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

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.

scholarly journals Antifungal Resistance Regarding Malassezia pachydermatis: Where Are We Now?

2020 ◽  
Vol 6 (2) ◽  
pp. 93
Author(s):  
Andrea Peano ◽  
Elizabeth Johnson ◽  
Elisa Chiavassa ◽  
Paolo Tizzani ◽  
Jacques Guillot ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Antifungal Agents ◽  
Standard Procedure ◽  
Resistance Mechanisms ◽  
Antifungal Resistance ◽  
Antifungal Drugs ◽  
Malassezia Pachydermatis ◽  
Development Of Resistance ◽  
Ear Canals

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.

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

2007 ◽  
Vol 51 (10) ◽  
pp. 3642-3649 ◽  
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.

scholarly journals 1306. Early Transition to Oral Antibiotics, Including Fluoroquinolone Therapy, for Streptococcus milleri Empyema Following Video-Assisted Thoracoscopic Surgery

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S741-S741
Author(s):  
Anais Ovalle ◽  
Ahmad Alsalman ◽  
Timothy Millington ◽  
Richard A Zuckerman
Keyword(s):  
Thoracoscopic Surgery ◽  
Rapid Development ◽  
Repeat Surgery ◽  
Video Assisted ◽  
Development Of Resistance ◽  
Streptococcus Milleri ◽  
Video Assisted Thoracoscopic Surgery ◽  
Early Transition

Abstract Background Pleural empyema from Streptococcus milleri (SM) is often complex and requires a combination of surgery and intravenous (IV) antibiotics. There is a paucity of data on the efficacy of oral (PO) treatment due to concerns about the development of resistance, particularly to fluoroquinolones (FQ). We report outcomes of postoperative antibiotic treatment for SM empyema over 3 years, including PO therapy. Methods A single-center retrospective chart review was performed of 20 patients treated with video-assisted thoracoscopic surgery (VATS) from October 2015 to March 2018 and SM diagnosed by thoracentesis or operative culture. We reviewed clinical factors, route and duration of antibiotics, complications (empyema recurrence, repeat surgery, 30-day readmission due to empyema), and mortality (30-day and 1-year) Results Of the 20 patients, 12 (60%) received all IV and 8 (40%) transitioned to PO therapy (Table 1). Median age was 60 and 58 in the IV and PO group, respectively. IV treated patients had more comorbidities. Cultures were primarily monomicrobial. Isolates tested were susceptible (S) to penicillin (Table 1), Of 10 tested specimen, all had moxifloxacin MIC < 0.19 μg/mL and 8/8 specimens tested were S to levofloxacin. The average duration of antibiotic therapy in the IV group was 34 days and 32 days in the PO group. There were no complications in the IV group: however, there were 2 deaths (1 patient died from comorbid complications and 1 patient was readmitted and died due to MSSA endocarditis). There were no complications or deaths in patients treated PO. Conclusion Our review suggests that early transition to PO antibiotics may be a viable option for operatively managed empyema caused by SM in certain patients. FQs have been generally avoided due to concerns about the rapid development of resistance that has been shown in-vitro; however, no in-vivo data have been reported regarding this concern. We show excellent outcomes with the use of PO therapy in susceptible isolates, particularly FQs, with no failure or reported resistance in patients with SM empyema treated with VATS. Further study is needed to validate these findings and determine optimal patient characteristics for transition to PO therapy. Disclosures All Authors: No reported disclosures

scholarly journals A Repurposing Approach for Uncovering the Anti-Tubercular Activity of FDA-Approved Drugs with Potential Multi-Targeting Profiles

Molecules ◽  
2019 ◽  
Vol 24 (23) ◽  
pp. 4373 ◽  
Author(s):  
Basem Battah ◽  
Giulia Chemi ◽  
Stefania Butini ◽  
Giuseppe Campiani ◽  
Simone Brogi ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Rapid Development ◽  
Antimycobacterial Activity ◽  
Multidrug Resistant ◽  
Biological Evaluation ◽  
Peripheral Blood Mononuclear ◽  
Development Of Resistance ◽  
Approved Drugs ◽  
Fda Approved Drugs

Tuberculosis (TB) is one of the top 10 causes of death worldwide. This scenario is further complicated by the insurgence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB. The identification of appropriate drugs with multi-target affinity profiles is considered to be a widely accepted strategy to overcome the rapid development of resistance. The aim of this study was to discover Food and Drug Administration (FDA)-approved drugs possessing antimycobacterial activity, potentially coupled to an effective multi-target profile. An integrated screening platform was implemented based on computational procedures (high-throughput docking techniques on the target enzymes peptide deformylase and Zmp1) and in vitro phenotypic screening assays using two models to evaluate the activity of the selected drugs against Mycobacterium tuberculosis (Mtb), namely, growth of Mtb H37Rv and of two clinical isolates in axenic media, and infection of peripheral blood mononuclear cells with Mtb. Starting from over 3000 FDA-approved drugs, we selected 29 marketed drugs for submission to biological evaluation. Out of 29 drugs selected, 20 showed antimycobacterial activity. Further characterization suggested that five drugs possessed promising profiles for further studies. Following a repurposing strategy, by combining computational and biological efforts, we identified marketed drugs with relevant antimycobacterial profiles.

scholarly journals In vitro anthelmintic effects of cysteine proteinases from plants against intestinal helminths of rodents

2007 ◽  
Vol 81 (4) ◽  
pp. 353-360 ◽  
Author(s):  
Gillian Stepek ◽  
Ann E. Lowe ◽  
David J. Buttle ◽  
Ian R. Duce ◽  
Jerzy M. Behnke
Keyword(s):  
Rapid Development ◽  
Intestinal Helminths ◽  
Cysteine Proteinases ◽  
Trichuris Muris ◽  
Heligmosomoides Polygyrus ◽  
Development Of Resistance ◽  
Taxonomic Groups ◽  
Gi Helminths

AbstractInfections with gastrointestinal (GI) nematodes are amongst the most prevalent worldwide, especially in tropical climates. Control of these infections is primarily through treatment with anthelmintic drugs, but the rapid development of resistance to all the currently available classes of anthelmintic means that alternative treatments are urgently required. Cysteine proteinases from plants such as papaya, pineapple and fig are known to be substantially effective against three rodent GI nematodes, Heligmosomoides polygyrus, Trichuris muris and Protospirura muricola, both in vitro and in vivo. Here, based on in vitro motility assays and scanning electron microscopy, we extend these earlier reports, demonstrating the potency of this anthelmintic effect of plant cysteine proteinases against two GI helminths from different taxonomic groups – the canine hookworm, Ancylostoma ceylanicum, and the rodent cestode, Rodentolepis microstoma. In the case of hookworms, a mechanism of action targeting the surface layers of the cuticle indistinguishable from that reported earlier appears to be involved, and in the case of cestodes, the surface of the tegumental layers was also the principal location of damage. Hence, plant cysteine proteinases have a broad spectrum of activity against intestinal helminths (both nematodes and cestodes), a quality that reinforces their suitability for development as a much-needed novel treatment against GI helminths of humans and livestock.

Rapid Development of Resistance to Antifolates In Vitro: Possible Clinical Implication

1991 ◽  
Vol 83 (1) ◽  
pp. 24-28 ◽  
Author(s):  
A. Sobrero ◽  
C. Aschele ◽  
R. Rosso ◽  
A. Nicolin ◽  
J.R. Bertino
Keyword(s):  
Clinical Implication ◽  
Rapid Development ◽  
Development Of Resistance

scholarly journals In-Vitro Evaluation of Antibacterial, Antifungal and Anti-HIV Effects of Calophyllum inophyllum Leaf Extract

2020 ◽  
Vol 13 (4) ◽  
pp. 2003-2014
Author(s):  
Arun Kumar ◽  
Yashika Garg
Keyword(s):  
Leaf Extract ◽  
Rapid Development ◽  
Human Pathogens ◽  
Bacterial Strains ◽  
Medicinal Uses ◽  
Development Of Resistance ◽  
Pure Compounds ◽  
Bacteria And Fungi ◽  
Antibacterial And Antifungal

Background:Calophylluminophyllum is an evergreen tree with ethno-medical value growing along the seashores and islands of the Pacific and Indian Ocean. All parts of the plant such as bark, seeds and leaves have diverse medicinal uses such as an antiseptic, analgesic in wound healing, astringent, diuretic, purgative and expectorant. Although many species of calophyllum have been studied phytochemically for pharmacological properties, reports on inophyllum species are scanty. Aim of the study:Keeping inview it’s medical importance and availability in India as well as the rapid development of resistance by pathogens to the commonly used synthetic antibiotics,the pharmacological effects of C. inophyllum leaf extract (CIE) on HIV, bacteria and fungi causative of many human diseases was assessed in this study. Material and Methods: Isolation of the pure compounds from the ethanolic CIE was performed by gross column chromatography and tested against lyophilized forms of 8 fungal and 14 bacterial strains grown on Sabouraud’s dextrose agar and nutrient agar media respectively. Fractions and pure compounds isolated from CIE were evaluated against HIV by the HIV-RT inhibition assay by using the RT assay kit(Roche). The results were tabulated and analysed. Results: Among the purified compounds, Inophyllum C & E exhibited significant antibacterial and antifungal properties. Moreover, Inophyllum E was more potent than Inophyllum C in inhibiting the tested strains of bacteria and fungi whereasInophyllum B shows highest antiretroviral activity. Conclusion:We conclude that CIEis aneffective antimicrobial agent against common human pathogens tested in this in-vitro pharmacological evaluation of CIE.

scholarly journals Tumor Resistance against ALK Targeted Therapy-Where It Comes From and Where It Goes

Cancers ◽  
2018 ◽  
Vol 10 (3) ◽  
pp. 62 ◽  
Author(s):  
Geeta Sharma ◽  
Ines Mota ◽  
Luca Mologni ◽  
Enrico Patrucco ◽  
Carlo Gambacorti-Passerini ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Resistance Mechanisms ◽  
Therapeutic Strategies ◽  
Tumor Resistance ◽  
Alk Inhibitors ◽  
Anaplastic Lymphoma ◽  
Development Of Resistance ◽  
Fda Approval ◽  
Novel Therapeutic Strategies

Anaplastic lymphoma kinase (ALK) is a validated molecular target in several ALK-rearranged malignancies, particularly in non-small-cell lung cancer (NSCLC), which has generated considerable interest and effort in developing ALK tyrosine kinase inhibitors (TKI). Crizotinib was the first ALK inhibitor to receive FDA approval for ALK-positive NSCLC patients treatment. However, the clinical benefit observed in targeting ALK in NSCLC is almost universally limited by the emergence of drug resistance with a median of occurrence of approximately 10 months after the initiation of therapy. Thus, to overcome crizotinib resistance, second/third-generation ALK inhibitors have been developed and received, or are close to receiving, FDA approval. However, even when treated with these new inhibitors tumors became resistant, both in vitro and in clinical settings. The elucidation of the diverse mechanisms through which resistance to ALK TKI emerges, has informed the design of novel therapeutic strategies to improve patients disease outcome. This review summarizes the currently available knowledge regarding ALK physiologic function/structure and neoplastic transforming role, as well as an update on ALK inhibitors and resistance mechanisms along with possible therapeutic strategies that may overcome the development of resistance.

scholarly journals Rapid Development of Candida krusei Echinocandin Resistance during Caspofungin Therapy

2015 ◽  
Vol 59 (11) ◽  
pp. 6975-6982 ◽  
Author(s):  
A. Forastiero ◽  
V. Garcia-Gil ◽  
O. Rivero-Menendez ◽  
R. Garcia-Rubio ◽  
M. C. Monteiro ◽  
...  
Keyword(s):  
Hot Spot ◽  
Rapid Development ◽  
Lymphocytic Leukemia ◽  
Molecular Evidence ◽  
Intrinsic Resistance ◽  
Content Type ◽  
Rapid Acquisition ◽  
Clinical Resistance ◽  
Echinocandin Resistance

ABSTRACTIn invasive candidiasis, there has been an epidemiological shift fromCandida albicansto non-albicansspecies infections, including infections withC. glabrata,C. parapsilosis,C. tropicalis, andC. krusei. Although the prevalence ofC. kruseiremains low among yeast infections, its intrinsic resistance to fluconazole raises epidemiological and therapeutic concerns. Echinocandins havein vitroactivity against mostCandidaspp. and are the first-line agents in the treatment of candidemia. Although resistance to echinocandin drugs is still rare, individual cases ofC. kruseiresistance have been reported in recent years, especially with strains that have been under selective pressure. A total of 15C. kruseistrains, isolated from the blood, urine, and soft tissue of an acute lymphocytic leukemia patient, were analyzed. Strains developed echinocandin resistance during 10 days of caspofungin therapy. The molecular epidemiology of the isolates was investigated using two different typing methods: PCR-based amplification of the species-specific repetitive polymorphic CKRS-1 sequence and multilocus sequence typing. All isolates were genetically related, and the mechanism involved in decreased echinocandin susceptibility was characterized. Clinical resistance was associated with an increase in echinocandin MICsin vitroand was related to three different mutations in hot spot 1 of the target enzyme Fks1p. Molecular evidence of the rapid acquisition of resistance by different mutations inFKS1highlights the need to monitor the development of resistance inC. kruseiinfections treated with echinocandin drugs.

scholarly journals Genetic Dissection of Azole Resistance Mechanisms in Candida albicans and Their Validation in a Mouse Model of Disseminated Infection

2010 ◽  
Vol 54 (4) ◽  
pp. 1476-1483 ◽  
Author(s):  
Donna M. MacCallum ◽  
Alix Coste ◽  
Françoise Ischer ◽  
Mette D. Jacobsen ◽  
Frank C. Odds ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Genetic Manipulation ◽  
Genetic Resistance ◽  
Resistance Mechanism ◽  
Diploid Species ◽  
Resistance Mechanisms ◽  
Genetic Dissection ◽  
Genetic Manipulations ◽  
Development Of Resistance

ABSTRACT Principal mechanisms of resistance to azole antifungals include the upregulation of multidrug transporters and the modification of the target enzyme, a cytochrome P450 (Erg11) involved in the 14α-demethylation of ergosterol. These mechanisms are often combined in azole-resistant Candida albicans isolates recovered from patients. However, the precise contributions of individual mechanisms to C. albicans resistance to specific azoles have been difficult to establish because of the technical difficulties in the genetic manipulation of this diploid species. Recent advances have made genetic manipulations easier, and we therefore undertook the genetic dissection of resistance mechanisms in an azole-resistant clinical isolate. This isolate (DSY296) upregulates the multidrug transporter genes CDR1 and CDR2 and has acquired a G464S substitution in both ERG11 alleles. In DSY296, inactivation of TAC1, a transcription factor containing a gain-of-function mutation, followed by sequential replacement of ERG11 mutant alleles with wild-type alleles, restored azole susceptibility to the levels measured for a parent azole-susceptible isolate (DSY294). These sequential genetic manipulations not only demonstrated that these two resistance mechanisms were those responsible for the development of resistance in DSY296 but also indicated that the quantitative level of resistance as measured in vitro by MIC determinations was a function of the number of genetic resistance mechanisms operating in any strain. The engineered strains were also tested for their responses to fluconazole treatment in a novel 3-day model of invasive C. albicans infection of mice. Fifty percent effective doses (ED50s) of fluconazole were highest for DSY296 and decreased proportionally with the sequential removal of each resistance mechanism. However, while the fold differences in ED50 were proportional to the fold differences in MICs, their magnitude was lower than that measured in vitro and depended on the specific resistance mechanism operating.

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