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1.
J Drugs Dermatol ; 21(5): 496-501, 2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-35533026

RESUMO

Over the last decade, major advances in antifungal drug development have occurred. Novel drugs in the pipeline include ME1111, MAT2203, rezafungin, ibrexafungerp, olorofim, fosmanogepix, MGCD290, VT-1161, NP213, T-2307, aureobasidin A, and nikkomycin Z. While most of these “future fungal fighters” have been developed to address invasive fungal infections (IFI), there is potential for dermatologists to benefit as these drugs may be adapted for superficial infections. Here, we review the major developments in novel antifungals and examine the ways in which dermatologists may gain from these recent innovations. J Drugs Dermatol. 2022;21(5):496-501. doi:10.36849/JDD.6373.


Assuntos
Dermatologia , Infecções Fúngicas Invasivas , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Desenvolvimento de Medicamentos , Farmacorresistência Fúngica , Humanos , Infecções Fúngicas Invasivas/tratamento farmacológico , Infecções Fúngicas Invasivas/microbiologia
2.
Front Cell Infect Microbiol ; 12: 841138, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35531335

RESUMO

A sexual cycle was described in 2009 for the opportunistic fungal pathogen Aspergillus fumigatus, opening up for the first time the possibility of using techniques reliant on sexual crossing for genetic analysis. The present study was undertaken to evaluate whether the technique 'bulk segregant analysis' (BSA), which involves detection of differences between pools of progeny varying in a particular trait, could be applied in conjunction with next-generation sequencing to investigate the underlying basis of monogenic traits in A. fumigatus. Resistance to the azole antifungal itraconazole was chosen as a model, with a dedicated bioinformatic pipeline developed to allow identification of SNPs that differed between the resistant progeny pool and resistant parent compared to the sensitive progeny pool and parent. A clinical isolate exhibiting monogenic resistance to itraconazole of unknown basis was crossed to a sensitive parent and F1 progeny used in BSA. In addition, the use of backcrossing and increasing the number in progeny pools was evaluated as ways to enhance the efficiency of BSA. Use of F1 pools of 40 progeny led to the identification of 123 candidate genes with SNPs distributed over several contigs when aligned to an A1163 reference genome. Successive rounds of backcrossing enhanced the ability to identify specific genes and a genomic region, with BSA of progeny (using 40 per pool) from a third backcross identifying 46 genes with SNPs, and BSA of progeny from a sixth backcross identifying 20 genes with SNPs in a single 292 kb region of the genome. The use of an increased number of 80 progeny per pool also increased the resolution of BSA, with 29 genes demonstrating SNPs between the different sensitive and resistant groupings detected using progeny from just the second backcross with the majority of variants located on the same 292 kb region. Further bioinformatic analysis of the 292 kb region identified the presence of a cyp51A gene variant resulting in a methionine to lysine (M220K) change in the CYP51A protein, which was concluded to be the causal basis of the observed resistance to itraconazole. The future use of BSA in genetic analysis of A. fumigatus is discussed.


Assuntos
Aspergillus fumigatus , Azóis , Antifúngicos/farmacologia , Aspergillus fumigatus/metabolismo , Azóis/farmacologia , Farmacorresistência Fúngica/genética , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Itraconazol/metabolismo , Itraconazol/farmacologia , Testes de Sensibilidade Microbiana
3.
Front Cell Infect Microbiol ; 12: 859439, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35601096

RESUMO

Objectives: The antifungal susceptibility testing (AFST) of yeast pathogen alerts clinicians about the potential emergence of resistance. In this study, we compared two commercial microdilution AFST methods: Sensititre YeastOne read visually (YO) and MICRONAUT-AM read visually (MN) or spectrophotometrically (MNV), interpreted with Clinical and Laboratory Standards Institute and European Committee on Antimicrobial Susceptibility Testing criteria, respectively. Methods: Overall, 97 strains from 19 yeast species were measured for nine antifungal drugs including a total of 873 observations. First, the minimal inhibitory concentration (MIC) was compared between YO and MNV, and between MNV and MN, either directly or by assigning them to five susceptibility categories. Those categories were based on the number of MIC dilutions around the breakpoint or epidemiological cut-off reference values (ECOFFs or ECVs). Second, YO and MNV methods were evaluated for their ability to detect the elevation of MICs due to mutation in antifungal resistance genes, thanks to pairs or triplets of isogenic strains isolated from a single patient along a treatment previously analyzed for antifungal resistance gene mutations. Reproducibility measurement was evaluated, thanks to three quality control (QC) strains. Results: YO and MNV direct MIC comparisons obtained a global agreement of 67%. Performing susceptibility category comparisons, only 22% and 49% of the MICs could be assigned to categories using breakpoints and ECOFFs/ECVs, respectively, and 40% could not be assigned due to the lack of criteria in both consortia. The YO and MN susceptibility categories gave accuracies as low as 50%, revealing the difficulty to implement this method of comparison. In contrast, using the antifungal resistance gene sequences as a gold standard, we demonstrated that both methods (YO and MN) were equally able to detect the acquisition of resistance in the Candida strains, even if MN showed a global lower MIC elevation than YO. Finally, no major differences in reproducibility were observed between the three AFST methods. Conclusion: This study demonstrates the valuable use of both commercial microdilution AFST methods to detect antifungal resistance due to point mutations in antifungal resistance genes. We highlighted the difficulty to conduct conclusive analyses without antifungal gene sequence data as a gold standard. Indeed, MIC comparisons taking into account the consortia criteria of interpretation remain difficult even after the effort of harmonization.


Assuntos
Antifúngicos , Farmacorresistência Fúngica , Antifúngicos/farmacologia , Candida , Farmacorresistência Fúngica/genética , Humanos , Testes de Sensibilidade Microbiana , Reprodutibilidade dos Testes , Leveduras
4.
Pan Afr Med J ; 41: 34, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35382049

RESUMO

Introduction: diabetic foot ulcer is the leading cause of hospital admissions, lower limb amputation and death among diabetic patients. Little information is available on fungal isolation in diabetic foot ulcer patients, especially in sub-Saharan Africa. This study aimed to describe Candida species infecting diabetic foot ulcers in patients receiving clinical care at Kenyatta National Hospital and assess their antifungal susceptibility profile. Methods: this was a cross-sectional study carried out at Kenyatta National Hospital among adult diabetic foot ulcer patients over a three-month period. Species identification of Candida was performed using VITEK - 2 System and further confirmed by Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry. Antifungal susceptibility testing was determined using VITEK-2 System. Data were analysed using WHONET and SPSS. Results: among the 152 study patients recruited, 98% (n=149) had type 2 diabetes. Sixty one percent of the participants were male. The mean age of the study participants was 50.7 years (SD 12.9). A total of 36 Candida species were isolated, of which 75% (n=27) were Candida albicans. Candida lusitaniae (8%, n=3) and C. dubliniensis (5%, n=2) were the predominant non-albicans Candida species. The overall prevalence of diabetic foot ulcer candidiasis was 20% (n=31). C. albicans isolates (26%) were resistant to caspofungin, fluconazole, micafungin, and voriconazole but highly susceptible to amphotericin B and flucytosine (81-96%). Non-albicans Candida species isolated were susceptible (90-100%) to a majority of the antifungal agents tested. Conclusion: Candida albicans was the predominant species isolated and showed low resistance rates to the commonly administered antifungal agents. There is need to include fungal diagnosis in the investigation of diabetic foot ulcer infection.


Assuntos
Diabetes Mellitus Tipo 2 , Pé Diabético , Adulto , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Candida , Estudos Transversais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Farmacorresistência Fúngica , Fluconazol , Humanos , Quênia/epidemiologia , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Centros de Atenção Terciária
5.
Pestic Biochem Physiol ; 183: 105058, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35430062

RESUMO

Sensitivity of B. cinerea to commonly used fungicides against Gray mold with emphasis to the newer quinone outside inhibitor (QoIs), and succinate dehydrogenase inhibitors (SDHIs) was assessed during a monitoring survey from vegetable greenhouses in four representative regions of Crete. 42% from a total of 168 isolates were simultaneously resistant to boscalid, fluopyram, pyraclostrobin and fenhexamid but not to fludioxonil making this phenylpyrrole fungicide an excellent anti-resistance antifungal agent. Isolates with double resistance to SDHIs and QoIs were found in very high frequencies indicating a selection towards double resistance due to the use of pyraclostrobin-boscalid mixtures. A number of sdhB resistance mutations (H272R, N230I and P225F/H) were found in isolates also carrying the G143A cytb resistance mutation in the above isolates. A novel sdhB point mutation (I274V) was identified for the first time in B. cinerea isolates collected from greenhouses with a fluopyram spray history with specific resistance to SDHIs. A PCR-RFLP diagnostic assay was developed for the detection of this mutation in the sdhB gene. Mutations P225F/H and I274V were found to be associated with fitness penalties in terms of mycelial growth, sporulation or pathogenicity. Results suggest that, in order to retain effective control of gray mold in Crete, appropriate anti-resistance strategies should be implemented taking into account the high double SDHI and QoI resistance frequencies. Additional studies for monitoring the already known and the new SDHI-resistance mutations, are necessary in order to hinder the further spread and establishment of single or double resistant isolates of B. cinerea detected in greenhouses in Crete.


Assuntos
Botrytis , Fungicidas Industriais , Botrytis/genética , Farmacorresistência Fúngica/genética , Fungicidas Industriais/farmacologia , Mutação , Doenças das Plantas/microbiologia
6.
Microbiol Spectr ; 10(2): e0164221, 2022 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-35377226

RESUMO

Due to the emergence of multidrug-resistant strains of yeasts belonging to the Candida genus, there is an urgent need to discover antifungal agents directed at alternative molecular targets. The aim of the current study was to evaluate the capacity of three different series of synthetic compounds to inhibit the Candida glabrata enzyme denominated 3-hydroxy-methyl-glutaryl-CoA reductase and thus affect ergosterol synthesis and yeast viability. Compounds 1c (α-asarone-related) and 5b (with a pyrrolic core) were selected as the best antifungal candidates among over 20 synthetic compounds studied. Both inhibited the growth of fluconazole-resistant and fluconazole-susceptible C. glabrata strains. A yeast growth rescue experiment based on the addition of exogenous ergosterol showed that the compounds act by inhibiting the mevalonate synthesis pathway. A greater recovery of yeast growth occurred for the C. glabrata 43 fluconazole-resistant (versus fluconazole-susceptible) strain and after treatment with 1c (versus 5b). Given that the compounds decreased the concentration of ergosterol in the yeast strains, they probably target ergosterol synthesis. According to the docking analysis, the inhibitory effect of 1c and 5b could possibly be mediated by their interaction with the amino acid residues of the catalytic site of the enzyme. Since 1c displayed higher binding energy than α-asarone and 5b, it is the best candidate for further research, which should include structural modifications to increase its specificity and potency. The derivatives could then be examined with in vivo animal models using a therapeutic dose. IMPORTANCE Within the context of the COVID-19 pandemic, there is currently an epidemiological alert in health care services due to outbreaks of Candida auris, Candida glabrata, and other fungal species multiresistant to conventional antifungals. Therefore, it is important to propose alternative molecular targets, as well as new antifungals. The three series of synthetic compounds herein designed and synthesized are inhibitors of ergosterol synthesis in yeasts. Of the more than 20 compounds studied, two were selected as the best antifungal candidates. These compounds were able to inhibit the growth and synthesis of ergosterol in C. glabrata strains, whether susceptible or resistant to fluconazole. The rational design of antifungal compounds derived from clinical drugs (statins, fibrates, etc.) has many advantages. Future studies are needed to modify the structure of the two present test compounds to obtain safer and less toxic antifungals. Moreover, it is important to carry out a more in-depth mechanistic approach.


Assuntos
COVID-19 , Candida glabrata , Acil Coenzima A , Animais , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Candida glabrata/metabolismo , Farmacorresistência Fúngica , Ergosterol/metabolismo , Ácidos Fíbricos/metabolismo , Fluconazol/metabolismo , Fluconazol/farmacologia , Humanos , Hidroximetilglutaril-CoA Redutases/química , Hidroximetilglutaril-CoA Redutases/metabolismo , Testes de Sensibilidade Microbiana , Pandemias , Pirróis/metabolismo , Pirróis/farmacologia
7.
Microbiol Spectr ; 10(2): e0125321, 2022 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-35384691

RESUMO

We used a Vitek 2 AST-YS08 (YS08) system and the broth microdilution method (BMD) adopted by the Clinical and Laboratory Standards Institute (CLSI) to compare the susceptibility of 184 isolates of 11 Candida species to fluconazole, voriconazole, micafungin, caspofungin, amphotericin B, and flucytosine. In Candida albicans, the categorical agreement (CA) was 79.2%, 91.7%, 95.8%, and 95.8% for fluconazole, voriconazole, micafungin, and caspofungin, respectively. About 12.5% and 4.2% of very major errors were detected for fluconazole and voriconazole, respectively. C. glabrata showed excellent essential agreements (EAs) (>90%) for azoles but different MIC distributions for fluconazole and caspofungin. The CA between BMD fluconazole MICs and YS08 voriconazole MICs by the method-specific clinical breakpoint (CBP) was 90% in C. glabrata. Over 80% of C. glabrata and C. krusei isolates identified as micafungin-susceptible were labeled intermediate or resistant to caspofungin in YS08. In C. parapsilosis, 5.3% of very major errors and 10.5% of minor errors were found, whereas 33.3% of minor errors were observed in C. tropicalis for fluconazole. For C. tropicalis, 13 (61.9%) non-wild type (WT) isolates of fluconazole and 7 (33.3%) non-WTs of voriconazole were classified in YS08 as WT. For C. auris, the EAs were 93.3%, 100%, 82.2%, 97.8%, and 97.8% for fluconazole, voriconazole, micafungin, caspofungin, and amphotericin B, respectively. YS08 showed comparable results to the BMD. However, considering the lower YS08 fluconazole MIC results compared with BMD in Candida species and YS08 caspofungin results in C. glabrata and C. krusei, improvements are needed. IMPORTANCE The new Vitek 2 AST-YS08 (YS08) card has been updated to reflect the recently revised Clinical and Laboratory Standards Institute (CLSI) guideline. In this study, antifungal drug susceptibility tests were performed using the YS08 card and compared with the CLSI broth microdilution (BMD) method. In conclusion, YS08 showed similar results to BMD, including with C. auris. However, about 12.5% and 4.2% of major errors were detected for fluconazole and voriconazole, respectively, in C. albicans. More than 80% of C. glabrata and C. krusei isolates identified as susceptible to micafungin were labeled moderate or resistant to caspofungin in YS08. The categorical agreement between BMD fluconazole MICs and YS08 voriconazole MICs was 90% by the method-specific CBP of voriconazole, 80% by the current epidemiological cutoff value (ECV) (0.25 µg/mL) of voriconazole, and 85% by the previous ECV (0.5 µg/mL) of voriconazole. Further improvements in YS08 for the detection of fluconazole and echinocandin resistance are thus needed.


Assuntos
Antifúngicos , Candida , Anfotericina B , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Candida albicans , Caspofungina/farmacologia , Farmacorresistência Fúngica , Fluconazol , Micafungina , Testes de Sensibilidade Microbiana , Voriconazol/farmacologia
8.
Future Microbiol ; 17: 607-620, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35411812

RESUMO

Objective: The present study investigated the antifungal action of dexamethasone disodium phosphate (Dex). Methodology: Susceptibility testing was performed using the Clinical & Laboratory Standards Institute protocol; M27-A3, checkerboard test and biofilm were evaluated with two isolates of Candida albicans, hyphal production test, molecular docking analysis and flow cytometry analysis. Result: Dex and fluconazole (FLC) together had a synergistic effect. Mature biofilm was reduced when treated with Dex alone or in combination. Dex and FLC promoted a decrease in the production of hyphae and changes in the level of mitochondrial depolarization, increased generation of reactive oxygen species, loss of membrane integrity, increased phosphatidylserine externalization and molecular docking; there was interaction with ALS3 and SAP5 targets. Conclusion: Dex showed antifungal activity against FLC-resistant C. albicans strains.


This study aimed to evaluate the antifungal action of dexamethasone against FLC-resistant C. albicans strains.


Assuntos
Candida albicans , Fluconazol , Antifúngicos/farmacologia , Biofilmes , Dexametasona/farmacologia , Farmacorresistência Fúngica , Sinergismo Farmacológico , Fluconazol/farmacologia , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular
9.
Commun Biol ; 5(1): 292, 2022 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-35361876

RESUMO

Microbial drug resistance is an emerging global challenge. Current drug resistance assays tend to be simplistic, ignoring complexities of resistance manifestations and mechanisms, such as multicellularity. Here, we characterize multicellular and molecular sources of drug resistance upon deleting the AMN1 gene responsible for clumping multicellularity in a budding yeast strain, causing it to become unicellular. Computational analysis of growth curve changes upon drug treatment indicates that the unicellular strain is more sensitive to four common antifungals. Quantitative models uncover entwined multicellular and molecular processes underlying these differences in sensitivity and suggest AMN1 as an antifungal target in clumping pathogenic yeasts. Similar experimental and mathematical modeling pipelines could reveal multicellular and molecular drug resistance mechanisms, leading to more effective treatments against various microbial infections and possibly even cancers.


Assuntos
Proteínas de Saccharomyces cerevisiae , Saccharomycetales , Antifúngicos/farmacologia , Farmacorresistência Fúngica/genética , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética
10.
Nat Microbiol ; 7(5): 663-674, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35469019

RESUMO

Infections caused by the fungal pathogen Aspergillus fumigatus are increasingly resistant to first-line azole antifungal drugs. However, despite its clinical importance, little is known about how susceptible patients acquire infection from drug-resistant genotypes in the environment. Here, we present a population genomic analysis of 218 A. fumigatus isolates from across the UK and Ireland (comprising 153 clinical isolates from 143 patients and 65 environmental isolates). First, phylogenomic analysis shows strong genetic structuring into two clades (A and B) with little interclade recombination and the majority of environmental azole resistance found within clade A. Second, we show occurrences where azole-resistant isolates of near-identical genotypes were obtained from both environmental and clinical sources, indicating with high confidence the infection of patients with resistant isolates transmitted from the environment. Third, genome-wide scans identified selective sweeps across multiple regions indicating a polygenic basis to the trait in some genetic backgrounds. These signatures of positive selection are seen for loci containing the canonical genes encoding fungicide resistance in the ergosterol biosynthetic pathway, while other regions under selection have no defined function. Lastly, pan-genome analysis identified genes linked to azole resistance and previously unknown resistance mechanisms. Understanding the environmental drivers and genetic basis of evolving fungal drug resistance needs urgent attention, especially in light of increasing numbers of patients with severe viral respiratory tract infections who are susceptible to opportunistic fungal superinfections.


Assuntos
Anti-Infecciosos , Aspergillus fumigatus , Aspergillus fumigatus/genética , Azóis/farmacologia , Farmacorresistência Fúngica/genética , Humanos , Metagenômica , Testes de Sensibilidade Microbiana
11.
Arch Oral Biol ; 138: 105415, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35390561

RESUMO

OBJECTIVE: As the emerging resistance of Candida species to common antifungals is a major global concern, we assessed the antifungal susceptibility of oral yeast isolates from a healthy, Thai adult cohort, and correlated the yeast prevalence with oral disease indices. METHODS: Oral rinse samples collected from 100 Thai adults were concentrated and cultured on CHROMagar Candida. The yeasts were then isolated, identified and finally speciated using Matrix Assisted Laser Desorption ionization-time of flight mass spectrometry. Their antifungal sensitivity against fluconazole, itraconazole, voriconazole, and amphotericin B were investigated using standard Etest strips. The decayed, missing, filled teeth (DMFT) and the periodontal health were recorded and correlated with mycological data. RESULTS: The overall oral yeast prevalence was 25%. C. albicans was the commonest species isolated, followed by C. tropicalis and C. dubliniensis. Non-albicans-Candida was noted in approximately one-third, and included C. lusitaniae and C. nivariensis; Trichosporon asahii, was also detected in one subject. A majority of C. albicans isolates, (> 54%), exhibited resistance to fluconazole and voriconazole, while approximately a quarter (27%) were resistant to itraconazole. The vast majority (92%) however, were susceptible to amphotericin B. Those with oral yeasts had a significantly higher DMFT score (p < 0.05). CONCLUSION: The resistance of a majority of Candida spp. to common azoles, described here for the first time in a Thai cohort, is disconcerting, and appear to confirm the creeping emergence of antifungal resistance globally. An incidental finding was the positive correlation between oral yeast carriage and DMFT score in Thai subjects.


Assuntos
Antifúngicos , Fluconazol , Adulto , Anfotericina B/farmacologia , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Candida , Candida albicans , Candida tropicalis , Farmacorresistência Fúngica , Fluconazol/farmacologia , Humanos , Itraconazol/farmacologia , Testes de Sensibilidade Microbiana , Filogenia , Prevalência , Tailândia/epidemiologia , Voriconazol/farmacologia
12.
G3 (Bethesda) ; 12(5)2022 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-35377435

RESUMO

Birds are highly susceptible to aspergillosis, which can manifest as a primary infection in both domestic and wild birds. Aspergillosis in wild birds causes mortalities ranging in scale from single animals to large-scale epizootic events. However, pathogenicity factors associated with aspergillosis in wild birds have not been examined. Specifically, it is unknown whether wild bird-infecting strains are host-adapted (i.e. phylogenetically related). Similarly, it is unknown whether epizootics are driven by contact with clonal strains that possess unique pathogenic or virulence properties, or by distinct and equally pathogenic strains. Here, we use a diverse collection of Aspergillus fumigatus isolates taken from aspergillosis-associated avian carcasses, representing 24 bird species from a wide geographic range, and representing individual bird mortalities as well as epizootic events. These isolates were sequenced and analyzed along with 130 phylogenetically diverse human clinical isolates to investigate the genetic diversity and phylogenetic placement of avian-associated A. fumigatus, the geographic and host distribution of avian isolates, evidence for clonal outbreaks among wild birds, and the frequency of azole resistance in avian isolates. We found that avian isolates were phylogenetically diverse, with no clear distinction from human clinical isolates, and no sign of host or geographic specificity. Avian isolates from the same epizootic events were diverse and phylogenetically distant, suggesting that avian aspergillosis is not contagious among wild birds and that outbreaks are likely driven by environmental spore loads or host comorbidities. Finally, all avian isolates were susceptible to Voriconazole and none contained the canonical azole resistance gene variants.


Assuntos
Aspergilose , Aspergillus fumigatus , Animais , Antifúngicos/farmacologia , Aspergilose/epidemiologia , Aspergilose/veterinária , Aspergillus fumigatus/genética , Azóis , Aves , Farmacorresistência Fúngica/genética , Proteínas Fúngicas/genética , Genótipo , Especificidade de Hospedeiro , Testes de Sensibilidade Microbiana , Filogenia
13.
Washington, D.C.; OPAS; 2022-04-27. (OPAS/CDE/AMR/COVID-19/22-0006).
em Português | PAHO-IRIS | ID: phr-55936

RESUMO

A pandemia de COVID-19 acelerou a atual crise mundial de resistência aos antimicrobianos (RAM) devido ao aumento do uso de antibióticos para tratar os pacientes com COVID-19, as interrupções nas práticas de prevenção e controle de infecções em sistemas de saúde sobrecarregados, e o desvio de recursos humanos e financeiros da vigilância e da resposta às ameaças da RAM. Além disso, é provável que a RAM tenha causado mais mortes por COVID-19, pois infecções bacterianas secundárias podem piorar o resultado de doenças graves e críticas de COVID-19. Portanto, é mais urgente do que nunca priorizar os esforços para a contenção da RAM e apoiar os países para melhorar a detecção, caracterização e resposta rápida à RAM emergente. Este informe de política compila informações estratégicas para que tomadores de decisões continuem priorizando a resposta à RAM e a implementação dos planos de ação nacionais sobre a RAM, garantindo ao mesmo tempo que recursos adequados sejam alocados para o último. Também incentiva os países a medir e monitorar o impacto da pandemia de COVID-19 na epidemiologia da RAM na Região.


Assuntos
Resistência Microbiana a Medicamentos , Farmacorresistência Bacteriana , Farmacorresistência Fúngica , COVID-19 , América
14.
Washington, D.C.; OPS; 2022-04-26. (OPS/CDE/AMR/COVID-19/22-0006).
em Espanhol | PAHO-IRIS | ID: phr-55928

RESUMO

La pandemia de COVID-19 ha acelerado la crisis mundial de resistencia a los antimicrobianos (RAM) debido al aumento del consumo de antibióticos para tratar a los pacientes con COVID-19, las interrupciones en las prácticas de prevención y control de infecciones en sistemas de salud desbordados, y a la desviación de recursos humanos y financieros de las actividades de vigilancia y respuesta a las amenazas de la RAM. Además, es probable que la RAM haya causado más muertes por COVID-19, ya que las infecciones bacterianas secundarias pueden empeorar el desenlace de una enfermedad grave y crítica. Por lo tanto, es más urgente que nunca priorizar las iniciativas en favor de la contención de la RAM y apoyar a los países para mejorar la detección, caracterización y respuesta rápida a la RAM emergente. Esta síntesis de política recopila información estratégica para que los responsables de formular políticas y tomar decisiones continúen priorizando la respuesta a la RAM y la aplicación de los planes de acción nacionales en la materia, al tiempo que garantizan una asignación adecuada de recursos. También alienta a los países a medir y monitorear el impacto de la pandemia de COVID-19 en las características epidemiológicas de la RAM en la Región de las Américas.


Assuntos
Resistência Microbiana a Medicamentos , Farmacorresistência Fúngica , Antivirais , COVID-19 , América
15.
Front Cell Infect Microbiol ; 12: 851769, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35372131

RESUMO

Drug resistance is one of the major challenges to skin fungal infections, especially in tropical and subtropical infections caused by dermatophytes. This study aimed to determine the antifungal susceptibility of clinically dermatophytes and evaluate point mutations in terbinafine-resistant isolates. A total number of 123 clinical dermatophyte isolates in eight species were evaluated in terms of sensitivity to seven major antifungals. Furthermore, the point mutation in squalene epoxidase (SQLE) gene responsible for terbinafine resistance was studied. The dermatophytes species were identified by morphological characteristics and confirmed by the ITS sequencing. Also, the phylogenetic tree was drawn using the RAxML analyses for 123 dermatophytes isolates. A new XXIX genotype was also found in 4 Trichophyton mentagrophytes isolates. Based on the results obtained, terbinafine was the most effective antifungal drug followed by itraconazole and voriconazole. Trichophyton rubrum and Trichophyton tonsurans were the most susceptible species (MIC50 = 0.01, 0.09 µg/ml), and T. mentagrophytes was the most resistant species (MIC50 = 0.125 µg/ml) to terbinafine. Of the 123 dermatophytes isolates, six isolates showed reduced susceptibility to terbinafine, and only Trichophyton indotineae had a mutation in SQLE gene as a Phe397Leu substitution. Overall, the antifungal susceptibility test is necessary for managing dermatophytosis. These results help physicians to control the course of the disease and provide further insights to select effective drugs for patients with dermatophytosis, especially in tropical and subtropical regions of the world, where dermatophytosis is still a public health problem.


Assuntos
Arthrodermataceae , Tinha , Antifúngicos/farmacologia , Arthrodermataceae/genética , Farmacorresistência Fúngica/genética , Humanos , Testes de Sensibilidade Microbiana , Filogenia , Mutação Puntual , Esqualeno Mono-Oxigenase/genética
16.
Antimicrob Agents Chemother ; 66(4): e0227421, 2022 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-35254091

RESUMO

Aspergillus terreus is an opportunistic causative agent of invasive aspergillosis and, in most cases, it is refractory to amphotericin B (AMB) therapy. Notably, AMB-susceptible Aspergillus terreus sensu stricto (s.s.) representatives exist which are also associated with poor clinical outcomes. Such findings may be attributable to drug tolerance, which is not detectable by antifungal susceptibility testing. Here, we tested in vitro antifungal susceptibility (AFST) and the fungicidal activity of AMB against 100 clinical isolates of A. terreus species complex in RPMI 1640 and antibiotic medium 3 (AM3). MICs ranged from 0.5 to 16 µg/mL for RPMI 1640 and from 1 to >16 mg/L for AM3. AMB showed medium-dependent activity, with fungicidal effects only in antibiotic medium 3, not in RPMI 1640. Furthermore, the presence of AMB-tolerant phenotypes of A. terreus has been examined by assessing the minimum duration for killing 99% of the population (MDK99) and evaluating the data obtained in a Galleria mellonella infection model. A time-kill curve analysis revealed that A. terreus with AMB MICs of ≤1 mg/L (susceptible range) displayed AMB-tolerant phenotypes, exhibiting MDK99s at 18 and 36 h, respectively. Survival rates of infected G. mellonella highlighted that AMB was effective against susceptible A. terreus isolates, but not against tolerant or resistant isolates. Our analysis reveals that A. terreus isolates which are defined as susceptible based on MIC may comprise tolerant phenotypes, which may, in turn, explain the worse outcome of AMB therapy for phenotypically susceptible isolates.


Assuntos
Anfotericina B , Antifúngicos , Anfotericina B/farmacologia , Antibacterianos/uso terapêutico , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Aspergillus , Farmacorresistência Fúngica , Tolerância a Medicamentos , Testes de Sensibilidade Microbiana
17.
Antimicrob Agents Chemother ; 66(4): e0239321, 2022 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-35341316

RESUMO

The multi-antifungal drug-resistant strain (NUBS21012) of Trichophyton rubrum was isolated from a patient with recurrent tinea corporis. The resistant strain encoded Phe at codon 393 instead of Leu (L393F) in the squalene epoxidase (SQLE) gene. The expression of genes encoding ATP-binding cassette transporter proteins increased in the strain compared to that of other strains. This result provides evidence that ATP-binding cassette transporter proteins are closely associated with azole resistance.


Assuntos
Antifúngicos , Trichophyton , Transportadores de Cassetes de Ligação de ATP , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Arthrodermataceae , Farmacorresistência Fúngica/genética , Humanos , Testes de Sensibilidade Microbiana , Terbinafina
18.
Antimicrob Agents Chemother ; 66(4): e0006722, 2022 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-35343781

RESUMO

Candida auris is an emerging yeast pathogen with a remarkable ability to develop antifungal resistance, in particular to fluconazole and other azoles. Azole resistance in C. auris was shown to result from different mechanisms, such as mutations in the target gene ERG11 or gain-of-function (GOF) mutations in the transcription factor TAC1b and overexpression of the drug transporter Cdr1. The roles of the transcription factor Mrr1 and of the drug transporter Mdr1 in azole resistance is still unclear. Previous works showed that deletion of MRR1 or MDR1 had no or little impact on azole susceptibility of C. auris. However, an amino acid substitution in Mrr1 (N647T) was identified in most C. auris isolates of clade III that were fluconazole resistant. This study aimed at investigating the role of the transcription factor Mrr1 in azole resistance of C. auris. While the MRR1N647T mutation was always concomitant to hot spot ERG11 mutations, MRR1 deletion in one of these isolates only resulted in a modest decrease of azole MICs. However, introduction of the MRR1N647T mutation in an azole-susceptible C. auris isolate from another clade with wild-type MRR1 and ERG11 alleles resulted in significant increase of fluconazole and voriconazole MICs. We demonstrated that this MRR1 mutation resulted in reduced azole susceptibility via upregulation of the drug transporter MDR1 and not CDR1. In conclusion, this work demonstrates that the Mrr1-Mdr1 axis may contribute to C. auris azole resistance by mechanisms that are independent from ERG11 mutations and from CDR1 upregulation.


Assuntos
Azóis , Fluconazol , Antifúngicos/farmacologia , Azóis/farmacologia , Candida albicans , Farmacorresistência Fúngica/genética , Fluconazol/farmacologia , Proteínas Fúngicas/genética , Testes de Sensibilidade Microbiana , Fatores de Transcrição/genética
19.
Antimicrob Agents Chemother ; 66(4): e0210521, 2022 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-35343782

RESUMO

As an opportunistic fungal pathogen, Candida albicans is a major cause of superficial and systemic infections in immunocompromised patients. The increasing rate of azole resistance in C. albicans has brought further challenges to clinical therapy. In this study, we collected five isogenic C. albicans strains recovered over discrete intervals from an HIV-infected patient who suffered 2-year recurrent oropharyngeal candidiasis. Azole resistance was known from the clinical history to have developed gradually in this patient, and this was confirmed by MIC assays of each strain. Proteomic techniques can be used to investigate more comprehensively how resistance develops in pathogenic fungi over time. Our study is the first to use tandem mass tag (TMT) labeling combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) technology to investigate the acquired resistance mechanisms of serial C. albicans isolates at the proteomic level. A total of 4,029 proteins have been identified, of which 3,766 have been quantified. Compared with Ca1, bioinformatics analysis showed that differentially expressed proteins were mainly associated with aspects such as the downregulation of glycolysis/gluconeogenesis, pyruvate metabolism, fatty acid degradation, and oxidative stress response proteins in all four subsequent strains but, remarkably, the activation of amino acid metabolism in Ca8 and Ca14 and increased protection against osmotic stress or excessive copper toxicity, upregulation of respiratory chain activity, and suppression of iron transport in Ca17. By tracing proteomic alterations in this set of isogenic resistance isolates, we acquire mechanistic insight into the steps involved in the acquisition of azole resistance in C. albicans.


Assuntos
Candida albicans , Candidíase , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Azóis , Biomarcadores Tumorais , Candidíase/tratamento farmacológico , Cromatografia Líquida , Farmacorresistência Fúngica/genética , Fluconazol/farmacologia , Fluconazol/uso terapêutico , Humanos , Testes de Sensibilidade Microbiana , Proteômica , Espectrometria de Massas em Tandem
20.
Infect Immun ; 90(4): e0062621, 2022 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-35289633

RESUMO

Polymicrobial infections are challenging to treat because we don't fully understand how pathogens interact during infection and how these interactions affect drug efficacy. Candida albicans and Pseudomonas aeruginosa are opportunistic pathogens that can be found in similar sites of infection such as in burn wounds and most importantly in the lungs of CF and mechanically ventilated patients. C. albicans is particularly difficult to treat because of the paucity of antifungal agents, some of which lack fungicidal activity. In this study, we investigated the efficacy of anti-fungal treatment during C. albicans-P. aeruginosa coculture in vitro and co-infection in the mucosal zebrafish infection model analogous to the lung. We find that P. aeruginosa enhances the activity of fluconazole (FLC), an anti-fungal drug that is fungistatic in vitro, to promote both clearance of C. albicans during co-infection in vivo and fungal killing in vitro. This synergy between FLC treatment and bacterial antagonism is partly due to iron piracy, as it is reduced upon iron supplementation and knockout of bacterial siderophores. Our work demonstrates that FLC has enhanced activity in clinically relevant contexts and highlights the need to understand antimicrobial effectiveness in the complex environment of the host with its associated microbial communities.


Assuntos
Coinfecção , Fluconazol , Animais , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Candida , Candida albicans , Coinfecção/tratamento farmacológico , Farmacorresistência Fúngica , Fluconazol/farmacologia , Fluconazol/uso terapêutico , Humanos , Ferro , Testes de Sensibilidade Microbiana , Pseudomonas , Pseudomonas aeruginosa , Peixe-Zebra
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