala, Ninon; Maubon, Danièle; Zhou, Yingsheng; Harbut, Mike; Spittler, Didier; Garnaud, Cécile; Courçon, Marie; Chauvel, Murielle; d'Enfert, Christophe; Kashemirov, Boris A.; Hull, Mitchell; Cornet, Muriel; McKenna, Charles E.; Govin, Jérôme; Petosa, Carlo

2017-01-01

Invasive fungal infections cause significant morbidity and mortality among immunocompromised individuals, posing an urgent need for new antifungal therapeutic strategies. Here we investigate a chromatin-interacting module, the bromodomain (BD) from the BET family of proteins, as a potential antifungal target in Candida albicans, a major human fungal pathogen. We show that the BET protein Bdf1 is essential in C. albicans and that mutations inactivating its two BDs result in a loss of viability in vitro and decreased virulence in mice. We report small-molecule compounds that inhibit C. albicans Bdf1 with high selectivity over human BDs. Crystal structures of the Bdf1 BDs reveal binding modes for these inhibitors that are sterically incompatible with the human BET-binding pockets. Furthermore, we report a dibenzothiazepinone compound that phenocopies the effects of a Bdf1 BD-inactivating mutation on C. albicans viability. These findings establish BET inhibition as a promising antifungal therapeutic strategy and identify Bdf1 as an antifungal drug target that can be selectively inhibited without antagonizing human BET function. PMID:28516956

The antifungal effect of silver nanoparticles on Trichosporon asahii.

PubMed

Xia, Zhi-Kuan; Ma, Qiu-Hua; Li, Shu-Yi; Zhang, De-Quan; Cong, Lin; Tian, Yan-Li; Yang, Rong-Ya

2016-04-01

Silver nanoparticles are receiving increasing attention in biomedical applications. This study aims at evaluating the antifungal properties of silver nanoparticles against the pathogenic fungus Trichosporon asahii. The growth of T. asahii on potato dextrose agar medium containing different concentrations of silver nanoparticles was examined and the antifungal effect was evaluated using minimum inhibitory concentration. Scanning and transmission electron microscopy were also used to investigate the antifungal effect of silver nanoparticles on T. asahii. Silver nanoparticles had a significant inhibitory effect on the growth of T. asahii. The minimum inhibitory concentration of silver nanoparticles against T. asahii was 0.5 μg/mL, which was lower than amphotericin B, 5-flucytosine, caspofungin, terbinafine, fluconazole, and itraconazole and higher than voriconazole. Silver nanoparticles obviously damaged the cell wall, cell membrane, mitochondria, chromatin, and ribosome. Our results demonstrate that silver nanoparticles have good antifungal activity against T. asahii. Based on our electron microscopy observations, silver nanoparticles may inhibit the growth of T. asahii by permeating the fungal cell and damaging the cell wall and cellular components. Copyright © 2014. Published by Elsevier B.V.

Fixed-dose combination therapy for the prevention of cardiovascular disease

PubMed Central

de Cates, Angharad N; Farr, Matthew RB; Wright, Nicola; Jarvis, Morag C; Rees, Karen; Ebrahim, Shah; Huffman, Mark D

2014-01-01

Background Cardiovascular disease (CVD) is the leading cause of death and disability worldwide, yet CVD risk factor control and secondary prevention rates remain low. A fixed-dose combination of blood pressure and cholesterol lowering and antiplatelet treatments into a single pill, or polypill, has been proposed as one strategy to reduce the global burden of CVD by up to 80% given its potential for better adherence and lower costs. Objectives To determine the effectiveness of fixed-dose combination therapy on reducing fatal and non-fatal CVD events and on improving blood pressure and lipid CVD risk factors for both primary and secondary prevention of CVD. We also aimed to determine discontinuation rates, adverse events, health-related quality of life, and costs of fixed-dose combination therapy. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library(2013, Issue 6), MEDLINE Ovid (1946 to week 2 July 2013), EMBASE Ovid (1980 to Week 28 2013), ISI Web of Science (1970 to 19 July 2013), and the Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment Database (HTA), and Health Economics Evaluations Database (HEED) (2011, Issue 4) in The Cochrane Library. We used no language restrictions. Selection criteria We included randomised controlled trials of a fixed-dose combination therapy including at least one blood pressure lowering and one lipid lowering component versus usual care, placebo, or a single drug active component for any treatment duration in adults ≥ 18 years old with no restrictions on presence or absence of pre-existing cardiovascular disease. Data collection and analysis Three review authors independently selected studies for inclusion and extracted the data. We evaluated risk of bias using the Cochrane risk of bias assessment tool. We sought to include outcome data on all-cause mortality, fatal and non-fatal CVD events, adverse events, changes in systolic and diastolic blood

Evaluation of the Efficacy of Combined Therapy of Methotrexate and Etanercept versus Methotrexate as a Mono-Therapy

PubMed Central

Rexhepi, Sylejman; Rexhepi, Mjellma; Rexhepi, Blerta; Sahatçiu-Meka, Vjollca; Mahmutaj, Vigan

2018-01-01

AIM: This study aims to evaluate the efficacy of Methotrexate (MTX) alone and combined therapy with Etanercept (ETN) and Methotrexate in patients with active rheumatoid arthritis (RA). METHODS: In the randomised control study, conducted in the period from March 2014 until March 2016, we evaluated the efficacy of the treatment of patients with RA with MTX as monotherapy and combination treatment with MTX and ETN. In the Clinic of Rheumatology in Prishtina, 90 adult patients with RA were treated in combination with ETN (doses of 50 mg subcutaneously/weekly), with oral MTX (doses up to 20 mg weekly), and MTX alone (doses up to 20 mg weekly) during this period of two years. Clinical response was assessed using European League against Rheumatism (EULAR)/American College of Rheumatology (ACR) Criteria and the Disease Activity Score (DAS28). Radiographic changes were measured in the beginning and at the end of the study using Larsen’s method. RESULTS: Of the cohort groups of 90 patients, mean age of 55.63, 15 patients, (16.6 %) were treated with combined therapy (ETN plus MTX) and 75 patients (83.3%) with monotherapy (MTX). After two years of treatment the group with combined therapy resulted with improvement of acute phase reactants as erythrocyte sedimentation rate (ESR) for the first hour (41.1 vs. 10.3 mm/hour) and C - reactive protein (CRP) (40.8 vs. 6 mg/liter), and compared to the group treated with monotherapy, there were no significant changes (ESR: 45.7 vs 34.3 mm/hour; CRP: 48 vs 24 mg/liter). Before the treatment, the severity of the disease was high, wherein the group with combined therapy DAS28 was 5.32, compared to the monotherapy group whom DAS28 was 5.90. After 2 years of treatment, we had significant changes in the results of DAS28, wherein the group treated with ETN plus MTX DAS28 was 2.12 ± 0.15, while in the group of patients treated with MTX DAS28 were 3.75 ± 0.39 (t = 13.03; df = 58; p < 0.0001). The group with combined therapy showed no

Antibacterial, antifungal, antispasmodic and Ca++ antagonist effects of Caesalpinia bonducella.

PubMed

Khan, Hidayat-Ullah; Ali, Irshad; Khan, Arif-Ullah; Naz, Rubina; Gilani, Anwarul Hassan

2011-02-01

Caesalpinia bonducella F. (Leguminosae) has been used as a folk medicine for a variety of ailments. The crude extract of C. bonducella and its fractions were studied for antibacterial, antifungal, antispasmodic and Ca++ antagonistic properties. The strongest antibacterial effect was displayed by the n-butanol (72%) and ethyl acetate (80%) fractions, followed by the crude extract (46% and 42%), against Escherichia coli and Bacillus subtilis, respectively. The plant extract and its fractions showed mild to excellent activity in antifungal bioassays, with maximum antifungal activity against Candida glaberata (80%) and Aspergillus flavus (70%) by the n-butanol and chloroform fractions, followed by the crude extract (70% and 65%). Caesalpinia bonducella extract caused concentration-dependent inhibition of spontaneous and high K+ (80 mM)-induced contractions of isolated rabbit jejunum preparations, similar to that caused by Verapamil. These results indicate that C. bonducella exhibits antibacterial, antifungal, spasmolytic and Ca++ channel blocking actions.

What is the role of combination drug therapy in the treatment of overactive bladder? ICI-RS 2014.

PubMed

Visco, Anthony G; Fraser, Matthew O; Newgreen, Donald; Oelke, Matthias; Cardozo, Linda

2016-02-01

The role of combination therapy using oral antimuscarinic medications for the treatment of overactive bladder was proposed at the 2014 International Consultation on Incontinence-Research Society in Bristol, UK to identify key factors to consider when making clinical decisions and to guide future research design. Combination therapy is justified if monotherapy is associated with suboptimal efficacy or bothersome side effects. Combination therapy has the potential to improve efficacy with fewer side effects than monotherapy. Two Phase 2 studies comparing combination therapy that included an antimuscarinic demonstrated improvement in mean voided volume, the primary outcome chosen, with some combinations showing improved micturition frequency and quality of life. The two studies found no evidence of an increased safety risk with combination therapy compared to monotherapy. Future studies should use clinically meaningful or patient reported outcomes such as incontinence episodes when comparing efficacy. If surrogate measures are used, a clear justification should be provided. Cost analyses should be planned for clinical research trials evaluating combination drug therapy. Combination therapy is reasonable when monotherapy has suboptimal efficacy or bothersome side effects. Future research studies evaluating combination therapy for urgency urinary incontinence should ideally(1) be performed as part of a randomized clinical trial,(2) evaluate non-responders to monotherapy,(3) evaluate combination therapy using medications with different mechanisms of action,(4) include clinically meaningful and patient reported outcomes when evaluating efficacy, and(5) include cost-effectiveness analyses to justify any increased cost by showing improvement in efficacy or reduction in side effects. © 2016 Wiley Periodicals, Inc.

Visually augmented targeted combination light therapy for acne vulgaris: a case report.

PubMed

Yazdi, Alireza; Lyons, Colin-William; Roberts, Niamh

2017-10-31

Acne vulgaris is a common skin disease. Pharmacological modalities for treatment are proven to be efficacious but have limitations. Light therapy for acne vulgaris has shown promise in previous studies. This case report and its accompanying images show how a novel approach of visually augmented high fluence light therapy has been used to good effect. A 26-year-old Caucasian woman with acne vulgaris resistant to treatment with topical therapy underwent three sessions of combination potassium titanyl phosphate laser (532 nm)/neodymium-doped: yttrium aluminum garnet laser (1064 nm) light therapy with visually augmented narrow spot size and high fluence. A 73% reduction in total inflammatory lesions was evident 6 months after the initial treatment. This case report illustrates that there may be utility in this novel approach of narrow spot size, magnification-assisted, high fluence targeted combination laser therapy for inflammatory acne.

Combination Therapy of Rosuvastatin and Ezetimibe in Patients with High Cardiovascular Risk.

PubMed

Yang, Young-June; Lee, Sang-Hak; Kim, Byung Soo; Cho, Yun-Kyeong; Cho, Hyun-Jai; Cho, Kyoung Im; Kim, Seok-Yeon; Ryu, Jae Kean; Cho, Jin-Man; Park, Joong-Il; Park, Jong-Seon; Park, Chang Gyu; Chun, Woo Jung; Kim, Myung-A; Jin, Dong-Kyu; Lee, Namho; Kim, Byung Jin; Koh, Kwang Kon; Suh, Jon; Lee, Seung-Hwan; Lee, Byoung-Kwon; Oh, Seung-Jin; Jin, Han-Young; Ahn, Youngkeun; Lee, Sang-Gon; Bae, Jang-Ho; Park, Woo Jung; Lee, Sang-Chol; Lee, Han Cheol; Lee, Jaewon; Park, Cheolwon; Lee, Backhwan; Jang, Yangsoo

2017-01-01

The aim of this study was to evaluate the efficacy and tolerability of rosuvastatin/ezetimibe combination therapy in Korean patients with high cardiovascular risk. This was a 12-week, randomized, double-blind, placebo-controlled, multicenter study. A total of 337 patients were screened. After a 4-week run-in period, 245 of these patients with high or moderately high risk as defined by the National Cholesterol Education Program Adult Treatment Panel III guidelines were randomly assigned. Patients received 1 of 6 regimens for 8 weeks as follows: (1) rosuvastatin 5 mg, (2) rosuvastatin 5 mg/ezetimibe 10 mg, (3) rosuvastatin 10 mg, (4) rosuvastatin 10 mg/ezetimibe 10 mg, (5) rosuvastatin 20 mg, or (6) rosuvastatin 20 mg/ezetimibe 10 mg. The primary outcome variable was percentage change in the level of LDL-C at week 8 of drug treatment. Secondary outcome variables included percentage changes of other lipid variables and achievement rates of LDL-C targets. Tolerability analyses were also performed. The percentage change of LDL-C ranged from -45% to -56% (mean, -51%) in the monotherapy groups and from -58% to -63% (mean, -60%) in the combination therapy groups. The percentage change was greater in the pooled combination therapy group than in the counterpart (P < 0.001 for the pooled groups); this difference was more obvious for regimens with a lower statin dose. The percentage reductions of total cholesterol and triglycerides were greater in the combination groups than in the monotherapy groups. The LDL-C target achievement rates were 64% to 87% (mean, 73%) in the monotherapy groups and 87% to 95% (mean, 91%) in the combination groups (P = 0.01 for the pooled groups). The rates were significantly greater in patients receiving the combination therapy than in the monotherapy at lower doses of rosuvastatin. The proportions of patients with various adverse events were not significantly different between the groups. Rosuvastatin/ezetimibe combination therapy has better

Molecular Tools for the Detection and Deduction of Azole Antifungal Drug Resistance Phenotypes in Aspergillus Species.

PubMed

Dudakova, Anna; Spiess, Birgit; Tangwattanachuleeporn, Marut; Sasse, Christoph; Buchheidt, Dieter; Weig, Michael; Groß, Uwe; Bader, Oliver

2017-10-01

The incidence of azole resistance in Aspergillus species has increased over the past years, most importantly for Aspergillus fumigatus . This is partially attributable to the global spread of only a few resistance alleles through the environment. Secondary resistance is a significant clinical concern, as invasive aspergillosis with drug-susceptible strains is already difficult to treat, and exclusion of azole-based antifungals from prophylaxis or first-line treatment of invasive aspergillosis in high-risk patients would dramatically limit drug choices, thus increasing mortality rates for immunocompromised patients. Management options for invasive aspergillosis caused by azole-resistant A. fumigatus strains were recently reevaluated by an international expert panel, which concluded that drug resistance testing of cultured isolates is highly indicated when antifungal therapy is intended. In geographical regions with a high environmental prevalence of azole-resistant strains, initial therapy should be guided by such analyses. More environmental and clinical screening studies are therefore needed to generate the local epidemiologic data if such measures are to be implemented on a sound basis. Here we propose a first workflow for evaluating isolates from screening studies, and we compile the MIC values correlating with individual amino acid substitutions in the products of cyp51 genes for interpretation of DNA sequencing data, especially in the absence of cultured isolates. Copyright © 2017 American Society for Microbiology.

Biodirected synthesis of Miconazole-conjugated bacterial silver nanoparticles and their application as antifungal agents and drug delivery vehicles.

PubMed

Kumar, C Ganesh; Poornachandra, Y

2015-01-01

The recent strategy to improve the efficacy of drugs is to combine them with metal nanoparticles for the control of microbial infections. Considering this fact, we developed a low cost and eco-friendly method for silver nanoparticles synthesis using the cell free supernatant of Delftia sp. strain KCM-006 and their application as antifungal agents and as a drug carrier. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) analysis revealed the formation of spherical and monodispersed silver nanoparticles with an average size of 9.8 nm. The synthesized nanoparticles were found to be photoluminescent, highly stable and crystalline in nature having a zeta potential of -31 mV. The silver nanoparticles exhibited very good antifungal activity against various pathogenic Candida strains. Furthermore, the efficacy of nanoparticles was increased by conjugating the antifungal drug Miconazole to silver nanoparticles which exhibited significant fungicidal activity, inhibition of ergosterol biosynthesis and biofilm inhibition by increasing ROS levels. In addition, the cell viability and immunocytochemistry analysis against different normal cell lines including Chinese hamster ovary cells (CHO), human lung cell line (MRC5) and human vascular endothelial cells (HUVEC) demonstrated that these nanoparticles were non-toxic up to a concentration of 20 μM. In conclusion, these results suggest that the synthesized nanoparticles find application as both antifungal agents and drug delivery vehicles. This is a first report on the preparation of silver nanoparticles using culture supernatant from Delftia sp. and also on the conjugation of Miconazole, an antifungal drug, to the bacterial silver nanoparticles. Copyright © 2014 Elsevier B.V. All rights reserved.

Genomic identification of potential targets unique to Candida albicans for the discovery of antifungal agents.

PubMed

Tripathi, Himanshu; Luqman, Suaib; Meena, Abha; Khan, Feroz

2014-01-01

Despite of modern antifungal therapy, the mortality rates of invasive infection with human fungal pathogen Candida albicans are up to 40%. Studies suggest that drug resistance in the three most common species of human fungal pathogens viz., C. albicans, Aspergillus fumigatus (causing mortality rate up to 90%) and Cryptococcus neoformans (causing mortality rate up to 70%) is due to mutations in the target enzymes or high expression of drug transporter genes. Drug resistance in human fungal pathogens has led to an imperative need for the identification of new targets unique to fungal pathogens. In the present study, we have used a comparative genomics approach to find out potential target proteins unique to C. albicans, an opportunistic fungus responsible for severe infection in immune-compromised human. Interestingly, many target proteins of existing antifungal agents showed orthologs in human cells. To identify unique proteins, we have compared proteome of C. albicans [SC5314] i.e., 14,633 total proteins retrieved from the RefSeq database of NCBI, USA with proteome of human and non-pathogenic yeast Saccharomyces cerevisiae. Results showed that 4,568 proteins were identified unique to C. albicans as compared to those of human and later when these unique proteins were compared with S. cerevisiae proteome, finally 2,161 proteins were identified as unique proteins and after removing repeats total 1,618 unique proteins (42 functionally known, 1,566 hypothetical and 10 unknown) were selected as potential antifungal drug targets unique to C. albicans.

Femara® and the future: tailoring treatment and combination therapies with Femara

PubMed Central

Ma, Cynthia

2007-01-01

Long-term estrogen deprivation treatment for breast cancer can, in some patients, lead to the activation of alternate cellular pathways, resulting in the re-emergence of the disease. This is a distressing scenario for oncologists and patients, but recent intensive molecular and biochemical studies are beginning to unravel these pathways, revealing opportunities for new targeted treatments. Far from making present therapies redundant, these new discoveries open the door to novel combination therapies that promise to provide enhanced efficacy or overcome treatment resistance. Letrozole, one of the most potent aromatase inhibitors, is the ideal candidate for combination therapy; indeed, it is one of the most intensively studied aromatase inhibitors in the evolving combinatorial setting. Complementary to the use of combination therapy is the development of molecular tools to identify patients who will benefit the most from these new treatments. Microarray gene profiling studies, designed to detect letrozole-responsive targets, are currently under way to understand how the use of the drug can be tailored more efficiently to specific patient needs. PMID:17912640

Antifungal resistance: current trends and future strategies to combat

PubMed Central

Wiederhold, Nathan P

2017-01-01

Antifungal resistance represents a major clinical challenge to clinicians responsible for treating invasive fungal infections due to the limited arsenal of systemically available antifungal agents. In addition current drugs may be limited by drug–drug interactions and serious adverse effects/toxicities that prevent their prolonged use or dosage escalation. Fluconazole resistance is of particular concern in non-Candida albicans species due to the increased incidence of infections caused by these species in different geographic locations worldwide and the elevated prevalence of resistance to this commonly used azole in many institutions. C. glabrata resistance to the echinocandins has also been documented to be rising in several US institutions, and a higher percentage of these isolates may also be azole resistant. Azole resistance in Aspergillus fumigatus due to clinical and environmental exposure to this class of agents has also been found worldwide, and these isolates can cause invasive infections with high mortality rates. In addition, several species of Aspergillus, and other molds, including Scedosporium and Fusarium species, have reduced susceptibility or pan-resistance to clinically available antifungals. Various investigational antifungals are currently in preclinical or clinical development, including several of them that have the potential to overcome resistance observed against the azoles and the echinocandins. These include agents that also target ergosterol and b-glucan biosynthesis, as well as compounds with novel mechanisms of action that may also overcome the limitations of currently available antifungal classes, including both resistance and adverse effects/toxicity. PMID:28919789

Antifungal susceptibilities of Candida species isolated from urine culture.

PubMed

Toka Özer, Türkan; Durmaz, Süleyman; Yula, Erkan

2016-09-01

Candida spp. are the most common opportunistic mycosis worldwide. Although Candida albicans is the most common cause of urinary tract infections, the frequency of non-albicans Candida species is increasing with common use of antifungal in the prophylaxis and treatment. This may lead to difficulties in treatment. Antifungal tests should be applied with identification of species for effective treatment. In this study, identification of Candida species isolated from urine culture and investigation of susceptibility of these strains to amphotericin B, flucytosine, fluconazole, voriconazole was aimed. In this study, 58 Candida strains isolated from urine cultures at Osmaniye State Hospital between January 2012 and April 2013 were included. Urine culture and antifungal susceptibility tests were applied. Incidence rate of Candida spp. was determined as C. albicans (56.9%), Candida glabrata (20.6%), Candida tropicalis (10.3%), Candida parapsilosis (7%), Candida krusei (3.4%), Candida kefyr (1.8%). Most of the isolates were susceptible to amphotericin B, flucytosine, fluconazole, voriconazole. Twenty three (39.7%) Candida strains were isolated from internal medical branches and Intensive Care Unit and 12 (20.6%) from the Surgical Medical Branches. C. albicans and C. glabrata species were isolated most frequently as a candiduria factor in this hospital between January 2012 and April 2013. The analysis of antifungal susceptibility profile shows no significant resistance to antifungals. Copyright © 2016 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Light- and singlet oxygen-mediated antifungal activity of phenylphenalenone phytoalexins.

PubMed

Lazzaro, Alejandra; Corominas, Montserrat; Martí, Cristina; Flors, Cristina; Izquierdo, Laura R; Grillo, Teresa A; Luis, Javier G; Nonell, Santi

2004-07-01

The light-induced singlet oxygen production and antifungal activity of phenylphenalenone phytoalexins isolated from infected banana plants (Musa acuminata) are reported. Upon absorption of light energy all studied phenylphenalenones sensitise the production of singlet oxygen in polar and non-polar media. Antifungal activity of these compounds towards Fusarium oxysporum is enhanced in the presence of light. These results, together with the correlation of IC50 values under illumination with the quantum yield of singlet oxygen production and the enhancing effect of D2O on the antifungal activity, suggest the intermediacy of singlet oxygen produced by electronic excitation of the phenylphenalenone phytoalexins.

Synthesis of inulin derivatives with quaternary phosphonium salts and their antifungal activity.

PubMed

Chen, Yuan; Tan, Wenqiang; Li, Qing; Dong, Fang; Gu, Guodong; Guo, Zhanyong

2018-07-01

Inulin is a kind of renewable and biodegradable carbohydrate with good water solubility and numerous physiological functions. For further utilization of inulin, chemical modification can be applied to improve its bioactivities. In this paper, five novel inulin derivatives were synthesized via chemical modification with quaternary phosphonium salt. Their antifungal activity against three kinds of plant pathogens including Colletotrichum lagenarium, Phomopsis asparagi, and Fusarium oxysporum was assessed with radial growth assay in vitro. Results revealed that all the inulin derivatives exhibited improved antifungal activity compared with inulin. Particularly, inulin modified with triphenylphosphine (TPhPAIL) exhibited the best antifungal activity with inhibitory indices of 80.0%, 78.8%, and 87.4% against Colletotrichum lagenarium, Phomopsis asparagi, and Fusarium oxysporum at 1.0mg/mL respectively. The results clearly showed that chemical modification of inulin with quaternary phosphonium salt could efficiently improve derivatives' antifungal activity. Further analysis of results indicated that the antifungal activity was influenced by alkyl chain length or electron-withdrawing ability of the grafted quaternary phosphonium salts. Longer alkyl chain lengths or the stronger electron-withdrawing groups would lead to enhanced antifungal efficacy. Copyright © 2018 Elsevier B.V. All rights reserved.

Azole Antifungal Resistance in Candida albicans and Emerging Non-albicans Candida Species

PubMed Central

Whaley, Sarah G.; Berkow, Elizabeth L.; Rybak, Jeffrey M.; Nishimoto, Andrew T.; Barker, Katherine S.; Rogers, P. David

2017-01-01

Within the limited antifungal armamentarium, the azole antifungals are the most frequent class used to treat Candida infections. Azole antifungals such as fluconazole are often preferred treatment for many Candida infections as they are inexpensive, exhibit limited toxicity, and are available for oral administration. There is, however, extensive documentation of intrinsic and developed resistance to azole antifungals among several Candida species. As the frequency of azole resistant Candida isolates in the clinical setting increases, it is essential to elucidate the mechanisms of such resistance in order to both preserve and improve upon the azole class of antifungals for the treatment of Candida infections. This review examines azole resistance in infections caused by C. albicans as well as the emerging non-albicans Candida species C. parapsilosis, C. tropicalis, C. krusei, and C. glabrata and in particular, describes the current understanding of molecular basis of azole resistance in these fungal species. PMID:28127295

Development of an Antifungal Denture Adhesive Film for Oral Candidiasis Utilizing Hot Melt Extrusion Technology

PubMed Central

Park, Jun-Bom; Prodduturi, Suneela; Morott, Joe; Kulkarni, Vijay I.; Jacob, Melissa R.; Khan, Shabana I.; Stodghill, Steven P.; Repka, Michael A.

2017-01-01

Objectives The overall goal of this research was to produce a stable hot-melt extruded “Antifungal Denture Adhesive film” (ADA) system for the treatment of oral candidiasis. Methods The ADA systems with hydroxypropyl cellulose (HPC) and/or polyethylene oxide (PEO) containing clotrimazole (10%) or nystatin (10%) were extruded utilizing a lab scale twin-screw hot-melt extruder. Rolls of the antifungal-containing films were collected and subsequently die-cut into shapes adapted for a maxillary (upper) and mandibular (lower) denture. Results DSC and PXRD results indicated that the crystallinity of both APIs was changed to amorphous phase after hot-melt extrusion. The ADA system, containing blends of HPC and PEO, enhanced the effectiveness of the antimicrobials a maximum of 5-fold toward the inhibition of cell adherence of C. albicans to mammalian cells/Vero cells. Remarkably, a combination of the two polymers without drug also demonstrated a 38% decrease in cell adhesion to the fungi due to the viscosity and the flexibility of the polymers. Drug-release profiles indicated that both drug concentrations were above the minimum inhibitory concentration (MIC) for C. albicans within 10 minutes and was maintained for over 10 hours. In addition, based on the IC50 and MIC values, it was observed that the antifungal activities of both drugs were increased significantly in the ADA systems. Conclusions Based on these findings, the ADA system may be used for primary, prophylaxis or adjunct treatment of oral or pharyngeal candidiasis via controlled-release of the antifungal agent from the polymer matrix. PMID:25169007

Development of an antifungal denture adhesive film for oral candidiasis utilizing hot melt extrusion technology.

PubMed

Park, Jun-Bom; Prodduturi, Suneela; Morott, Joe; Kulkarni, Vijay I; Jacob, Melissa R; Khan, Shabana I; Stodghill, Steven P; Repka, Michael A

2015-01-01

The overall goal of this research was to produce a stable hot-melt extruded 'Antifungal Denture Adhesive film' (ADA) system for the treatment of oral candidiasis. The ADA systems with hydroxypropyl cellulose (HPC) and/or polyethylene oxide (PEO) containing clotrimazole (10%) or nystatin (10%) were extruded utilizing a lab scale twin-screw hot-melt extruder. Rolls of the antifungal-containing films were collected and subsequently die-cut into shapes adapted for a maxillary (upper) and mandibular (lower) denture. Differential scanning calorimeter and powder X-ray diffraction results indicated that the crystallinity of both APIs was changed to amorphous phase after hot-melt extrusion. The ADA system, containing blends of HPC and PEO, enhanced the effectiveness of the antimicrobials a maximum of fivefold toward the inhibition of cell adherence of Candida albicans to mammalian cells/Vero cells. Remarkably, a combination of the two polymers without drug also demonstrated a 38% decrease in cell adhesion to the fungi due to the viscosity and the flexibility of the polymers. Drug-release profiles indicated that both drug concentrations were above the minimum inhibitory concentration (MIC) for C. albicans within 10 min and was maintained for over 10 h. In addition, based on the IC50 and MIC values, it was observed that the antifungal activities of both drugs were increased significantly in the ADA systems. Based on these findings, the ADA system may be used for primary, prophylaxis or adjunct treatment of oral or pharyngeal candidiasis via controlled release of the antifungal agent from the polymer matrix.

Determination of antifungal activities in serum samples from mice treated with different antifungal drugs allows detection of an active metabolite of itraconazole.

PubMed

Maki, Katsuyuki; Watabe, Etsuko; Iguchi, Yumi; Nakamura, Hideko; Tomishima, Masaki; Ohki, Hidenori; Yamada, Akira; Matsumoto, Satoru; Ikeda, Fumiaki; Tawara, Shuichi; Mutoh, Seitaro

2006-01-01

To establish an in vitro method of predicting in vivo efficacy of antifungal drugs against Candida albicans and Aspergillus fumigatus, the antifungal activities of fluconazole, itraconazole, and amphotericin B were determined in mouse serum. The minimum inhibitory concentration (MIC) of each drug was measured using mouse serum as a diluent. For C. albicans, the assay endpoint of azoles was defined as inhibition of mycelial extension (mMIC) and for A. fumigatus, as no growth (MIC). The MICs of amphotericin B for both pathogens were defined as the MIC at which no mycelial growth occurred. Serum MIC or mMIC determinations were then used to estimate the concentration of the drugs in serum of mice treated with antifungal drugs by multiplying the antifungal titer of the serum samples by the serum (m)MIC. The serum drug concentrations were also determined by HPLC. The serum concentrations estimated microbiologically showed good agreement with those determined by HPLC, except for itraconazole. Analysis of the serum samples from itraconazole-treated mice by a sensitive bioautography revealed the presence of additional spots, not seen in control samples of itraconazole. The bioautography assay demonstrated that the additional material detected in serum from mice treated with itraconazole was an active metabolite of itraconazole. The data showed that the apparent reduction in the itraconazole serum concentration as determined by HPLC was the result of the formation of an active metabolite, and that the use of a microbiological method to measure serum concentrations of drugs can provide a method for prediction of in vivo efficacy of antifungal drugs.

Modeling antibiotic treatment in hospitals: A systematic approach shows benefits of combination therapy over cycling, mixing, and mono-drug therapies.

PubMed

Tepekule, Burcu; Uecker, Hildegard; Derungs, Isabel; Frenoy, Antoine; Bonhoeffer, Sebastian

2017-09-01

Multiple treatment strategies are available for empiric antibiotic therapy in hospitals, but neither clinical studies nor theoretical investigations have yielded a clear picture when which strategy is optimal and why. Extending earlier work of others and us, we present a mathematical model capturing treatment strategies using two drugs, i.e the multi-drug therapies referred to as cycling, mixing, and combination therapy, as well as monotherapy with either drug. We randomly sample a large parameter space to determine the conditions determining success or failure of these strategies. We find that combination therapy tends to outperform the other treatment strategies. By using linear discriminant analysis and particle swarm optimization, we find that the most important parameters determining success or failure of combination therapy relative to the other treatment strategies are the de novo rate of emergence of double resistance in patients infected with sensitive bacteria and the fitness costs associated with double resistance. The rate at which double resistance is imported into the hospital via patients admitted from the outside community has little influence, as all treatment strategies are affected equally. The parameter sets for which combination therapy fails tend to fall into areas with low biological plausibility as they are characterised by very high rates of de novo emergence of resistance to both drugs compared to a single drug, and the cost of double resistance is considerably smaller than the sum of the costs of single resistance.

Antifungal mechanism of a novel antifungal protein from pumpkin rinds against various fungal pathogens.

PubMed

Park, Seong-Cheol; Kim, Jin-Young; Lee, Jong-Kook; Hwang, Indeok; Cheong, Hyeonsook; Nah, Jae-Woon; Hahm, Kyung-Soo; Park, Yoonkyung

2009-10-14

A novel antifungal protein (Pr-2) was identified from pumpkin rinds using water-soluble extraction, ultrafiltration, cation exchange chromatography, and reverse-phase high-performance liquid chromatography. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry indicated that the protein had a molecular mass of 14865.57 Da. Automated Edman degradation showed that the N-terminal sequence of Pr-2 was QGIGVGDNDGKRGKR-. The Pr-2 protein strongly inhibited in vitro growth of Botrytis cinerea, Colletotrichum coccodes, Fusarium solani, Fusarium oxysporum, and Trichoderma harzianum at 10-20 microM. The results of confocal laser scanning microscopy and SYTOX Green uptake demonstrated that its effective region was the membrane of the fungal cell surface. In addition, this protein was found to be noncytotoxic and heat-stable. Taken together, the results of this study indicate that Pr-2 is a good candidate for use as a natural antifungal agent.

[Combined l-thyroxine and l-triiodothyronine replacement therapy in congenital hypothyroidism].

PubMed

Péter, Ferenc; Muzsnai, Agota

2013-05-12

L-thyroxine replacement therapy is the treatment of choice for hypothyroidism. Recently, several studies suggested to complete it with l-triiodothyronine in acquired hypothyroidism. To study the role of combined l-thyroxine and l-triiodothyronine therapy in special cases with congenital hypothyroidism. Data of 16 patients (age: 11.9 ± 6.3 years; mean ± SD) are presented who had high serum free thyroxine values or even above the upper limit of reference range (21.16 ± 2.5 pmol/l) together with nonsuppressed TSH levels (15.7 ± 5.7 mIU/l), and therefore received l-triiodothyronine in completion (0.18 ± 0.09 μg/kg) once a day. The combined replacement therapy resulted in a rapid improvement of the hormone parameters (TSH: 4.2 ± 3.15 mIU/l; free thyroxine: 16.55 ± 2.4 and free triiodothyronine: 7.4 ± 1.8 pmol/l). The efficiency of this combined therapy proved to be more evident (TSH: 4.33 ± 3.2 mIU/l; free thyroxine: 16.85 ± 3.1 and free triiodothyronine: 6.4 ± 0.85 pmol/l) in 10 patients treated for a longer period of time (duration of treatment: 2.9 ± 2.0 years). The dose of thyroxine substitution decreased from 2.6 ± 0.9 to 2.18 ± 0.6 μg/kg/day), the ratio of these hormones was between 5:1 and 19:1 and the quotient of free fractions was normalized (3.8 ± 0.4→2.6 ± 0.3) during the replacement therapy. According to the observation of the authors a serious disturbance of feed-back mechanism may develop in some (>5%) children with congenital hypothyroidism (increased TSH release despite elevated free thyroxine level) after normal function of the feed-back system for years. Hormone parameters of these patients improve, then become normal on combined therapy supporting the rationale for this treatment method.

Mirror therapy combined with functional electrical stimulation for rehabilitation of stroke survivors' ankle dorsiflexion.

PubMed

Salhab, Ghadir; Sarraj, Ahmad Rifaii; Saleh, Soha

2016-08-01

This study investigates the effect of combining both mirror therapy with Electrical Stimulation (ES) on improvement of the function of lower extremity compared to conventional therapy. 18 stroke survivors (sub acute stage) were recruited, 9 of them were randomly assigned to receive conventional treatment and another 9 started the mirror therapy combined with ES treatment. Duration of each session in both interventions was 50 minutes, done 4 times per week over two weeks. After 2 weeks, subjects took one week rest before switching they type of treatment; those started with conventional therapy continued with mirror therapy combined with ES, and vice versa. The duration of this phase was 2 weeks with same schedule as the 1st one. Ankle dorsi-flexion range of motion, lower extremity sensory-motor function, and walking duration were measured at baseline, after 1st 2 weeks, and immediately after the last two weeks, and 4 weeks after end of training (retention test). Repeated Measures ANCOVA was done to compare outcome measures scores in both groups and between all testing days, and paired T-test was used measure the difference between groups. Significant increase in all outcome measures was found after the (MT+ES) training, which is higher than conventional therapy training (p<;0.0001). In conclusion, the results suggest that combination of mirror therapy and ES is more effective than conventional therapy in improving lower limb motor function after stroke.

Combined Therapies of Modified Taiyi Miraculous Moxa Roll and Cupping for Patients with Lumbar Intervertebral Disc Herniation

PubMed Central

Dong, Dayong; Xue, Jinbiao; Zheng, Xiaoting

2018-01-01

Lumbar intervertebral disc herniation is a kind of syndrome caused by stimulation or pressure of nerve root and cauda equina due to intervertebral disc disorder, fibrous ring rupture, and pulpiform nucleus protrusion. Application of traditional Chinese medicine (TCM) including acupuncture therapy and cupping therapy is unique and effective treatment for lumbar intervertebral disc herniation in China. Hence, we try to investigate the combined clinical efficacy of modified Taiyi miraculous moxa roll and cupping therapy on patients with lumbar intervertebral disc herniation. Seventy patients were randomly assigned into combined treatment group (n = 35) and control group (n = 35). The treatment group received combined therapy of modified Taiyi miraculous moxa roll and cupping therapy, while control group received acupuncture therapy alone. Diagnostic criteria of TCM syndrome, Japanese Orthopedic Association (JOA) score, and simplified McGill pain questionnaire (MPQ) were used to evaluate the therapy. 11 and 13 out of 35 subjects in the combined treatment group had improvement > 75% and between 50% and 75%, respectively. The corresponding number was 2 and 22 of 35 subjects in the acupuncture group. There was significant difference in the clinical efficacy between the treatment group and control group (P = 0.036). The scores of JOA and MPQ detected in the patients of the two groups (P < 0.05) also showed statistically significant differences. Moreover, no serious adverse events occurred in the patients, who received cupping therapy or acupuncture. The combined or alone therapies can effectively improve the treatment efficacy in the patients with lumbar intervertebral disc herniation, while the combined therapies show more comparative effectiveness. Furthermore, the combined therapies are potentially safe and cost-effective and also benefit the improvement of short-term pain. Therefore, the combined therapies of the two ancient TCM deserve further clinical applications

Combined Therapies of Modified Taiyi Miraculous Moxa Roll and Cupping for Patients with Lumbar Intervertebral Disc Herniation.

PubMed

Cai, Chunyue; Gong, Yuefeng; Dong, Dayong; Xue, Jinbiao; Zheng, Xiaoting; Zhong, Zhangfeng; Shao, Jialong; Mi, Daguo

2018-01-01

Lumbar intervertebral disc herniation is a kind of syndrome caused by stimulation or pressure of nerve root and cauda equina due to intervertebral disc disorder, fibrous ring rupture, and pulpiform nucleus protrusion. Application of traditional Chinese medicine (TCM) including acupuncture therapy and cupping therapy is unique and effective treatment for lumbar intervertebral disc herniation in China. Hence, we try to investigate the combined clinical efficacy of modified Taiyi miraculous moxa roll and cupping therapy on patients with lumbar intervertebral disc herniation. Seventy patients were randomly assigned into combined treatment group ( n = 35) and control group ( n = 35). The treatment group received combined therapy of modified Taiyi miraculous moxa roll and cupping therapy, while control group received acupuncture therapy alone. Diagnostic criteria of TCM syndrome, Japanese Orthopedic Association (JOA) score, and simplified McGill pain questionnaire (MPQ) were used to evaluate the therapy. 11 and 13 out of 35 subjects in the combined treatment group had improvement > 75% and between 50% and 75%, respectively. The corresponding number was 2 and 22 of 35 subjects in the acupuncture group. There was significant difference in the clinical efficacy between the treatment group and control group ( P = 0.036). The scores of JOA and MPQ detected in the patients of the two groups ( P < 0.05) also showed statistically significant differences. Moreover, no serious adverse events occurred in the patients, who received cupping therapy or acupuncture. The combined or alone therapies can effectively improve the treatment efficacy in the patients with lumbar intervertebral disc herniation, while the combined therapies show more comparative effectiveness. Furthermore, the combined therapies are potentially safe and cost-effective and also benefit the improvement of short-term pain. Therefore, the combined therapies of the two ancient TCM deserve further clinical

The Yeast Anaerobic Response Element AR1b Regulates Aerobic Antifungal Drug-dependent Sterol Gene Expression*

PubMed Central

Gallo-Ebert, Christina; Donigan, Melissa; Liu, Hsing-Yin; Pascual, Florencia; Manners, Melissa; Pandya, Devanshi; Swanson, Robert; Gallagher, Denise; Chen, WeiWei; Carman, George M.; Nickels, Joseph T.

2013-01-01

Saccharomyces cerevisiae ergosterol biosynthesis, like cholesterol biosynthesis in mammals, is regulated at the transcriptional level by a sterol feedback mechanism. Yeast studies defined a 7-bp consensus sterol-response element (SRE) common to genes involved in sterol biosynthesis and two transcription factors, Upc2 and Ecm22, which direct transcription of sterol biosynthetic genes. The 7-bp consensus SRE is identical to the anaerobic response element, AR1c. Data indicate that Upc2 and Ecm22 function through binding to this SRE site. We now show that it is two novel anaerobic AR1b elements in the UPC2 promoter that direct global ERG gene expression in response to a block in de novo ergosterol biosynthesis, brought about by antifungal drug treatment. The AR1b elements are absolutely required for auto-induction of UPC2 gene expression and protein and require Upc2 and Ecm22 for function. We further demonstrate the direct binding of recombinant expressed S. cerevisiae ScUpc2 and pathogenic Candida albicans CaUpc2 and Candida glabrata CgUpc2 to AR1b and SRE/AR1c elements. Recombinant endogenous promoter studies show that the UPC2 anaerobic AR1b elements act in trans to regulate ergosterol gene expression. Our results indicate that Upc2 must occupy UPC2 AR1b elements in order for ERG gene expression induction to take place. Thus, the two UPC2-AR1b elements drive expression of all ERG genes necessary for maintaining normal antifungal susceptibility, as wild type cells lacking these elements have increased susceptibility to azole antifungal drugs. Therefore, targeting these specific sites for antifungal therapy represents a novel approach to treat systemic fungal infections. PMID:24163365

Antifungal activity of Morinda citrifolia fruit extract against Candida albicans.

PubMed

Jainkittivong, Aree; Butsarakamruha, Tassanee; Langlais, Robert P

2009-09-01

The objective of the study was to investigate the antifungal activity of Morinda citrifolia fruit extract on Candida albicans. Juice extract from M. citrifolia fruit was lyophilized and used in antifungal testing. Antifungal activity of M. citrifolia fruit extract against C. albicans was tested in vitro at various concentrations and for different contact times. The inhibitory effect of M. citrifolia extract on C. albicans was determined by cultures and an applied broth dilution test. Using cultures, growth of C. albicans was not detected with 50 mg/mL of extract at 30-minute contact time or with 60 mg/mL of extract at 15-minute contact time. By the broth dilution test, the minimum fungicidal concentration of extract against C. albicans was 40 mg/mL at 90-minute contact time or with 50 mg/mL at 15-minute contact time. M. citrifolia fruit extract had an antifungal effect on C. albicans and the inhibitory effect varied with concentration and contact time.

A Prototype Antifungal Contact Lens

PubMed Central

Ciolino, Joseph B.; Hudson, Sarah P.; Mobbs, Ashley N.; Hoare, Todd R.; Iwata, Naomi G.; Fink, Gerald R.

2011-01-01

Purpose. To design a contact lens to treat and prevent fungal ocular infections. Methods. Curved contact lenses were created by encapsulating econazole-impregnated poly(lactic-co-glycolic) acid (PLGA) films in poly(hydroxyethyl methacrylate) (pHEMA) by ultraviolet photopolymerization. Release studies were conducted in phosphate-buffered saline at 37°C with continuous shaking. The contact lenses and their release media were tested in an antifungal assay against Candida albicans. Cross sections of the pre- and postrelease contact lenses were characterized by scanning electron microscopy and by Raman spectroscopy. Results. Econazole-eluting contact lenses provided extended antifungal activity against Candida albicans fungi. Fungicidal activity varied in duration and effectiveness depending on the mass of the econazole-PLGA film encapsulated in the contact lens. Conclusions. An econazole-eluting contact lens could be used as a treatment for fungal ocular infections. PMID:21527380

Irreversible profound symptomatic bradycardia requiring pacemaker after tizanidine/loxoprofen combination therapy: a case report.

PubMed

Li, Xiaolin; Jin, Yunpeng

2018-01-01

A 37-year-old man suffered irreversible profound symptomatic bradycardia requiring a pacemaker 3 days after beginning tizanidine/loxoprofen combination therapy for neck pain. This combination therapy is prescribed frequently for joint pain; however, combining loxoprofen with tizanidine could increase the risk of symptomatic bradycardia that is both permanent and severe. Similar cases have not been reported. This case suggests that tizanidine should be used cautiously when combined with loxoprofen, and drug interaction screening should be performed.

A Randomized Controlled Trial of Cognitive-Behavioral Therapy, Light Therapy, and Their Combination for Seasonal Affective Disorder

ERIC Educational Resources Information Center

Rohan, Kelly J.; Roecklein, Kathryn A.; Tierney Lindsey, Kathryn; Johnson, Leigh G.; Lippy, Robert D.; Lacy, Timothy J.; Barton, Franca B.

2007-01-01

This first controlled psychotherapy trial for seasonal affective disorder (SAD) compared SAD-tailored cognitive-behavioral therapy (CBT), light therapy (LT), and their combination to a concurrent wait-list control. Adults (N = 61) with major depression, recurrent with seasonal pattern, were randomized to one of four 6-week conditions: CBT (1.5-hr…

Antifungal Activity of Maytenin and Pristimerin

PubMed Central

Gullo, Fernanda P.; Sardi, Janaina C. O.; Santos, Vânia A. F. F. M.; Sangalli-Leite, Fernanda; Pitangui, Nayla S.; Rossi, Suélen A.; de Paula e Silva, Ana C. A.; Soares, Luciana A.; Silva, Julhiany F.; Oliveira, Haroldo C.; Furlan, Maysa; Silva, Dulce H. S.; Bolzani, Vanderlan S.; Mendes-Giannini, Maria José S.; Fusco-Almeida, Ana Marisa

2012-01-01

Fungal infections in humans have increased alarmingly in recent years, particularly in immunocompromised individuals. Among the infections systemic candidiasis, aspergillosis, cryptococcosis, paracoccidioidomycosis, and histoplasmosis mortality are more prevalent and more severe in humans. The current high incidence of dermatophytosis is in humans, especially as the main etiologic agents Trichophyton rubrum and Trichophyton mentagrophytes. Molecules pristimerin and maytenin obtained from the plant Maytenus ilicifolia (Celastraceae) are known to show various pharmacological activities. This study aimed to evaluate the spectrum of antifungal activity of maytenin and pristimerin and their cytotoxicity in human keratinocytes (NOK cells of the oral mucosa). It was concluded that the best spectrum of antifungal activity has been shown to maytenin with MIC varying from 0.12 to 125 mg/L, although it is also active with pristimerin MIC ranging between 0.12 and 250 mg/L. Regarding the toxicity, both showed to have high IC50. The SI showed high pristimerin against some species of fungi, but SI maytenin was above 1.0 for all fungi tested, showing a selective action of fungi. However, when comparing the two substances, maytenin also showed better results. The two molecules can be a possible prototype with a broad spectrum of action for the development of new antifungal agents. PMID:22675379

Ebselen exerts antifungal activity by regulating glutathione (GSH) and reactive oxygen species (ROS) production in fungal cells.

PubMed

Thangamani, Shankar; Eldesouky, Hassan E; Mohammad, Haroon; Pascuzzi, Pete E; Avramova, Larisa; Hazbun, Tony R; Seleem, Mohamed N

2017-01-01

Ebselen, an organoselenium compound and a clinically safe molecule has been reported to possess potent antifungal activity, but its antifungal mechanism of action and in vivo antifungal activity remain unclear. The antifungal effect of ebselen was tested against Candida albicans, C. glabrata, C. tropicalis, C. parapsilosis, Cryptococcus neoformans, and C. gattii clinical isolates. Chemogenomic profiling and biochemical assays were employed to identify the antifungal target of ebselen. Ebselen's antifungal activity in vivo was investigated in a Caenorhabditis elegans animal model. Ebselen exhibits potent antifungal activity against both Candida spp. and Cryptococcus spp., at concentrations ranging from 0.5 to 2μg/ml. Ebselen rapidly eradicates a high fungal inoculum within 2h of treatment. Investigation of the drug's antifungal mechanism of action indicates that ebselen depletes intracellular glutathione (GSH) levels, leading to increased production of reactive oxygen species (ROS), and thereby disturbs the redox homeostasis in fungal cells. Examination of ebselen's in vivo antifungal activity in two Caenorhabditis elegans models of infection demonstrate that ebselen is superior to conventional antifungal drugs (fluconazole, flucytosine and amphotericin) in reducing Candida and Cryptococcus fungal load. Ebselen possesses potent antifungal activity against clinically relevant isolates of both Candida and Cryptococcus by regulating GSH and ROS production. The potent in vivo antifungal activity of ebselen supports further investigation for repurposing it for use as an antifungal agent. The present study shows that ebselen targets glutathione and also support that glutathione as a potential target for antifungal drug development. Copyright © 2016 Elsevier B.V. All rights reserved.

Combined analgesics in (headache) pain therapy: shotgun approach or precise multi-target therapeutics?

PubMed

Straube, Andreas; Aicher, Bernhard; Fiebich, Bernd L; Haag, Gunther

2011-03-31

Pain in general and headache in particular are characterized by a change in activity in brain areas involved in pain processing. The therapeutic challenge is to identify drugs with molecular targets that restore the healthy state, resulting in meaningful pain relief or even freedom from pain. Different aspects of pain perception, i.e. sensory and affective components, also explain why there is not just one single target structure for therapeutic approaches to pain. A network of brain areas ("pain matrix") are involved in pain perception and pain control. This diversification of the pain system explains why a wide range of molecularly different substances can be used in the treatment of different pain states and why in recent years more and more studies have described a superior efficacy of a precise multi-target combination therapy compared to therapy with monotherapeutics. In this article, we discuss the available literature on the effects of several fixed-dose combinations in the treatment of headaches and discuss the evidence in support of the role of combination therapy in the pharmacotherapy of pain, particularly of headaches. The scientific rationale behind multi-target combinations is the therapeutic benefit that could not be achieved by the individual constituents and that the single substances of the combinations act together additively or even multiplicatively and cooperate to achieve a completeness of the desired therapeutic effect.As an example the fixed-dose combination of acetylsalicylic acid (ASA), paracetamol (acetaminophen) and caffeine is reviewed in detail. The major advantage of using such a fixed combination is that the active ingredients act on different but distinct molecular targets and thus are able to act on more signalling cascades involved in pain than most single analgesics without adding more side effects to the therapy. Multitarget therapeutics like combined analgesics broaden the array of therapeutic options, enable the completeness

Combined analgesics in (headache) pain therapy: shotgun approach or precise multi-target therapeutics?

PubMed Central

2011-01-01

Background Pain in general and headache in particular are characterized by a change in activity in brain areas involved in pain processing. The therapeutic challenge is to identify drugs with molecular targets that restore the healthy state, resulting in meaningful pain relief or even freedom from pain. Different aspects of pain perception, i.e. sensory and affective components, also explain why there is not just one single target structure for therapeutic approaches to pain. A network of brain areas ("pain matrix") are involved in pain perception and pain control. This diversification of the pain system explains why a wide range of molecularly different substances can be used in the treatment of different pain states and why in recent years more and more studies have described a superior efficacy of a precise multi-target combination therapy compared to therapy with monotherapeutics. Discussion In this article, we discuss the available literature on the effects of several fixed-dose combinations in the treatment of headaches and discuss the evidence in support of the role of combination therapy in the pharmacotherapy of pain, particularly of headaches. The scientific rationale behind multi-target combinations is the therapeutic benefit that could not be achieved by the individual constituents and that the single substances of the combinations act together additively or even multiplicatively and cooperate to achieve a completeness of the desired therapeutic effect. As an example the fixesd-dose combination of acetylsalicylic acid (ASA), paracetamol (acetaminophen) and caffeine is reviewed in detail. The major advantage of using such a fixed combination is that the active ingredients act on different but distinct molecular targets and thus are able to act on more signalling cascades involved in pain than most single analgesics without adding more side effects to the therapy. Summary Multitarget therapeutics like combined analgesics broaden the array of therapeutic

Design issues in a randomized controlled trial of a pre-emptive versus empiric antifungal strategy for invasive aspergillosis in patients with high-risk hematologic malignancies.

PubMed

Morrissey, C Orla; Chen, Sharon C-A; Sorrell, Tania C; Bradstock, Kenneth F; Szer, Jeffrey; Halliday, Catriona L; Gilroy, Nicole M; Schwarer, Anthony P; Slavin, Monica A

2011-02-01

Invasive aspergillosis (IA) is a major cause of mortality in patients with hematological malignancies, due largely to the inability of traditional culture and biopsy methods to make an early or accurate diagnosis. Diagnostic accuracy studies suggest that Aspergillus galactomannan (GM) enzyme immunoassay (ELISA) and Aspergillus PCR-based methods may overcome these limitations, but their impact on patient outcomes should be evaluated in a diagnostic randomized controlled trial (D-RCT). This article describes the methodology of a D-RCT which compares a new pre-emptive strategy (GM-ELISA- and Aspergillus PCR-driven antifungal therapy) with the standard fever-driven empiric antifungal treatment strategy. Issues including primary end-point and patient selection, duration of screening, choice of tests for the pre-emptive strategy, antifungal prophylaxis and bias control, which were considered in the design of the trial, are discussed. We suggest that the template presented herein is considered by researchers when evaluating the utility of new diagnostic tests (ClinicalTrials.gov number, NCT00163722).

A versatile nanoplatform for synergistic combination therapy to treat human esophageal cancer.

PubMed

Wang, Xin-Shuai; Kong, De-Jiu; Lin, Tzu-Yin; Li, Xiao-Cen; Izumiya, Yoshihiro; Ding, Xue-Zhen; Zhang, Li; Hu, Xiao-Chen; Yang, Jun-Qiang; Gao, She-Gan; Lam, Kit S; Li, Yuan-Pei

2017-06-01

One of the major goals of precision oncology is to promote combination therapy to improve efficacy and reduce side effects of anti-cancer drugs based on their molecular mechanisms. In this study, we aimed to develop and validate new nanoformulations of docetaxel (DTX) and bortezomib (BTZ) for targeted combination therapy to treat human esophageal cancer. By leveraging our versatile disulfide cross-linked micelles (DCMs) platform, we developed nanoformulations of DTX and BTZ (named DTX-DCMs and BTZ-DCMs). Their physical properties were characterized; their anti-cancer efficacies and mechanisms of action were investigated in a human esophageal cancer cell line in vitro. Furthermore, the in vitro anti-tumor activities of combination therapies (concurrent drug treatment, sequential drug treatment, and treatment using different ratios of the drugs) were examined in comparison with the single drug treatment and free drug strategies. These drug-loaded nanoparticles were spherical in shape and relatively small in size of approximately 20-22 nm. The entrapment efficiencies of DTX and BTZ into nanoparticles were 82.4% and 84.1%, respectively. The drug release rates of DTX-DCMs and BTZ-DCMs were sustained, and greatly increased in the presence of GSH. These nanodrugs were effectively internalized by KYSE30 esophageal cancer cells, and dose-dependently induced cell apoptosis. We further revealed a strong synergistic effect between DTX-DCMs and BTZ-DCMs against KYSE30 esophageal cancer cells. Sequential combination therapy with DTX-DCMs followed by BTZ-DCMs exhibited the best anti-tumor efficacy in vitro. This study demonstrates that DTX and BTZ could be successfully nanoformulated into disulfide cross-linked micelles. The nanoformulations of DTX and BTZ demonstrate an immense potential for synergistic combination therapy to treat human esophageal cancer.

The bacteriome-mycobiome interaction and antifungal host defense.

PubMed

Oever, Jaap Ten; Netea, Mihai G

2014-11-01

Large communities of microorganisms, collectively termed the microbiome, inhabit our body surfaces. With the advent of next-generation sequencing, the diversity and abundance of these communities are being unravelled. Besides an imporant role in metabolic processes, the microbiome is essential for proper functioning of our immune system, including the defense against fungi. Despite the progress of the past years, studies aimed at characterizing our fungal colonizers (the mycobiome) are limited; nevertheless fungi are important players of the microbiome, either as a cofactor in disease or as potential pathogens. In this review, we describe the role of the bacterial microbiome in antifungal host defense. On the one hand, bacteria provide colonization resistance to fungi, inhibit Candida virulence by preventing yeast-hyphal transition and contribute to epithelial integrity, all factors are important for the pathogenesis of invasive fungal disease. On the other hand, several bacterial species modulate mucosal (antifungal) immune responses. Murine studies demonstrate important effects of the microbiome on the antifungal responses of T-helper 17 cells, regulatory T cells and innate lymphoid cells. Inferred from these studies, perturbation of the healthy microbiome should be avoided and microbiome manipulation and interventions based on bacteria-derived pathways involved in immunomodulation are attractive options for modulating antifungal host defense. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

[In vitro antimicrobial, antiadherent and antifungal activity of Brazilian medicinal plants on oral biofilm microorganisms and strains of the genus Candida].

PubMed

Alves, Pollianna Muniz; Queiroz, Lélia Maria Guedes; Pereira, Jozinete Vieira; Pereira, Maria do Socorro Vieira

2009-01-01

The antimicrobial, antifungal and antiadherent activity of aroeira-do-sertão, mallow and guava tree on oral biofilm microorganisms and oral candidiasis was evaluated in vitro. The extracts were shown to be effective in inhibiting the growth of bacteria of the oral biofilm and fungi of oral candidiasis, thus suggesting that these extracts can be used as alternative means of dental therapy.

Theranostic GO-based nanohybrid for tumor induced imaging and potential combinational tumor therapy.

PubMed

Qin, Si-Yong; Feng, Jun; Rong, Lei; Jia, Hui-Zhen; Chen, Si; Liu, Xiang-Ji; Luo, Guo-Feng; Zhuo, Ren-Xi; Zhang, Xian-Zheng

2014-02-12

Graphene oxide (GO)-based theranostic nanohybrid is designed for tumor induced imaging and potential combinational tumor therapy. The anti-tumor drug, Doxorubicin (DOX) is chemically conjugated to the poly(ethylenimine)-co-poly(ethylene glycol) (PEI-PEG) grafted GO via a MMP2-cleavable PLGLAG peptide linkage. The therapeutic efficacy of DOX is chemically locked and its intrinsic fluorescence is quenched by GO under normal physiological condition. Once stimulated by the MMP2 enzyme over-expressed in tumor tissues, the resulting peptide cleavage permits the unloading of DOX for tumor therapy and concurrent fluorescence recovery of DOX for in situ tumor cell imaging. Attractively, this PEI-bearing nanohybrid can mediate efficient DNA transfection and shows great potential for combinational drug/gene therapy. This tumor induced imaging and potential combinational therapy will open a window for tumor treatment by offering a unique theranostic approach through merging the diagnostic capability and pathology-responsive therapeutic function. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Antifungal activities of ethanolic extract from Jatropha curcas seed cake.

PubMed

Saetae, Dolaporn; Suntornsuk, Worapot

2010-02-01

Phorbol ester extraction was carried out from Jatropha curcas seed cake, a by-product from the bio-diesel fuel industry. Four repeated extractions from 5 g J. curcas seed cake using 15 ml of 90% (v/v) ethanol and a shaking speed of 150 rev/min gave the highest yield of phosbol esters. The ethanolic extract of J. curcas seed cake showed antifungal activities against important phytofungal pathogens: Fusarium oxysporum, Pythium aphanidermatum, Lasiodiplodia theobromae, Curvularia lunata, Fusarium semitectum, Colletotrichum capsici and Colletotrichum gloeosporiodes. The extract contained phorbol esters mainly responsible for antifungal activities. The extract could therefore be used as an antifungal agent for agricultural applications.

A novel and exploitable antifungal peptide from kale (Brassica alboglabra) seeds.

PubMed

Lin, Peng; Ng, Tzi Bun

2008-10-01

The aim of this study was to purify and characterize antifungal peptides from kale seeds in view of the paucity of information on antifungal peptides from the family Brassicaceae, and to compare its characteristics with those of published Brassica antifungal peptides. A 5907-Da antifungal peptide was isolated from kale seeds. The isolation procedure comprised affinity chromatography on Affi-gel blue gel, ion exchange chromatography on SP-Sepharose and Mono S, and gel filtration on Superdex Peptide. The peptide was adsorbed on the first three chromatographic media. It inhibited mycelial growth in a number of fungal species including Fusarium oxysporum, Helminthosporium maydis, Mycosphaerella arachidicola and Valsa mali, with an IC(50) of 4.3microM, 2.1microM, 2.4microM, and 0.15microM, respectively and exhibited pronounced thermostability and pH stability. It inhibited proliferation of hepatoma (HepG2) and breast cancer (MCF7) cells with an IC(50) of 2.7microM and 3.4microM, and the activity of HIV-1 reverse transcriptase with an IC(50) of 4.9microM. Its N-terminal sequence differed from those of antifungal proteins which have been reported to date.

Antifungal activity of Zuccagnia punctata Cav.: evidence for the mechanism of action.

PubMed

Svetaz, Laura; Agüero, María Belén; Alvarez, Sandra; Luna, Lorena; Feresin, Gabriela; Derita, Marcos; Tapia, Alejandro; Zacchino, Susana

2007-08-01

Petroleum ether and dichloromethane extracts of fruits, aerial parts and exudate of Zuccagnia punctata Cav. (Fabaceae) showed moderate antifungal activities against the yeasts C. albicans, S. cerevisiae and C. neoformans (MICs: 62.5 - 250 microg/mL) and very strong antifungal activities against the dermatophytes M. gypseum, T. rubrum and T. mentagrophytes (MICs: 8 - 16 microg/mL) thus supporting the ethnopharmacological use of this plant. Antifungal activity-directed fractionation of active extracts by using bioautography led to the isolation of 2',4'-dihydroxy-3'-methoxychalcone (1) and 2',4'-dihydroxychalcone (2) as the compounds responsible for the antifungal activity. Second-order studies included MIC (80), MIC (50) and MFC of both chalcones in an extended panel of clinical isolates of the most sensitive fungi, and also comprised a series of targeted assays. They showed that the most active chalcone 2 is fungicidal rather than fungistatic, does not disrupt the fungal membranes up to 4 x MFC and does not act by inhibiting the fungal cell wall. So, 2',4'-dihydroxychalcone would act by a different mechanism of action than the antifungal drugs in current clinical use, such as amphotericin B, azoles or echinocandins, and thus appears to be very promising as a novel antifungal agent.

Feasibility Study Combining Art Therapy or Cognitive Remediation Therapy with Family-based Treatment for Adolescent Anorexia Nervosa.

PubMed

Lock, James; Fitzpatrick, Kathleen Kara; Agras, William S; Weinbach, Noam; Jo, Booil

2018-01-01

Adolescents with anorexia nervosa who have obsessive-compulsive (OC) features respond poorly to family-based treatment (FBT). This study evaluated the feasibility of combining FBT with either cognitive remediation therapy (CRT) or art therapy (AT) to improve treatment response in this at-risk group. Thirty adolescents with anorexia nervosa and OC features were randomized to 15 sessions of FBT + CRT or AT. Recruitment rate was 1 per month, and treatment attrition was 16.6% with no differences between groups. Suitability, expectancy and therapeutic relationships were acceptable for both combinations. Correlations between changes in OC traits and changes in cognitive inefficiencies were found for both combinations. Moderate changes in cognitive inefficiencies were found in both groups but were larger in the FBT + AT combination. This study suggests that an RCT for poor responders to FBT because of OC traits combining FBT with either CRT or AT is feasible to conduct. Copyright © 2017 John Wiley & Sons, Ltd and Eating Disorders Association. Copyright © 2017 John Wiley & Sons, Ltd and Eating Disorders Association.

Quantitative structure-antifungal activity relationships of some benzohydrazides against Botrytis cinerea.

PubMed

Reino, José L; Saiz-Urra, Liane; Hernandez-Galan, Rosario; Aran, Vicente J; Hitchcock, Peter B; Hanson, James R; Gonzalez, Maykel Perez; Collado, Isidro G

2007-06-27

Fourteen benzohydrazides have been synthesized and evaluated for their in vitro antifungal activity against the phytopathogenic fungus Botrytis cinerea. The best antifungal activity was observed for the N',N'-dibenzylbenzohydrazides 3b-d and for the N-aminoisoindoline-derived benzohydrazide 5. A quantitative structure-activity relationship (QSAR) study has been developed using a topological substructural molecular design (TOPS-MODE) approach to interpret the antifungal activity of these synthetic compounds. The model described 98.3% of the experimental variance, with a standard deviation of 4.02. The influence of an ortho substituent on the conformation of the benzohydrazides was investigated by X-ray crystallography and supported by QSAR study. Several aspects of the structure-activity relationships are discussed in terms of the contribution of different bonds to the antifungal activity, thereby making the relationships between structure and biological activity more transparent.

Atorvastatin Combined Nitroglycerin Therapy Confer Additive Effects on Rabbits with Dyslipidemia.

PubMed

Yang, Fang; Wang, Jindong; Li, Fei; Cui, Lei

2016-06-01

Endogenous nitric oxide (NO) is beneficial for inhibiting Rho-associated kinase 2 (ROCK2) expression. However, the effect of exogenous NO on ROCK2 expression is less investigated. Rabbits with dyslipidemia were produced and randomly assigned into untreated, atorvastatin, nitroglycerin and combined groups (n=10 in each group). Medication therapy was lasted for 2 weeks. Parameters of interest including lipid profiles, liver enzyme, C-reactive protein (CRP), malondialdehyde (MDA), NO level and ROCK2 level were assessed at baseline, 2 weeks of dyslipidemia establishment and 2 weeks of medication treatment. No significant difference in parameters was found between groups at baseline. With 2 weeks of dyslipidemia establishment, as compared to baseline, serum levels of lipid profiles, CRP and MDA were profoundly elevated. In addition, reduced NO generation and enhanced ROCK2 expression were also observed. With 2 weeks of medication therapy, lipid profiles, systemic inflammation (reflected as serum CRP level) and oxidation (reflected as serum MDA level) were improved in the atorvastatin and combined groups but not in the nitroglycerin group (P<0.05). Furthermore, increased NO production in accompany with reduced ROCK2 expression were observed in both the atorvastatin and nitroglycerin groups, and these benefits were further enhanced by combined therapy (P<0.05). No liver enzymes elevation was observed after 2 weeks of medication therapy. Nitroglycerin-derived exogenous NO could effectively inhibit ROCK2 expression in rabbits with dyslipidemia which is independent of lipid-modification, and these efficacies could be enhanced by statins therapy. © Georg Thieme Verlag KG Stuttgart · New York.

Controlled Trial of Very Low Calorie Diet, Behavior Therapy, and Their Combination in the Treatment of Obesity.

ERIC Educational Resources Information Center

Wadden, Thomas A; Stunkard, Albert J.

1986-01-01

Assessed the effectiveness of a combined program of very low calorie diet and behavior therapy in treating obesity. Combined treatment and behavior therapy alone subjects maintained weight losses; none of the diet alone subjects met the criterion used to define maintenance. Only those receiving behavior therapy alone and combined treatment showed…

Antifungal compounds from turmeric and nutmeg with activity against plant pathogens

USDA-ARS?s Scientific Manuscript database

The antifungal activity of twenty-two common spices was evaluated against plant pathogens using direct-bioautography coupled Colletotrichum bioassays. Turmeric, nutmeg, ginger, clove, oregano, cinnamon, anise, fennel, basil, black cumin, and black pepper showed antifungal activity against the plant ...

The effect of a combination therapy with myo-inositol and a combined oral contraceptive pill versus a combined oral contraceptive pill alone on metabolic, endocrine, and clinical parameters in polycystic ovary syndrome.

PubMed

Minozzi, Massimo; Costantino, Demetrio; Guaraldi, Claudia; Unfer, Vittorio

2011-11-01

Compare the effects of a combined contraceptive pill (OCP) in combination with myo-inositol (MI) on endocrine, metabolic, and clinical parameters in patients with polycystic ovary syndrome (PCOS). One hundred fifty-five patients with PCOS were enrolled in this prospective, open-label clinical study. Patients were assigned to receive oral treatment with OCP alone (estradiol (EE) 30 μg/gestodene 75 μg) or in combination with myo-inositol 4 g/die, for 12 months. OCP plus MI therapy resulted in a higher reduction of FG score compared with OCP alone therapy. The combined therapy (OCP plus MI) significantly decreased hyperinsulinaemia, by positively affecting the fasting insulin and glucose levels and homeostasis model assessment-insulin resistance parameters, while no significant changes were observed in the OCP group. Androgens serum levels decreased in both groups, but significantly more in the combined therapy group. The lipid profile was improved in the combined therapy group, by reducing low-density lipoprotein cholesterol levels and enhancing high-density lipoprotein cholesterol levels. Our data show that a combination of combined contraceptive pill and MI may be more effective in controlling endocrine, metabolic, and clinical profile in patients with PCOS than OCP alone, and may reduce insulin levels and insulin resistance. Hence, combined treatment may become a more effective long-term therapeutic choice for controlling PCOS symptoms.

Combination Therapy of Etanercept and Fumarates versus Etanercept Monotherapy in Psoriasis: A Randomized Exploratory Study

PubMed Central

van Bezooijen, Ji Sun; Balak, Deepak M.W.; van Doorn, Martijn B.A.; Looman, Caspar W.N.; Schreurs, Marco W.J.; Koch, Birgit C.P.; van Gelder, Teun; Prens, Errol P.

2016-01-01

Background Biologics are a safe and efficacious therapy for psoriasis. The drug survival of biologics may be disappointing, primarily due to loss of efficacy. Therefore, safe combination treatments are sought to improve their clinical response. Objective To assess the efficacy, safety and tolerability of the combination therapy of etanercept with fumarates versus etanercept monotherapy. Methods Thirty-three patients with psoriasis were randomized 1:1 to receive etanercept combined with fumarates or etanercept monotherapy. The primary outcome measure was the difference in PASI-75 response after 24 weeks; additionally, a longitudinal analysis was performed. An important secondary outcome measure was the proportion of patients with a Physician Global Assessment (PGA) of clear or almost clear. Adverse events were collected throughout the study. Results In the combination therapy group, 78% (14 out of 18 patients) reached PASI-75 at week 24 versus 57% (8 out of 14 patients) in the monotherapy group (p = 0.27). The longitudinal analysis showed a PASI reduction of 5.97% per week for the combination therapy group and of 4.76% for the monotherapy group (p = 0.11). In the combination therapy group, 94% (17 out of 18 patients) of patients had a PGA of clear/almost clear versus 64% (9 out of 14 patients) in the monotherapy group (p = 0.064). The incidence of mild gastrointestinal complaints was higher in the combination group than in the monotherapy group. Conclusion Using the PGA, combination therapy showed a trend towards faster improvement in the first 24 weeks. The difference in the PASI score between the two groups was not statistically significant. Addition of fumarates to etanercept for 48 weeks appeared safe with an acceptable tolerability. PMID:27576483

Antifungal activity of 10 Guadeloupean plants.

PubMed

Biabiany, Murielle; Roumy, Vincent; Hennebelle, Thierry; François, Nadine; Sendid, Boualem; Pottier, Muriel; Aliouat, El Moukhtar; Rouaud, Isabelle; Lohézic-Le Dévéhat, Françoise; Joseph, Henry; Bourgeois, Paul; Sahpaz, Sevser; Bailleul, François

2013-11-01

Screening of the antifungal activities of ten Guadeloupean plants was undertaken to find new extracts and formulations against superficial mycoses such as onychomycosis, athlete's foot, Pityriasis versicolor, as well as the deep fungal infection Pneumocystis pneumonia. For the first time, the CMI of these plant extracts [cyclohexane, ethanol and ethanol/water (1:1, v/v)] was determined against five dermatophytes, five Candida species, Scytalidium dimidiatum, a Malassezia sp. strain and Pneumocystis carinii. Cytotoxicity tests of the most active extracts were also performed on an HaCat keratinocyte cell line. Results suggest that the extracts of Bursera simaruba, Cedrela odorata, Enterolobium cyclocarpum and Pluchea carolinensis have interesting activities and could be good candidates for developing antifungal formulations. Copyright © 2012 John Wiley & Sons, Ltd.

Exploring the molecular basis of antifungal synergies using genome-wide approaches

USDA-ARS?s Scientific Manuscript database

This is a review article summarizing genomic profiling strategies for determining the mechanism of action of antifungal synergies, and highlighting the potential applications of these technologies. Given the limitations of currently available antifungal agents and the development of drug resistance...

In vitro production and antifungal activity of peptide ABP-dHC-cecropin A.

PubMed

Zhang, Jiaxin; Movahedi, Ali; Xu, Junjie; Wang, Mengyang; Wu, Xiaolong; Xu, Chen; Yin, Tongming; Zhuge, Qiang

2015-04-10

The antimicrobial peptide ABP-dHC-cecropin A is a small cationic peptide with potent activity against a wide range of bacterial species. Evidence of antifungal activity has also been suggested; however, testing of this peptide has been limited due to the low expression of cecropin proteins in Escherichia coli. To improve expression of this peptide in E. coli, ABP-dHC-cecropin A was cloned into a pSUMO vector and transformed into E. coli, resulting in the production of a pSUMO-ABP-dHC-cecropin A fusion protein. The soluble form of this protein was then purified by Ni-IDA chromatography, yielding a total of 496-mg protein per liter of fermentation culture. The SUMO-ABP-dHC-cecropin A fusion protein was then cleaved using a SUMO protease and re-purified by Ni-IDA chromatography, yielding a total of 158-mg recombinant ABP-dHC-cecropin A per liter of fermentation culture at a purity of ≥94%, the highest yield reported to date. Antifungal activity assays performed using this purified recombinant peptide revealed strong antifungal activity against both Candida albicans and Neurospora crassa, as well as Rhizopus, Fusarium, Alternaria, and Mucor species. Combined with previous analyses demonstrating strong antibacterial activity against a number of important bacterial pathogens, these results confirm the use of ABP-dHC-cecropin A as a broad-spectrum antimicrobial peptide, with significant therapeutic potential. Copyright © 2015 Elsevier B.V. All rights reserved.

Advances in combination therapy of lung cancer: Rationales, delivery technologies and dosage regimens.

PubMed

Wu, Lan; Leng, Donglei; Cun, Dongmei; Foged, Camilla; Yang, Mingshi

2017-08-28

Lung cancer is a complex disease caused by a multitude of genetic and environmental factors. The progression of lung cancer involves dynamic changes in the genome and a complex network of interactions between cancer cells with multiple, distinct cell types that form tumors. Combination therapy using different pharmaceuticals has been proven highly effective due to the ability to affect multiple cellular pathways involved in the disease progression. However, the currently used drug combination designs are primarily based on empirical clinical studies, and little attention has been given to dosage regimens, i.e. how administration routes, onsets, and durations of the combinations influence the therapeutic outcome. This is partly because combination therapy is challenged by distinct physicochemical properties and in vivo pharmacokinetics/pharmacodynamics of the individual pharmaceuticals, including small molecule drugs and biopharmaceuticals, which make the optimization of dosing and administration schedule challenging. This article reviews the recent advances in the design and development of combinations of pharmaceuticals for the treatment of lung cancer. Focus is primarily on rationales for the selection of specific combination therapies for lung cancer treatment, and state of the art of delivery technologies and dosage regimens for the combinations, tested in preclinical and clinical trials. Copyright © 2017 Elsevier B.V. All rights reserved.

Combining Dopaminergic Facilitation with Robot-Assisted Upper Limb Therapy in Stroke Survivors

PubMed Central

Tran, Duc A.; Pajaro-Blazquez, Marta; Daneault, Jean-Francois; Gallegos, Jaime G.; Pons, Jose; Fregni, Felipe; Bonato, Paolo; Zafonte, Ross

2016-01-01

ABSTRACT Despite aggressive conventional therapy, lasting hemiplegia persists in a large percentage of stroke survivors. The aim of this article is to critically review the rationale behind targeting multiple sites along the motor learning network by combining robotic therapy with pharmacotherapy and virtual reality–based reward learning to alleviate upper extremity impairment in stroke survivors. Methods for personalizing pharmacologic facilitation to each individual’s unique biology are also reviewed. At the molecular level, treatment with levodopa was shown to induce long-term potentiation-like and practice-dependent plasticity. Clinically, trials combining conventional therapy with levodopa in stroke survivors yielded statistically significant but clinically unconvincing outcomes because of limited personalization, standardization, and reproducibility. Robotic therapy can induce neuroplasticity by delivering intensive, reproducible, and functionally meaningful interventions that are objective enough for the rigors of research. Robotic therapy also provides an apt platform for virtual reality, which boosts learning by engaging reward circuits. The future of stroke rehabilitation should target distinct molecular, synaptic, and cortical sites through personalized multimodal treatments to maximize motor recovery. PMID:26829074

Clinical experience in treating hypertension with fixed-dose combination therapy: angiotensin II receptor blocker losartan plus hydrochlorothiazide.

PubMed

Abe, Masanori; Okada, Kazuyoshi; Matsumoto, Koichi

2009-10-01

The goal of antihypertensive treatment is to reduce cardiovascular and cerebrovascular events associated with high blood pressure. A combination therapy with different antihypertensive agents is more successful than monotherapy in most hypertensive patients, with the added advantage of a better safety profile. Therefore, treatment of hypertensive patients with fixed-dose combination therapy consisting of the angiotensin II receptor blocker losartan along with hydrochlorothiazide (HCTZ) has several potential benefits over monotherapy with each individual component. It provides more effective blood pressure control, a reduction in the likelihood of adverse effects and facilitation of patient compliance due to a simple once-daily regimen. One of the advantages of the combination of losartan with HCTZ is the potential reduction in HCTZ-induced metabolic disorders; in particular, this combination can have attractive benefits for patients of hyperuricemia. Losartan plus HCTZ fixed-dose combination therapy is frequently recommended for the treatment of hypertension and lowers blood pressure in mild-to-moderate and even severe hypertensive patients to a level comparable with other classes of antihypertensive agents in combination with HCTZ. Fixed-dose combination therapy with losartan plus HCTZ is a logical choice as antihypertensive therapy for patients in whom combination therapy is necessary to achieve additional blood pressure reduction.

Cancer nanomedicine: gold nanoparticle mediated combined cancer therapy

NASA Astrophysics Data System (ADS)

Yang, C.; Bromma, Kyle; Chithrani, B. D.

2018-02-01

Recent developments in nanotechnology has provided new tools for cancer therapy and diagnosis. Among other nanomaterial systems, gold nanoparticles are being used as radiation dose enhancers and anticancer drug carriers in cancer therapy. Fate of gold nanoparticles within biological tissues can be probed using techniques such as TEM (transmission electron microscopy) and SEM (Scanning Electron Microscopy) due to their high electron density. We have shown for the first time that cancer drug loaded gold nanoparticles can reach the nucleus (or the brain) of cancer cells enhancing the therapeutic effect dramatically. Nucleus of the cancer cells are the most desirable target in cancer therapy. In chemotherapy, smart delivery of highly toxic anticancer drugs through packaging using nanoparticles will reduce the side effects and improve the quality and care of cancer patients. In radiation therapy, use of gold nanoparticles as radiation dose enhancer is very promising due to enhanced localized dose within the cancer tissue. Recent advancement in nanomaterial characterization techniques will facilitate mapping of nanomaterial distribution within biological specimens to correlate the radiobiological effects due to treatment. Hence, gold nanoparticle mediated combined chemoradiation would provide promising tools to achieve personalized and tailored cancer treatments in the near future.

Combination therapies - the next logical step for the treatment of synucleinopathies?

PubMed Central

Valera, E.; Masliah, E.

2015-01-01

Currently there are no disease-modifying alternatives for the treatment of most neurodegenerative disorders. The available therapies for diseases such as Parkinson’s disease (PD), PD dementia (PDD), Dementia with Lewy bodies (DLB) and Multiple system atrophy (MSA), in which the protein alpha-synuclein (α-syn) accumulates within neurons and glial cells with toxic consequences, are focused on managing the disease symptoms. However, utilizing strategic drug combinations and/or multi-target drugs might increase the treatment efficiency when compared to monotherapies. Synucleinopathies are complex disorders that progress through several stages, and toxic α-syn aggregates exhibit prion-like behavior spreading from cell to cell. Therefore, it follows that these neurodegenerative disorders might require equally complex therapeutic approaches in order to obtain significant and long-lasting results. Hypothetically, therapies aimed at reducing α-syn accumulation and cell-to-cell transfer, such as immunotherapy against α-syn, could be combined with agents that reduce neuroinflammation with potential synergistic outcomes. Here we review the current evidence supporting this type of approach, suggesting that such rational therapy combinations, together with the use of multi-target drugs, may hold promise as the next logical step for the treatment of synucleinopathies. PMID:26388203

Histoplasmosis Complicating Tumor Necrosis Factor–α Blocker Therapy: A Retrospective Analysis of 98 Cases

PubMed Central

Vergidis, Paschalis; Avery, Robin K.; Wheat, L. Joseph; Dotson, Jennifer L.; Assi, Maha A.; Antoun, Smyrna A.; Hamoud, Kassem A.; Burdette, Steven D.; Freifeld, Alison G.; McKinsey, David S.; Money, Mary E.; Myint, Thein; Andes, David R.; Hoey, Cynthia A.; Kaul, Daniel A.; Dickter, Jana K.; Liebers, David E.; Miller, Rachel A.; Muth, William E.; Prakash, Vidhya; Steiner, Frederick T.; Walker, Randall C.; Hage, Chadi A.

2015-01-01

Background. Histoplasmosis may complicate tumor necrosis factor (TNF)–α blocker therapy. Published case series provide limited guidance on disease management. We sought to determine the need for long-term antifungal therapy and the safety of resuming TNF-α blocker therapy after successful treatment of histoplasmosis. Methods. We conducted a multicenter retrospective review of 98 patients diagnosed with histoplasmosis between January 2000 and June 2011. Multivariate logistic regression was used to evaluate risk factors for severe disease. Results. The most commonly used biologic agent was infliximab (67.3%). Concomitant corticosteroid use (odds ratio [OR], 3.94 [95% confidence interval {CI}, 1.06–14.60]) and higher urine Histoplasma antigen levels (OR, 1.14 [95% CI, 1.03–1.25]) were found to be independent predictors of severe disease. Forty-six (47.4%) patients were initially treated with an amphotericin B formulation for a median duration of 2 weeks. Azole treatment was given for a median of 12 months. TNF-α blocker therapy was initially discontinued in 95 of 98 (96.9%) patients and later resumed in 25 of 74 (33.8%) patients at a median of 12 months (range, 1–69 months). The recurrence rate was 3.2% at a median follow-up period of 32 months. Of the 3 patients with recurrence, 2 had restarted TNF-α blocker therapy, 1 of whom died. Mortality rate was 3.2%. Conclusions. In this study, disease outcomes were generally favorable. Discontinuation of antifungal treatment after clinical response and an appropriate duration of therapy, probably at least 12 months, appears safe if pharmacologic immunosuppression has been held. Resumption of TNF-α blocker therapy also appears safe, assuming that the initial antifungal therapy was administered for 12 months. PMID:25870331

Histoplasmosis complicating tumor necrosis factor-α blocker therapy: a retrospective analysis of 98 cases.

PubMed

Vergidis, Paschalis; Avery, Robin K; Wheat, L Joseph; Dotson, Jennifer L; Assi, Maha A; Antoun, Smyrna A; Hamoud, Kassem A; Burdette, Steven D; Freifeld, Alison G; McKinsey, David S; Money, Mary E; Myint, Thein; Andes, David R; Hoey, Cynthia A; Kaul, Daniel A; Dickter, Jana K; Liebers, David E; Miller, Rachel A; Muth, William E; Prakash, Vidhya; Steiner, Frederick T; Walker, Randall C; Hage, Chadi A

2015-08-01

Histoplasmosis may complicate tumor necrosis factor (TNF)-α blocker therapy. Published case series provide limited guidance on disease management. We sought to determine the need for long-term antifungal therapy and the safety of resuming TNF-α blocker therapy after successful treatment of histoplasmosis. We conducted a multicenter retrospective review of 98 patients diagnosed with histoplasmosis between January 2000 and June 2011. Multivariate logistic regression was used to evaluate risk factors for severe disease. The most commonly used biologic agent was infliximab (67.3%). Concomitant corticosteroid use (odds ratio [OR], 3.94 [95% confidence interval {CI}, 1.06-14.60]) and higher urine Histoplasma antigen levels (OR, 1.14 [95% CI, 1.03-1.25]) were found to be independent predictors of severe disease. Forty-six (47.4%) patients were initially treated with an amphotericin B formulation for a median duration of 2 weeks. Azole treatment was given for a median of 12 months. TNF-α blocker therapy was initially discontinued in 95 of 98 (96.9%) patients and later resumed in 25 of 74 (33.8%) patients at a median of 12 months (range, 1-69 months). The recurrence rate was 3.2% at a median follow-up period of 32 months. Of the 3 patients with recurrence, 2 had restarted TNF-α blocker therapy, 1 of whom died. Mortality rate was 3.2%. In this study, disease outcomes were generally favorable. Discontinuation of antifungal treatment after clinical response and an appropriate duration of therapy, probably at least 12 months, appears safe if pharmacologic immunosuppression has been held. Resumption of TNF-α blocker therapy also appears safe, assuming that the initial antifungal therapy was administered for 12 months. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

The Clinical Development of Molecularly Targeted Agents in Combination With Radiation Therapy: A Pharmaceutical Perspective

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ataman, Ozlem U., E-mail: ouataman@hotmail.com; Sambrook, Sally J.; Wilks, Chris

2012-11-15

Summary: This paper explores historical and current roles of pharmaceutical industry sponsorship of clinical trials testing radiation therapy combinations with molecularly targeted agents and attempts to identify potential solutions to expediting further combination studies. An analysis of clinical trials involving a combination of radiation therapy and novel cancer therapies was performed. Ongoing and completed trials were identified by searching the (clinicaltrials.gov) Web site, in the first instance, with published trials of drugs of interest identified through American Society of Clinical Oncology, European CanCer Organisation/European Society for Medical Oncology, American Society for Radiation Oncology/European Society for Therapeutic Radiology and Oncology, andmore » PubMed databases and then cross-correlated with (clinicaltrials.gov) protocols. We examined combination trials involving radiation therapy with novel agents and determined their distribution by tumor type, predominant molecular mechanisms examined in combination to date, timing of initiation of trials relative to a novel agent's primary development, and source of sponsorship of such trials. A total of 564 studies of targeted agents in combination with radiation therapy were identified with or without concomitant chemotherapy. Most studies were in phase I/II development, with only 36 trials in phase III. The tumor site most frequently studied was head and neck (26%), followed by non-small cell lung cancer. Pharmaceutical companies were the sponsors of 33% of studies overall and provided support for only 16% of phase III studies. In terms of pharmaceutical sponsorship, Genentech was the most active sponsor of radiation therapy combinations (22%), followed by AstraZeneca (14%). Most radiation therapy combination trials do not appear to be initiated until after drug approval. In phase III studies, the most common (58%) primary endpoint was overall survival. Collectively, this analysis suggests

Antimicrobial photodynamic therapy combined with conventional endodontic treatment to eliminate root canal biofilm infection.

PubMed

Garcez, Aguinaldo S; Ribeiro, Martha S; Tegos, George P; Núñez, Silvia C; Jorge, Antonio O C; Hamblin, Michael R

2007-01-01

To compare the effectiveness of antimicrobial photodynamic therapy (PDT), standard endodontic treatment and the combined treatment to eliminate bacterial biofilms present in infected root canals. Ten single-rooted freshly extracted human teeth were inoculated with stable bioluminescent Gram-negative bacteria, Proteus mirabilis and Pseudomonas aeruginosa to form 3-day biofilms in prepared root canals. Bioluminescence imaging was used to serially quantify bacterial burdens. PDT employed a conjugate between polyethylenimine and chlorin(e6) as the photosensitizer (PS) and 660-nm diode laser light delivered into the root canal via a 200-micro fiber, and this was compared and combined with standard endodontic treatment using mechanical debridement and antiseptic irrigation. Endodontic therapy alone reduced bacterial bioluminescence by 90% while PDT alone reduced bioluminescence by 95%. The combination reduced bioluminescence by >98%, and importantly the bacterial regrowth observed 24 hours after treatment was much less for the combination (P<0.0005) than for either single treatment. Bioluminescence imaging is an efficient way to monitor endodontic therapy. Antimicrobial PDT may have a role to play in optimized endodontic therapy. (c) 2006 Wiley-Liss, Inc.

Results from different patient populations using combined therapy with alprostadil and sildenafil: predictors of satisfaction.

PubMed

Mydlo, J H; Volpe, M A; MacChia, R J

2000-09-01

To evaluate the outcome of combined therapy (using intraurethral alprostadil and oral sildenafil) in private and clinic patients with erectile dysfunction, and thus assess predictors of satisfaction. In all, 360 men were treated for erectile dysfunction using single and/or combined therapy, comprising 214 private-practice and 166 clinic patients. Responses were evaluated using the International Index for Erectile Function (IIEF) questionnaire before and after treatment. Serum testosterone levels, education and socio-economic status were also assessed. Group 1a consisted of 33 private patients and Group 1b of 24 clinic patients who tried the maximum dose of intraurethral alprostadil monotherapy initially, followed by the maximum dose of sildenafil monotherapy, and remained dissatisfied. Group 2a consisted of 32 private patients and group 2b of 31 clinic patients who tried the maximum dose of sildenafil monotherapy initially, followed by the maximum dose of alprostadil monotherapy, and were also dissatisfied. These two groups of 65 private and 55 clinic patients then underwent combined therapy. The mean (SD) score for erectile function was 24.1 (2) for combined therapy (a 123% improvement), and 19.8 (1. 8) (83% improvement) and 15.2 (1.6) (41% improvement) for sildenafil and alprostadil monotherapies (P < 0.05 for both patient groups). The men also reported an improvement in their satisfaction with intercourse. However, at 18 months, 60 of the 65 private patients but only 40 of the 55 clinic patients continued with combined therapy; thus, the discontinuation rate was three times greater among clinic than among private patients. Furthermore, the private patients had an overall improvement in the satisfaction score of 128%, compared with 51% for the clinic patients. Although there were no significant differences in erectile function improvement within the two satisfied combined therapy groups, the differences in overall satisfaction and long-term withdrawal rates

Comparison of antifungal activities of Vietnamese citrus essential oils.

PubMed

Van Hung, Pham; Chi, Pham Thi Lan; Phi, Nguyen Thi Lan

2013-03-01

Citrus essential oils (EOs) are volatile compounds from citrus peels and widely used in perfumes, cosmetics, soaps and aromatherapy. In this study, inhibition of citrus EOs extracted from Vietnamese orange (Citrus sinensis), mandarin (Citrus reticulata Blanco), pomelo (Citrus grandis Osbeck) and lime (Citrus aurantifolia Swingle) on the growth of plant pathogenic fungi, Mucor hiemalis, Penicillium expansum and Fusarium proliferatum was investigated. The EOs of the citrus peels were obtained by cold-pressing method and the antifungal activity of EOs was evaluated using the agar dilution method. The results show that the EOs had significant antifungal activity. Lime EO was the best inhibitor of M. hiemalis and F. proliferatum while pomelo EO was the most effective against P. expansum. These results indicate that citrus EOs can be used as antifungal natural products in the food, pharmaceutical and cosmetic industries.

Access to artemisinin-based combination therapies and other anti-malarial drugs in Kinshasa.

PubMed

Nkoli Mandoko, P; Sinou, V; Moke Mbongi, D; Ngoyi Mumba, D; Kahunu Mesia, G; Losimba Likwela, J; Bi Shamamba Karhemere, S; Muepu Tshilolo, L; Tamfum Muyembe, J-J; Parzy, D

2018-06-01

Artemisinin-based combination therapies have been available since 2005 in the Democratic Republic of the Congo to treat malaria and to overcome the challenge of anti-malarial drug resistance as well as to improve access to effective treatments. The private sector is the primary distribution source for anti-malarial drugs and thus, has a key position among the supply chain actors for a rational and proper use of anti-malarial drugs. We aimed to assess access to nationally recommended anti-malarial drugs in private sector pharmacies of the capital-city of Kinshasa. We performed a cross-sectional survey of 404 pharmacies. Anti-malarial drugs were stocked in all surveyed pharmacies. Non-artemisinin-based anti-malarial therapies such as quinine or sulfadoxine-pyrimethamine, were the most frequently stocked drugs (93.8% of pharmacies). Artemisinin-based combination therapies were stocked in 88% of pharmacies. Artemether-lumefantrine combinations were the most frequently dispensed drugs (93% of pharmacies), but less than 3% were quality-assured products. Other non-officially recommended artemisinin-based therapies including oral monotherapies were widely available. Artemisinin-based combination therapies were widely available in the private pharmacies of Kinshasa. However, the private sector does not guarantee the use of nationally recommended anti-malarial drugs nor does it give priority to quality-assured anti-malarial drugs. These practices contribute to the risk of emergence and spread of resistance to anti-malarial drugs and to increasing treatment costs. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Dynamics of Mixed- Candida Species Biofilms in Response to Antifungals.

PubMed