Antifungal Resistance Regarding Malassezia pachydermatis: Where Are We Now?

Malassezia pachydermatis is a yeast inhabiting the skin and ear canals in healthy dogs. In the presence of various predisposing conditions it can cause otitis and dermatitis, which are treated with multiple antifungal agents, mainly azole derivatives. This manuscript aims to review the available evidence regarding the occurrence of resistance phenomena in this organism. Various findings support the capacity of M. pachydermatis for developing resistance. These include some reports of treatment failure in dogs, the reduced antifungal activity found against yeast isolates sampled from dogs with exposure to antifungal drugs and strains exposed to antifungal agents in vitro, and the description of resistance mechanisms. At the same time, the data reviewed may suggest that the development of resistance is a rare eventuality in canine practice. For example, only three publications describe confirmed cases of treatment failure due to antifungal resistance, and most claims of resistance made by past studies are based on interpretive breakpoints that lack sound support from the clinical perspective. However, it is possible that resistant cases are underreported in literature, perhaps due to the difficulty of obtaining a laboratory confirmation given that a standard procedure for susceptibility testing of M. pachydermatis is still unavailable. These considerations highlight the need for maintaining surveillance for the possible emergence of clinically relevant resistance, hopefully through a shared strategy put in place by the scientific community.

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Prevalence of Antifungal Resistance, Genetic Basis of Acquired Azole and Echinocandin Resistance, and Genotyping of Candida krusei recovered from an International Collection

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01856-21 ◽

2021 ◽

Author(s):

Hazim O. Khalifa ◽

Vit Hubka ◽

Akira Watanabe ◽

Minoru Nagi ◽

Yoshitsugu Miyazaki ◽

...

Keyword(s):

Rapid Development ◽

Resistance Mechanisms ◽

Candida Krusei ◽

Antifungal Resistance ◽

Development Of Resistance ◽

Low Concentrations ◽

Genetic Mechanisms ◽

Infection Source ◽

Echinocandin Resistance

This study was designed to evaluate the prevalence of antifungal resistance, genetic mechanisms associated with in vitro induction of azole and echinocandin resistance and genotyping of Candida krusei , which is intrinsically resistant to fluconazole and is recovered from clinical and non-clinical sources from different countries. Our results indicated that all the isolates were susceptible or had the wild phenotype (WT) to azoles, amphotericin B, and only 1.27% showed non-WT for flucytosine. Although 70.88% of the isolates were resistant to caspofungin, none of them were categorized as echinocandin-resistant as all were susceptible to micafungin and no FKS1 hotspot 1 (HS1) or HS2 mutations were detected. In vitro induction of azole and echinocandin resistance confirmed the rapid development of resistance at low concentrations of fluconazole (4 μg/ml), voriconazole (0.06 μg/ml) and micafungin (0.03 μg/ml), with no difference between clinical and non-clinical isolates in the resistance development. Overexpression of ABC1 gene and FKS1 HS1 mutations were the major mechanisms responsible for azole and echinocandin resistance, respectively. Genotyping of our 79 isolates coupled with 217 other isolates from different sources and geography confirmed that the isolates belong to two main subpopulations, with isolates from human clinical material and Asia being more predominant in cluster 1, and environmental and animals isolates and those from Europe in cluster 2. Our results are of critical concern, since realizing that the C. krusei resistance mechanisms and their genotyping are crucial for guiding specific therapy and for exploring the potential infection source.

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Antifungal Resistance among Less Prevalent Candida Non-albicans and Other Yeasts versus Established and under Development Agents: A Literature Review

Journal of Fungi ◽

10.3390/jof7010024 ◽

2021 ◽

Vol 7 (1) ◽

pp. 24

Author(s):

Ana Espinel-Ingroff ◽

Emilia Cantón ◽

Javier Pemán

Keyword(s):

Candida Species ◽

Resistance Mechanisms ◽

Fungal Species ◽

Antifungal Resistance ◽

Antifungal Drugs ◽

Candida Spp ◽

In Vitro Susceptibility ◽

Susceptibility Data ◽

Development Agents

Fungal diseases and antifungal resistance continue to increase, including those caused by rare or emerging species. However, the majority of the published in vitro susceptibility data are for the most common fungal species. We reviewed the literature in order to pool reference minimal inhibitory concentration (MIC) data (Clinical and Laboratory Standards Institute—CLSI and European Committee on Antimicrobial Susceptibility—EUCAST) for rare/non-prevalent Candida and other yeast species. MIC results were compared with those for Candida albicans, C. glabrata, and C. krusei. Data were listed for twenty rare and emerging Candida spp., including C. auris, as well as two Cryptococcus spp., two Trichosporon spp., Saccharomyces cerevisiae and five Malassezia spp. The best detectors of antimicrobial resistance are the breakpoints, which are not available for the less common Candida species. However, epidemiological cutoff values (ECVs/ECOFFs) have been calculated using merely in vitro data for both reference methods for various non-prevalent yeasts and recently the CLSI has established ECVs for other Candida species. The ECV could identify the non-wild type (NWT or mutants) isolates with known resistance mechanisms. Utilizing these ECVs, we were able to report additional percentages of NWT, especially for non-prevalent species, by analyzing the MIC distributions in the literature. In addition, since several antifungal drugs are under development, we are listing MIC data for some of these agents.

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Potential of Nanoparticles in Combating Candida Infections

Letters in Drug Design & Discovery ◽

10.2174/1570180815666181015145224 ◽

2019 ◽

Vol 16 (5) ◽

pp. 478-491 ◽

Cited By ~ 5

Author(s):

Faizan Abul Qais ◽

Mohd Sajjad Ahmad Khan ◽

Iqbal Ahmad ◽

Abdullah Safar Althubiani

Keyword(s):

Targeted Delivery ◽

Recent Progress ◽

Antifungal Agents ◽

Fungal Infections ◽

Fold Increase ◽

Antifungal Drugs ◽

Low Toxicity ◽

Candida Infections ◽

Made In

Aims: The aim of this review is to survey the recent progress made in developing the nanoparticles as antifungal agents especially the nano-based formulations being exploited for the management of Candida infections. Discussion: In the last few decades, there has been many-fold increase in fungal infections including candidiasis due to the increased number of immunocompromised patients worldwide. The efficacy of available antifungal drugs is limited due to its associated toxicity and drug resistance in clinical strains. The recent advancements in nanobiotechnology have opened a new hope for the development of novel formulations with enhanced therapeutic efficacy, improved drug delivery and low toxicity. Conclusion: Metal nanoparticles have shown to possess promising in vitro antifungal activities and could be effectively used for enhanced and targeted delivery of conventionally used drugs. The synergistic interaction between nanoparticles and various antifungal agents have also been reported with enhanced antifungal activity.

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In vitro combination of antifungal agents against Malassezia pachydermatis

Medical Mycology ◽

10.1093/mmy/myy043 ◽

2018 ◽

Vol 57 (3) ◽

pp. 324-327 ◽

Cited By ~ 1

Author(s):

Karine B Schlemmer ◽

Francielli P K de Jesus ◽

Erico S Loreto ◽

Julia B Farias ◽

Sydney H Alves ◽

...

Keyword(s):

Antifungal Agents ◽

Malassezia Pachydermatis

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Spectrum and theIn VitroAntifungal Susceptibility Pattern of Yeast Isolates in Ethiopian HIV Patients with Oropharyngeal Candidiasis

International Journal of Microbiology ◽

10.1155/2016/3037817 ◽

2016 ◽

Vol 2016 ◽

pp. 1-8 ◽

Cited By ~ 10

Author(s):

Birhan Moges ◽

Adane Bitew ◽

Aster Shewaamare

Keyword(s):

Antifungal Agents ◽

Antifungal Susceptibility ◽

Antifungal Drugs ◽

Assay Method ◽

Cryptococcus Laurentii ◽

Susceptibility Pattern ◽

Test Procedures ◽

Disk Diffusion Assay ◽

Diffusion Assay

Background.In Ethiopia, little is known regarding the distribution and thein vitroantifungal susceptibility profile of yeasts.Objective.This study was undertaken to determine the spectrum and thein vitroantifungal susceptibility pattern of yeasts isolated from HIV infected patients with OPC.Method.Oral pharyngeal swabs taken from oral lesions of study subjects were inoculated onto Sabouraud Dextrose Agar. Yeasts were identified by employing conventional test procedures and the susceptibility of yeasts to antifungal agents was evaluated by disk diffusion assay method.Result.One hundred and fifty-five yeast isolates were recovered of which 91 isolates were from patients that were not under HAART and 64 were from patients that were under HAART.C. albicanswas the most frequently isolated species followed byC. glabrata, C. tropicalis, C. krusei, C. kefyr, Cryptococcus laurentii, and Rhodotorulaspecies. Irrespective of yeasts isolated and identified, 5.8%, 5.8%, 12.3%, 8.4%, 0.6%, and 1.3% of the isolates were resistant to amphotericin B, clotrimazole, fluconazole, ketoconazole, miconazole, and nystatin, respectively.Conclusion.Yeast colonization rate of 69.2% and 31% resistance to six antifungal agents was documented. These highlight the need for nationwide study on the epidemiology of OPC and resistance to antifungal drugs.

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Development of Resistance in Wild-Type and Hypermutable Pseudomonas aeruginosa Strains Exposed to Clinical Pharmacokinetic Profiles of Meropenem and Ceftazidime Simulated In Vitro

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00160-07 ◽

2007 ◽

Vol 51 (10) ◽

pp. 3642-3649 ◽

Cited By ~ 19

Author(s):

Beate Henrichfreise ◽

Irith Wiegand ◽

Ingeborg Luhmer-Becker ◽

Bernd Wiedemann

Keyword(s):

Pseudomonas Aeruginosa ◽

Parent Strain ◽

Resistance Mechanisms ◽

In Vitro Models ◽

Wild Type ◽

Resistance Development ◽

Development Of Resistance ◽

Pharmacokinetic Profiles ◽

Mutant Prevention Concentration

ABSTRACT In this study we investigated the interplay of antibiotic pharmacokinetic profiles and the development of mutation-mediated resistance in wild-type and hypermutable Pseudomonas aeruginosa strains. We used in vitro models simulating profiles of the commonly used therapeutic drugs meropenem and ceftazidime, two agents with high levels of antipseudomonal activity said to have different potentials for stimulating resistance development. During ceftazidime treatment of the wild-type strain (PAO1), fully resistant mutants overproducing AmpC were selected rapidly and they completely replaced wild-type cells in the population. During treatment with meropenem, mutants of PAO1 were not selected as rapidly and showed only intermediate resistance due to the loss of OprD. These mutants also replaced the parent strain in the population. During the treatment of the mutator P. aeruginosa strain with meropenem, the slowly selected mutants did not accumulate several resistance mechanisms but only lost OprD and did not completely replace the parent strain in the population. Our results indicate that the commonly used dosing regimens for meropenem and ceftazidime cannot avoid the selection of mutants of wild-type and hypermutable P. aeruginosa strains. For the treatment outcome, including the prevention of resistance development, it would be beneficial for the antibiotic concentration to remain above the mutant prevention concentration for a longer period of time than it does in present regimens.

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Acylhydrazones as Antifungal Agents Targeting the Synthesis of Fungal Sphingolipids

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00156-18 ◽

2018 ◽

Vol 62 (5) ◽

Cited By ~ 32

Author(s):

Cristina Lazzarini ◽

Krupanandan Haranahalli ◽

Robert Rieger ◽

Hari Krishna Ananthula ◽

Pankaj B. Desai ◽

...

Keyword(s):

Mammalian Cells ◽

Antifungal Agents ◽

Fungal Infections ◽

Antifungal Drugs ◽

Fungal Resistance ◽

Content Type ◽

Highly Active ◽

Pharmacokinetic Properties ◽

Pass Through

ABSTRACTThe incidence of invasive fungal infections has risen dramatically in recent decades. Current antifungal drugs are either toxic, likely to interact with other drugs, have a narrow spectrum of activity, or induce fungal resistance. Hence, there is a great need for new antifungals, possibly with novel mechanisms of action. Previously our group reported an acylhydrazone called BHBM that targeted the sphingolipid pathway and showed strong antifungal activity against several fungi. In this study, we screened 19 derivatives of BHBM. Three out of 19 derivatives were highly active againstCryptococcus neoformansin vitroand had low toxicity in mammalian cells. In particular, one of them, called D13, had a high selectivity index and showed better activity in an animal model of cryptococcosis, candidiasis, and pulmonary aspergillosis. D13 also displayed suitable pharmacokinetic properties and was able to pass through the blood-brain barrier. These results suggest that acylhydrazones are promising molecules for the research and development of new antifungal agents.

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In Vitro Antifungal Activities of a Series of Dication-Substituted Carbazoles, Furans, and Benzimidazoles

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.42.10.2503 ◽

1998 ◽

Vol 42 (10) ◽

pp. 2503-2510 ◽

Cited By ~ 58

Author(s):

Maurizio Del Poeta ◽

Wiley A. Schell ◽

Christine C. Dykstra ◽

Susan K. Jones ◽

Richard R. Tidwell ◽

...

Keyword(s):

Antimicrobial Activity ◽

Candida Albicans ◽

Fusarium Solani ◽

Antifungal Agents ◽

Antifungal Drugs ◽

Inhibitory Compounds ◽

Wide Range ◽

Fluconazole Resistant ◽

Resistant Strains

ABSTRACT Aromatic dicationic compounds possess antimicrobial activity against a wide range of eucaryotic pathogens, and in the present study an examination of the structures-functions of a series of compounds against fungi was performed. Sixty-seven dicationic molecules were screened for their inhibitory and fungicidal activities againstCandida albicans and Cryptococcus neoformans. The MICs of a large number of compounds were comparable to those of the standard antifungal drugs amphotericin B and fluconazole. Unlike fluconazole, potent inhibitory compounds in this series were found to have excellent fungicidal activities. The MIC of one of the most potent compounds against C. albicans was 0.39 μg/ml, and it was the most potent compound against C. neoformans (MIC, ≤0.09 μg/ml). Selected compounds were also found to be active againstAspergillus fumigatus, Fusarium solani,Candida species other than C. albicans, and fluconazole-resistant strains of C. albicans and C. neoformans. Since some of these compounds have been safely given to animals, these classes of molecules have the potential to be developed as antifungal agents.

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Antifungal Drugs Influence Neutrophil Effector Functions

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02409-18 ◽

2019 ◽

Vol 63 (6) ◽

Cited By ~ 2

Author(s):

Frederic Ries ◽

Astrid Alflen ◽

Pamela Aranda Lopez ◽

Hendrik Beckert ◽

Matthias Theobald ◽

...

Keyword(s):

Amphotericin B ◽

Antifungal Agents ◽

Antifungal Drugs ◽

Polymorphonuclear Neutrophils ◽

Enzyme Linked Immunosorbent Assay ◽

Activation Markers ◽

Effector Functions ◽

Enhanced Expression ◽

Almost All

ABSTRACTThere is a growing body of evidence for immunomodulatory side effects of antifungal agents on different immune cells, e.g., T cells. Therefore, the aim of our study was to clarify these interactions with regard to the effector functions of polymorphonuclear neutrophils (PMN). Human PMN were preincubated with fluconazole (FLC), voriconazole (VRC), posaconazole (POS), isavuconazole (ISA), caspofungin (CAS), micafungin (MFG), conventional amphotericin B (AMB), and liposomal amphotericin B (LAMB). PMN then were analyzed by flow cytometry for activation, degranulation, and phagocytosis and by dichlorofluorescein assay to detect reactive oxygen species (ROS). Additionally, interleukin-8 (IL-8) release was measured by enzyme-linked immunosorbent assay. POS led to enhanced activation, degranulation, and generation of ROS, whereas IL-8 release was reduced. In contrast, ISA-pretreated PMN showed decreased activation signaling, impaired degranulation, and lower generation of ROS. MFG caused enhanced expression of activation markers but impaired degranulation, phagocytosis, generation of ROS, and IL-8 release. CAS showed increased phagocytosis, whereas degranulation and generation of ROS were reduced. AMB led to activation of almost all effector functions besides impaired phagocytosis, whereas LAMB did not alter any effector functions. Independent from class, antifungal agents show variable influence on neutrophil effector functionsin vitro. Whether this is clinically relevant needs to be clarified.

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CandidaInfections, Causes, Targets, and Resistance Mechanisms: Traditional and Alternative Antifungal Agents

BioMed Research International ◽

10.1155/2013/204237 ◽

2013 ◽

Vol 2013 ◽

pp. 1-13 ◽

Cited By ~ 91

Author(s):

Claudia Spampinato ◽

Darío Leonardi

Keyword(s):

Antifungal Agents ◽

Fungal Infections ◽

Current Knowledge ◽

Resistance Mechanisms ◽

Antifungal Drugs ◽

Diagnostic Methods ◽

Opportunistic Pathogens ◽

Yeast Infection ◽

Life Threatening ◽

Therapeutic Alternatives

The genusCandidaincludes about 200 different species, but only a few species are human opportunistic pathogens and cause infections when the host becomes debilitated or immunocompromised.Candidainfections can be superficial or invasive. Superficial infections often affect the skin or mucous membranes and can be treated successfully with topical antifungal drugs. However, invasive fungal infections are often life-threatening, probably due to inefficient diagnostic methods and inappropriate initial antifungal therapies. Here, we briefly review our current knowledge of pathogenic species of the genusCandidaand yeast infection causes and then focus on current antifungal drugs and resistance mechanisms. An overview of new therapeutic alternatives for the treatment ofCandidainfections is also provided.

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