Effects of calcineurin inhibitors, cyclosporine A and tacrolimus (FK506), on the activity of antifungal drugs against Candida spp.

Introduction. The simultaneous use of antifungals with immunosuppressive agents has become a necessity for patients taking immunosuppressive therapy. However, antifungal drugs are problematic because of their limited target. Hypothesis. Scientists have been searching for new antifungals and some compounds with at least additive effects on antifungals. Calcineurin inhibitors used as immunosuppressive agents also attract attention due to their antifungal property. Aim. To evaluate the activity of two calcineurin inhibitors alone and in combination with amphotericin B (AMB), caspofungin (CAS), itraconazole (ITR), voriconazole (VOR) and fluconazole (FLU). Methodology. MICs of AMB, CAS, ITR, VOR, FLU and cyclosporine A (CsA) and tacrolimus (TAC) as calcineurin inhibitors were evaluated by the broth microdilution method against Candida albicans (n=13), C. krusei (n=7) and C. glabrata (n=10). Checkerboard and time-kill methods were performed to investigate the activity of combining calcineurin inhibitors with antifungal drugs. Results. The lowest MIC values were detected with VOR for all Candida isolates tested. Although we did not detect any inhibition for CsA or TAC alone at concentrations tested in this study, the combinations of CAS with CsA showed the highest synergistic activity (36.7%) by the checkerboard method, and CAS with CsA and ITR with TAC combinations exhibited apparent synergistic interaction by the time-kill method. However, the combinations of both CsA and TAC with AMB resulted in antagonistic interactions, especially against C. krusei isolate in time-kill testing. Conclusion. Synergistic interactions in the combinations of TAC or CsA with antifungal drugs, except for AMB, in many concentrations was found to be promising in terms of the treatment of patients with fungal infections.

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Antifungal Susceptibility of Dermatophytes Isolated From Cutaneous Fungal Infections: The Vietnamese Experience

Open Access Macedonian Journal of Medical Sciences ◽

10.3889/oamjms.2019.062 ◽

2019 ◽

Vol 7 (2) ◽

pp. 247-249

Author(s):

Chau Van Tro ◽

Khuong Ho Thi Ngoc ◽

Thuong Nguyen Van ◽

Khang Tran Hau ◽

Marco Gandolfi ◽

...

Keyword(s):

Fungal Infections ◽

Antifungal Susceptibility ◽

Antifungal Drugs ◽

Broth Microdilution ◽

Direct Examination ◽

Sensitivity Testing ◽

Microdilution Method ◽

Broth Microdilution Method ◽

Vietnamese Population

AIM: Evaluate the resistance of dermatophytes to systemic antifungal drugs in the Vietnamese population. METHODS: We enrolled 101 patients with cutaneous dermatophytosis at the Dermato-Venereology hospital in HCMC from August 2016 to March 2017. All the specimens were subjected to direct examination (10% KOH mount) and culture on Sabouraud dextrose agar. In vitro antifungal sensitivity testing was done on species isolated from a culture with broth microdilution method. RESULTS: Direct microscopy was positive for dermatophytes in all patients. However this pathogen was found in fungal cultures in only 61.38% of patients. The main causative agent isolated was Trichophyton spp. (90.3%), followed by Microsporum spp. (8%) and Epidermophyton spp. (1.7%). Trichophyton spp. Has shown resistance to fluconazole, griseofulvin, ketoconazole, and itraconazole in 92.9%, 46.4%, 5.4% and 1.8% of strains, respectively. All Microsporum spp. Strains were found resistant to fluconazole and griseofulvin while resistance to ketoconazole was demonstrated in only 20% of strains and none of them was resistant to itraconazole. Epidermophyton spp strains were all resistant to fluconazole, griseofulvin, ketoconazole while none of them was resistant to itraconazole. CONCLUSION: Based upon our results, Itraconazole shows the greatest probability of efficacy in the treatment of cutaneous dermatophytosis in Vietnamese patients.

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In vitro synergism of simvastatin and fluconazole against Candida species

Revista do Instituto de Medicina Tropical de São Paulo ◽

10.1590/s0036-46652012000400003 ◽

2012 ◽

Vol 54 (4) ◽

pp. 197-199 ◽

Cited By ~ 11

Author(s):

Everardo Albuquerque Menezes ◽

Antônio Alexandre de Vasconcelos Júnior ◽

Carlla Lorena Façanha Silva ◽

Fábio Ximenes Plutarco ◽

Maria da Conceição dos Santos Oliveira Cunha ◽

...

Keyword(s):

Synergistic Effect ◽

Susceptibility Testing ◽

Inhibitory Concentration ◽

Fungal Infections ◽

Candida Spp ◽

Microdilution Method ◽

Broth Microdilution Method ◽

Antifungal Action ◽

Systemic Infections

Systemic fungal infections are responsible for high mortality rates. Several species of fungi may be involved, but Candida spp. is the most prevalent. Simvastatin is used to lower cholesterol and also exhibits antifungal action. The aim of this study was to evaluate the synergistic action of simvastatin with fluconazole against strains of Candida spp. Susceptibility testing was performed according to protocol M27-A3, by broth microdilution method and the synergistic effect of simvastatin and fluconazole was calculated based on FICI (Fractional Inhibitory Concentration Index). Eleven strains were evaluated, and simvastatin showed a synergistic effect with fluconazole against 10 (91%) of the Candida spp. strains tested. Simvastatin may be a valuable drug in the treatment of systemic infections caused by Candida spp.

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Azoles resistance reversal by oridonin in Candida albicans

10.21203/rs.3.rs-22212/v1 ◽

2020 ◽

Author(s):

Wenna Shi ◽

Haisheng Chen ◽

Hui Li ◽

Cunxian Duan ◽

Chuanjie Song ◽

...

Keyword(s):

Candida Albicans ◽

Efflux Pump ◽

Fungal Infections ◽

Annexin V ◽

Housekeeping Gene ◽

Drug Efflux ◽

Synergistic Activity ◽

Microdilution Method ◽

Resistance Reversal ◽

Time Kill

Abstract Background Candida albicans (C. albicans) is a yeast causing hazardous fungal infections with high mortality, especially accompanied by resistance to azole drugs (fluconazole, itraconazole and voriconazole). To overcome the azoles resistance of C. albicans, we explored the Oridonin (ORI) with three azole drugs mainly focused on the synergistic activity. In this study, C. albicans strains were obtained from cancer patients, and the reversal of drug resistance of azole-resistant C. albicans was further studied. Methods The synergistic antifungal activities of ORI and azoles were measured by checkerboard microdilution and time-kill assays. The resistance reversal mechanisms, inhibition of drug efflux and induction of apoptosis, were investigated by flow cytometry after Annexin V-FITC/PI co-staining. The expression levels of efflux pump related genes CDR1 and CDR2 were quantitatively detected by qRT-PCR. Results The azole-resistant isolates identified by checkerboard microdilution method and time-kill curves. The efflux pump inhibition assay with ORI showed that the MIC of fluconazole (128-fold), itraconazole (64-fold) and voriconazole (250-fold) decreased significantly. The upregulation of genes coding for CDR1 and CDR2 were confirmed by qPCR with respect to the housekeeping gene ACT1 in the resistant strain. The sensitizing effect of ORI on fluconazole in the treatment of C. albicans also includes promoting apoptosis. We demonstrated that the combination of azoles with ORI exerted potent synergism and further displayed that ORI could promote the sensitization to azoles for azoles-resistant C. albicans. Conclusions We speculate that the resistance to azoles depends on the overexpression of efflux pump and its related genes CDR1 and CDR2, which reduces the accessibility of antifungal agents to C. albicans. The discovery that ORI can effectively inhibit drug efflux and promote apoptosis may provide new insights and therapeutic strategies for overcoming the increasing azole resistance in C. albicans infections.

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ANTIFUNGAL ACTIVITY OF THE ASSOCIATION OF CARVACROL WITH AMPHOTERICIN B OR WITH KETOCONAZOLE

Periódico Tchê Química ◽

10.52571/ptq.v16.n31.2019.18_periodico31_pgs_12_17.pdf ◽

2019 ◽

Vol 16 (31) ◽

pp. 12-17

Author(s):

Gustavo Lima SOARES ◽

Brenda Lavínia Calixto dos SANTOS ◽

Brenna Ravena Araújo LUZ ◽

Wylly Araújo de OLIVEIRA

Keyword(s):

Antifungal Activity ◽

Amphotericin B ◽

Inhibitory Concentration ◽

Fungal Infections ◽

Antifungal Drugs ◽

Aspergillus Species ◽

Microdilution Method ◽

Broth Microdilution Method ◽

Antifungal Action

Aspergillus species are a cause of a high number of fungal infections of difficult treatment, presenting an expressive number of deaths due to the complications in the severe cases of infection. The objective was to evaluate the antifungal action of carvacrol against Aspergillus species, as well as to evaluate the interactions when associated with amphotericin B or ketoconazole. The antifungal activity of carvacrol was evaluated by the broth microdilution method. The combinations of the substances were performed by the checkerboard methodology, to determine the Index of Fractional Inhibitory Concentration. Carvacrol showed antifungal activity against all Aspergillus strains used in the trials. In combinations of substances, only a combination of carvacrol and amphotericin B presented satisfactory results. Combinations of carvacrol and ketoconazole have not shown good. It is concluded that carvacrol is a good candidate for the antifungal drug because of its good activity against Aspergillus demonstrated in the present study, as well as in other studies in the literature. Their combination in vitro with amphotericin B or ketoconazole did not present any advantages over the use of antifungal drugs alone.

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Synthesis of 5-amino-1-aryl-3-methyl-1H-pyrazole-4-carbonitriles, Antifungal Activity and In Silico Analysis

Letters in Organic Chemistry ◽

10.2174/1570178617666200210105246 ◽

2020 ◽

Vol 17 (10) ◽

pp. 779-787

Author(s):

Luciana Terra ◽

Daiane de Jesus Viegas ◽

Alice Maria Rolim Bernardino ◽

Jéssica Venância Faria ◽

Percilene Fazolin Vegi ◽

...

Keyword(s):

Antifungal Activity ◽

Fungal Infections ◽

In Silico Analysis ◽

Single Step ◽

Antifungal Drugs ◽

Candida Spp ◽

Disk Diffusion Test ◽

Chemical Structures ◽

Microdilution Method ◽

Drug Classes

Serious fungal infections are increasing worldwide and have become a great concern in the medical field since antifungal drugs are restricted to a few drug classes. This work aims to evaluate the antifungal activity of a series of 5-amino-1-aryl-3-methyl-1H-pyrazole-4-carbonitriles (1a-g) and to establish a structure-activity relationship (SAR). The synthesis of these compounds was carried out in a single step followed by cyclization in good to excellent yields i.e. 73-94%. The chemical structures were confirmed by melting point, IR, 1H-NMR, 13C-NMR, and HRMS. These seven compounds were submitted to the disk diffusion test against Candida spp. and the active compound was evaluated by means of the microdilution method to determine the minimum inhibitory concentration (MIC). In addition, the stereo electronic descriptors were evaluated and pharmacokinetic and toxicological properties were calculated to predict the potential of these compounds as a drug. All the compounds presented good theoretical physicochemical parameters and one of them showed reasonably good antifungal activity.

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Chemical composition, antioxidant and antifungal activities of essential oils and extracts from Plectranthus spp. against dermatophytes fungi

Revista Brasileira de Saúde e Produção Animal ◽

10.1590/s1519-99402018000100010 ◽

2018 ◽

Vol 19 (1) ◽

pp. 105-115 ◽

Cited By ~ 1

Author(s):

Fransérgio Américo Ribeiro Alves ◽

Selene Maia de Morais ◽

Antonio Carlos Nogueira Sobrinho ◽

Isaac Neto Goes da Silva ◽

Clécio Galvão Martins ◽

...

Keyword(s):

Essential Oils ◽

Antioxidant Activities ◽

Fungal Infections ◽

Fungal Growth ◽

Antifungal Drugs ◽

Gas Chromatography Mass Spectrometry ◽

Microsporum Canis ◽

Synergistic Activity ◽

Antifungal Activities ◽

Broth Microdilution Method

SUMMARY Resistance to use antifungal drugs is a great concern seeking for scientists to discover new products to treat fungal infections. The aim of this study was to evaluate the antioxidant and antifungal activities of essential oils and extracts of Plectranthus grandis and Plectranthus ornatus against Trichophyton rubrum and Microsporum canis dermatophytes strains. Extracts were obtained from leaves by maceration in ethanol (96%) during 7 days. The oils were obtained by hydrodistillation and analyzed by gas chromatography/mass spectrometry. A total of 25 components were identified, as major constituents the sesquiterpenes β-caryophyllene, α-copaene, germacrene, β-caryophyllene and caryophyllene oxide. Antioxidant activities were evaluated using DPPH scavenging assay and antifungal action was determined by the broth microdilution method. The decocts obtained from the extraction of essential oil presented a greater antioxidant action when compared with the essential oils, with IC50 values of 12.35 μg/mL and 15.69 μg/mL to P. ornatus and P. grandis, respectively. Natural products presented significant antifungal activity, with MIC values ranging from 0.078 mg/mL to 0.31 mg/mL for all strains. The synergistic activity between Plectranthus spp. extracts and ketoconazole demonstrated a fungal growth inhibitory action when combined with a standard antifungal drug, indicating its potential for use in preventive veterinary medicine to treat dermatophytoses.

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Trends in Antifungal Drug Susceptibility of Cryptococcus neoformans Isolates Obtained through Population-Based Surveillance in South Africa in 2002-2003 and 2007-2008

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00048-11 ◽

2011 ◽

Vol 55 (6) ◽

pp. 2606-2611 ◽

Cited By ~ 43

Author(s):

Nelesh P. Govender ◽

Jaymati Patel ◽

Marelize van Wyk ◽

Tom M. Chiller ◽

Shawn R. Lockhart ◽

...

Keyword(s):

South Africa ◽

Cryptococcus Neoformans ◽

Amphotericin B ◽

Fungal Infections ◽

Antifungal Susceptibility ◽

Drug Susceptibility ◽

Population Based ◽

Content Type ◽

Microdilution Method ◽

Broth Microdilution Method

ABSTRACTCryptococcus neoformansis the most common cause of meningitis among adult South Africans with HIV infection/AIDS. Widespread use of fluconazole for treatment of cryptococcal meningitis and other HIV-associated opportunistic fungal infections in South Africa may lead to the emergence of isolates with reduced fluconazole susceptibility. MIC testing using a reference broth microdilution method was used to determine if isolates with reduced susceptibility to fluconazole or amphotericin B had emerged among cases of incident disease. Incident isolates were tested from two surveillance periods (2002-2003 and 2007-2008) when population-based surveillance was conducted in Gauteng Province, South Africa. These isolates were also tested for susceptibility to flucytosine, itraconazole, voriconazole, and posaconazole. Serially collected isolate pairs from cases at several large South African hospitals were also tested for susceptibility to fluconazole. Of the 487 incident isolates tested, only 3 (0.6%) demonstrated a fluconazole MIC of ≥16 μg/ml; all of these isolates were from 2002-2003. All incident isolates were inhibited by very low concentrations of amphotericin B and exhibited very low MICs to voriconazole and posaconazole. Of 67 cases with serially collected isolate pairs, only 1 case was detected where the isolate collected more than 30 days later had a fluconazole MIC value significantly higher than the MIC of the corresponding incident isolate. Although routine antifungal susceptibility testing of incident isolates is not currently recommended in clinical settings, it is still clearly important for public health to periodically monitor for the emergence of resistance.

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In VitroSynergistic Effect of Curcumin in Combination with Third Generation Cephalosporins against Bacteria Associated with Infectious Diarrhea

BioMed Research International ◽

10.1155/2014/561456 ◽

2014 ◽

Vol 2014 ◽

pp. 1-8 ◽

Cited By ~ 15

Author(s):

Nishanth Kumar Sasidharan ◽

Sreerag Ravikumar Sreekala ◽

Jubi Jacob ◽

Bala Nambisan

Keyword(s):

Synergistic Effect ◽

New Combination ◽

Normal Fibroblast ◽

Infectious Diarrhea ◽

Combination Drug ◽

Microdilution Method ◽

Broth Microdilution Method ◽

Time Kill ◽

Third Generation Cephalosporins

Diarrhea is one of the leading causes of morbidity and mortality in humans in developed and developing countries. Furthermore, increased resistance to antibiotics has resulted in serious challenges in the treatment of this infectious disease worldwide. Therefore, there exists a need to develop alternative natural or combination drug therapies. The aim of the present study was to investigate the synergistic effect of curcumin-1 in combination with three antibiotics against five diarrhea causing bacteria. The antibacterial activity of curcumin-1 and antibiotics was assessed by the broth microdilution method, checkerboard dilution test, and time-kill assay. Antimicrobial activity of curcumin-1 was observed against all tested strains. The MICs of curcumin-1 against test bacteria ranged from 125 to 1000 μg/mL. In the checkerboard test, curcumin-1 markedly reduced the MICs of the antibiotics cefaclor, cefodizime, and cefotaxime. Significant synergistic effect was recorded by curcumin-1 in combination with cefotaxime. The toxicity of curcumin-1 with and without antibiotics was tested against foreskin (FS) normal fibroblast and no significant cytotoxicity was observed. From our result it is evident that curcumin-1 enhances the antibiotic potentials against diarrhea causing bacteria inin vitrocondition. This study suggested that curcumin-1 in combination with antibiotics could lead to the development of new combination of antibiotics against diarrhea causing bacteria.

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8-hydroxyquinoline-5-(N-4-chlorophenyl) sulfonamide and fluconazole combination as a preventive strategy for Candida biofilm in haemodialysis devices

Journal of Medical Microbiology ◽

10.1099/jmm.0.001377 ◽

2021 ◽

Vol 70 (7) ◽

Author(s):

Letícia Fernandes da Rocha ◽

Bruna Pippi ◽

Angélica Rocha Joaquim ◽

Saulo Fernandes de Andrade ◽

Alexandre Meneghello Fuentefria

Keyword(s):

Biofilm Formation ◽

Synergistic Effects ◽

Local Treatment ◽

The Other ◽

Antibiofilm Activity ◽

Preventive Strategy ◽

Clinical Issue ◽

Microdilution Method ◽

Broth Microdilution Method ◽

Time Kill

Introduction. The presence of Candida biofilms in medical devices is a concerning and important clinical issue for haemodialysis patients who require constant use of prosthetic fistulae and catheters. Hypothesis/Gap Statement. This prolonged use increases the risk of candidaemia due to biofilm formation. PH151 and clioquinol are 8-hydroxyquinoline derivatives that have been studied by our group and showed interesting anti-Candida activity. Aim. This study evaluated the biofilm formation capacity of Candida species on polytetrafluoroethylene (PTFE) and polyurethane (PUR) and investigated the synergistic effects between the compounds PH151 and clioquinol and fluconazole, amphotericin B and caspofungin against biofilm cells removed from those materials. Further, the synergistic combination was evaluated in terms of preventing biofilm formation on PTFE and PUR discs. Methodology. Susceptibility testing was performed for planktonic and biofilm cells using the broth microdilution method. The checkerboard method and the time–kill assay were used to evaluate the interactions between antifungal agents. Antibiofilm activity on PTFE and PUR materials was assessed to quantify the prevention of biofilm formation. Results. Candida albicans, Candida glabrata and Candida tropicalis showed ability to form biofilms on both materials. By contrast, Candida parapsilosis did not demonstrate this ability. Synergistic interaction was observed when PH151 was combined with fluconazole in 77.8 % of isolates and this treatment was shown to be concentration- and time-dependent. On the other hand, indifferent interactions were predominantly observed with the other combinations. A reduction in biofilm formation on PUR material of more than 50 % was observed when using PH151 combined with fluconazole. Conclusion. PH151 demonstrated potential as a local treatment for use in a combination therapy approach against Candida biofilm formation on haemodialysis devices.

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Opportunistic yeast pathogen Candida spp.: Secreted and membrane-bound virulence factors

Medical Mycology ◽

10.1093/mmy/myab053 ◽

2021 ◽

Author(s):

Si Jie Lim ◽

Mohd Shukuri Mohamad Ali ◽

Suriana Sabri ◽

Noor Dina Muhd Noor ◽

Abu Bakar Salleh ◽

...

Keyword(s):

Virulence Factors ◽

Drug Targets ◽

Fungal Infections ◽

Antifungal Drugs ◽

Host Immune System ◽

Structural Studies ◽

Candida Spp ◽

Structural Investigations ◽

Membrane Bound ◽

Aspartyl Proteinases

Abstract Candidiasis is a fungal infection caused by Candida spp. especially Candida albicans, C. glabrata, C. parapsilosis and C. tropicalis. Although the medicinal therapeutic strategies have rapidly improved, the mortality rate due to candidiasis has continuously increased. The secreted and membrane-bound virulence factors (VFs) are responsible for fungal invasion, damage and translocation through the host enterocytes besides the evasion from host immune system. VFs such as agglutinin-like sequences (Als), heat shock protein 70, phospholipases, secreted aspartyl proteinases (Sap), lipases, enolases and phytases are mostly hydrolases which degrade the enterocyte membrane components except for candidalysin, the VF acts as a peptide toxin to induce necrotic cell lysis. To date, structural studies of the VFs remain underexplored, hindering their functional analyses. Among the VFs, only secreted aspartyl proteinases and agglutinin-like sequences have their structures deposited in Protein Data Bank (PDB). Therefore, this review scrutinizes the mechanisms of these VFs by discussing the VF-deficient studies of several Candida spp. and their abilities to produce these VFs. Nonetheless, their latest reported sequential and structural analyses are discussed to impart a wider perception of the host-pathogen interactions and potential vaccine or antifungal drug targets. This review signifies that more VFs structural investigations and mining in the emerging Candida spp. are required to decipher their pathogenicity and virulence mechanisms compared to the prominent C. albicans. Lay Abstract Candida virulence factors (VFs) including mainly enzymes and proteins play vital roles in breaching the human intestinal barrier and causing deadly candidiasis. Limited VFs’ structural studies hinder deeper comprehension of their mechanisms and thus the design of vaccines and antifungal drugs against fungal infections.

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