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This study evaluated combinations of amphotericin B with anidulafungin, caspofungin, and micafungin against 30 clinical isolates of Cryptococcus neoformans following the CLSI M27-A3 and the checkerboard microdilution method. The combination amphotericin B + micafungin showed 60% of synergistic effect against C. neoformans, while most of the other interactions were indifferent., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Cryptococcus species are an encapsulated fungal pathogen that cause cryptococcal meningitis. There are limited therapeutic options for this infection. The management includes the use of different antifungals such as amphotericin B, flucytosine, or fluconazole, either alone or in combination. However, numerous therapeutic failures, as well as the limited effectiveness of such therapeutics, have been described. Diphenyl diselenide is a chemically synthesised molecule with was found to have antimicrobial activity. In this study, we evaluated the antifungal activities of fluconazole, amphotericin B and flucytosine, in combination with diphenyl diselenide against 30 clinical isolates of Cryptococcus spp. using CLSI M27-A3 method and the checkerboard microdilution technique. Our results show that the combination of flucytosine and diphenyl diselenide displayed 100% of synergism. However, when we analysed (PhSe) 2 plus AMB or FLZ we observed around 70% of indifference. Our results suggest that the combination of diphenyl diselenide with other antifungal agents deserves attention as a new option for the development of alternative therapies for cryptococcosis., (© 2019 Blackwell Verlag GmbH.)

Background: Candida parapsilosis may acquire resistance to echinocandins, a fact that prompts the search for new therapeutic options., Aims: The present study aimed to evaluate the in vitro activity of antifungal agents, alone and in combination, against four groups of C. parapsilosis strains: (1) echinocandin-susceptible (ES) clinical isolates (MIC ≤ 2μg/ml), (2) anidulafungin-resistant strains (MIC ≥ 8μg/ml), (3) caspofungin-resistant strains (MIC ≥ 8μg/ml), and (4) micafungin-resistant strains (MIC ≥ 8μg/ml)., Methods: Antifungal interactions were evaluated by a checkerboard micro-dilution method. The determination of the MIC to each drug for every isolate according to the Clinical and Laboratory Standards Institute documents M27 (2017) and M60 (2017) was also done., Results: The echinocandins-resistant (ER) strains showed higher MICs to the tested antifungals than the ES strains, except for amphotericin B, for which the ER groups remained susceptible., Conclusions: Most combinations showed indifferent interactions. The use of monotherapy still seems to be the best option. As resistance to echinocandins is an emergent phenomenon, further studies are required to provide clearer information on the susceptibility differences between strains to these antifungal agents., (Copyright © 2019 Asociación Española de Micología. Publicado por Elsevier España, S.L.U. All rights reserved.)

The aim of this study was to evaluate the susceptibility of 20 clinical isolates of Fusarium spp. to classic antifungals [amphotericin B (AmB), itraconazole (ITR), voriconazole (VRC) and caspofungin (CAS)] and to non-antifungal agents [amiodarone (AMD), doxycycline (DOX) and moxifloxacin (MFX)] by the broth microdilution method. Combinations between these antifungal and non-antifungal agents were also evaluated to determine the fractional inhibitory concentration indices using the chequerboard technique. Synergistic interactions were observed for the following combinations (% synergism): AMD + VRC, 80%; MFX + AmB, 75%; AMD + AmB, 65%; DOX + VRC, 60%; MFX + VRC, 55%; DOX + AmB, 50%; and AMD + CAS, 30%. Synergism was not observed for associations with ITR. Antagonism was not seen in any combination. These findings suggest that the combinations of AMD, DOX or MFX with AmB or VRC to have potential for future in vivo investigations., (Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.)

The naturally high minimum inhibitory concentration exhibited by echinocandins against Candida parapsilosis has been known since the first introduction of these antifungal agents. Despite this awareness, clinical failures have not been reported; consequently, the resistance of C. parapsilosis to echinocandins remains unexplored. We exposed 30 isolates of C. parapsilosis to echinocandins (caspofungin, micafungin, and anidulafungin) in vitro and studied the effects of this exposure. After 60 exposures, 80, 67, and 60 % of the isolates changed from susceptible to non-susceptible to caspofungin, micafungin, and anidulafungin, respectively. In addition, four strains exhibited cross-resistance to all three echinocandins. Based on the M27-A3 (CLSI, 2008) and M27-S4 (CLSI, 2012) techniques, the susceptibility of the resistant strains to other antifungal agents was assayed. All of the tested echinocandin-resistant strains were susceptible to amphotericin B, and the resistance rate to fluconazole, voriconazole, and flucytosine was 73.3, 43.3, and 20 %, respectively. The exposure of C. parapsilosis to the three echinocandins generated cross-resistant strains and an unexpected in vitro resistance to azoles and flucytosine.

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.)

This study evaluated the synergistic interactions between amphotericin B (AMB) and azithromycin (AZM), daptomycin (DAP), linezolid (LNZ), minocycline (MINO), fluconazole (FLZ), flucytosine (5FC), linezolid (LZD), or tigecycline (TIG) against clinical isolates of Cryptococcus neoformans var. grubii before and after capsule induction. High synergism (>75%) was observed for the combinations, AMB+5FC, AMB+TIG, AMB+AZM, AMB+LZD and AMB+MINO but only in the strains after capsule induction. The results show that the presence of the capsule may lower the minimum inhibitory concentrations (MICs) of antifungal agents, but antimicrobial activity can be improved by combining antifungal and antibacterial agents., (© 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.)

The high mortality rates associated with candidemia episodes and the emergence of resistance to antifungal agents necessitate the monitoring of the susceptibility of fungal isolates to antifungal treatments. The new, recently approved, species-specific clinical breakpoints (SS-CBPs)(M27-S4) for evaluating susceptibility require careful interpretation and comparison with the former proposals made using the M27-A3 breakpoints, both from CLSI. This study evaluated the susceptibility of the different species of Candida that were isolated from candidemias based on these two clinical breakpoints. Four hundred and twenty-two isolates were identified and, among them, C. parapsilosis comprised 46.68%, followed by C. albicans (35.78%), C. tropicalis (9.71%), C. glabrata (3.55%), C. lusitaniae (1.65%), C. guilliermondii (1.65%) and C. krusei (0.94%). In accordance with the M27-A3 criteria, 33 (7.81%) non-susceptible isolates were identified, of which 16 (3.79%) were resistant to antifungal agents. According to SS-CBPs, 80 (18.95%) isolates were non-susceptible, and 10 (2.36%) of these were drug resistant. When the total number of non-susceptible isolates was considered, the new SS-CBPs detected 2.4 times the number of isolates that were detected using the M27-A3 interpretative criteria. In conclusion, the detection of an elevated number of non-susceptible species has highlighted the relevance of evaluating susceptibility tests using new, species-specific clinical breakpoints (SS-CBPs), which could impact the profile of non-susceptible Candida spp. to antifungal agents that require continuous susceptibility monitoring.

Background: Infections caused by Fusarium are difficult to treat because these fungi show in vitro and in vivo resistance to practically all the antifungal agents available, which explains the high mortality rates. An attempt to overcome fungal resistance is the combination of antifungal agents, especially those with different mechanisms of action., Aims: Evaluate the in vitro interactions of combinations of voriconazole or itraconazole with other antifungal agents against 32 isolates of Fusarium spp.: Fusarium chlamydosporum, Fusarium oxysporum, Fusarium proliferatum and Fusarium solani., Methods: Drug interactions were assessed by a checkerboard microdilution method that also included the determination of the MIC of each drug alone according to CLSI (Clinical and Laboratory Standards Institute) document M38-A2, 2008., Results: The best combinations were voriconazole+terbinafine which showed synergism against 84% of Fusarium strains. Other synergistic combinations were voriconazole+itraconazole (50%), voriconazole+fluconazole (50%), voriconazole+miconazole (38%), voriconazole+flucytosine (22%) and voriconazole+ketoconazole (25%). The synergisms observed with itraconazole combinations were itraconazole+terbinafine (25%) and itraconazole+flucytosine (9.37%). The antagonisms observed were: voriconazole+fluconazole (3%) and itraconazole+flucytosine (12.5%)., Conclusions: The synergism showed by voriconazole+terbinafine was remarkable. To better elucidate the potential usefulness of our findings, new in vivo and in vitro studies deserve be performed., (Copyright © 2012 Revista Iberoamericana de Micología. Published by Elsevier Espana. All rights reserved.)

Fusarium spp is an opportunistic fungal pathogen responsible for causing invasive hyalohyphomycosis in immunocompromised patients. Due to its susceptibility pattern with a remarkable resistance to antifungal agents the treatment failures and mortality rates are high. To overcome this situation, combination therapy may be considered which must be subjected to in vitro tests. In vitro activities of amphotericin B, itraconazole, and voriconazole associated with azithromycin, ciprofloxacin, fluvastatin, ibuprofen, metronidazole, and also the combination of amphotericin B plus rifampin against 23 strains of Fusarium spp. through the checkerboard technique based on M38-A2 [Clinical and Laboratory Standards Institute (2008). Reference method for broth dilution antifungal susceptibility testing of filamentous fungi; approved standard, 2nd ed. (CLSI document M38-A2) (ISBN 1-56238-668-9). Wayne, PA: CLSI] were evaluated. The best synergistic interactions with amphotericin B were with ibuprofen (43.5%) (FICI [fractional inhibitory concentration index] range = 0.25-2). Combinations with voriconazole showed synergism, mainly with ciprofloxacin (30.4%) (FICI range = 0.25-3) and metronidazole (30.4%) (FICI range = 0.1-4); however, all the combinations with itraconazole were indifferent. In general, antagonistic interactions were not registered. Our results showed that in vitro synergisms obtained by some combinations studied deserve attention since they were better than those showed by the antimycotic., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Fusarium species are common hyaline soil saprophytes and plant pathogens that are opportunistic fungal pathogens of immunocompromised patients. The treatment for fusariosis remains uncertain with an unfavourable prognosis; new possibilities for treatment, such as various synergistic drug interactions, must be uncovered. In this study, we evaluated the in vitro interactions of amphotericin B with caspofungin, ketoconazole, 5-flucytosine, itraconazole, miconazole, rifampin, fluconazole, terbinafine and voriconazole against isolates of Fusarium spp. using the chequerboard method with interactions evaluated by fractional inhibitory concentration indices. The highest percentages of synergistic interactions were observed for the combinations of amphotericin B and caspofungin (68.7%), amphotericin B and rifampin (68.7%), amphotericin B plus 5-flucytosine (59.3%) and amphotericin B with voriconazole (37.5%). The pattern of susceptibility to antifungal agents among Fusarium species and their consequence on the effects of drug combinations are also discussed., (© 2009 Blackwell Verlag GmbH.)