FKS Mutations and Elevated Echinocandin MIC Values among Candida glabrata Isolates from U.S. Population-Based Surveillance

ABSTRACT Candida glabrata is the second leading cause of candidemia in the United States. Its high-level resistance to triazole antifungal drugs has led to the increased use of the echinocandin class of antifungal agents for primary therapy of these infections. We monitored C. glabrata bloodstream isolates from a population-based surveillance study for elevated echinocandin MIC values (MICs of ≥0.25 μg/ml). From the 490 C. glabrata isolates that were screened, we identified 16 isolates with an elevated MIC value (2.9% of isolates from Atlanta and 2.0% of isolates from Baltimore) for one or more of the echinocandin drugs caspofungin, anidulafungin, and micafungin. All of the isolates with elevated MIC values had a mutation in the previously identified hot spot 1 of either the glucan synthase FKS1 (n = 2) or FKS2 (n = 14) gene. No mutations were detected in hot spot 2 of either FKS1 or FKS2. The predominant mutation was mutation of FKS2-encoded serine 663 to proline (S663P), found in 10 of the isolates with elevated echinocandin MICs. Two of the mutations, R631G for FKS1 and R665G for FKS2, have not been reported previously for C. glabrata. Multilocus sequence typing indicated that the predominance of the S663P mutation was not due to the clonal spread of a single sequence type. With a rising number of echinocandin therapy failures reported, it is important to continue to monitor rates of elevated echinocandin MIC values and the associated mutations.

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The Chemistry of Drugs to Treat Candida albicans

Current Topics in Medicinal Chemistry ◽

10.2174/1568026619666191025153124 ◽

2019 ◽

Vol 19 (28) ◽

pp. 2554-2566 ◽

Cited By ~ 2

Author(s):

Aurelio Ortiz ◽

Estibaliz Sansinenea

Keyword(s):

Candida Species ◽

Antifungal Drugs ◽

New Drugs ◽

Drug Classes ◽

Life Threatening ◽

Antifungal Substances ◽

High Level ◽

Systemic Infections ◽

New Compounds ◽

Level Resistance

Background:: Candida species are in various parts of the human body as commensals. However, they can cause local mucosal infections and, sometimes, systemic infections in which Candida species can spread to all major organs and colonize them. Objective:: For the effective treatment of the mucosal infections and systemic life-threatening fungal diseases, a considerably large number of antifungal drugs have been developed and used for clinical purposes that comprise agents from four main drug classes: the polyenes, azoles, echinocandins, and antimetabolites. Method: : The synthesis of some of these drugs is available, allowing synthetic modification of the molecules to improve the biological activity against Candida species. The synthetic methodology for each compound is reviewed. Results: : The use of these compounds has caused a high-level resistance against these drugs, and therefore, new antifungal substances have been described in the last years. The organic synthesis of the known and new compounds is reported. Conclusion: : This article summarizes the chemistry of the existing agents, both the old drugs and new drugs, in the treatment of infections due to C. albicans, including the synthesis of the existing drugs.

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Outbreak of Mupirocin-Resistant Staphylococci in a Hospital in Warsaw, Poland, Due to Plasmid Transmission and Clonal Spread of Several Strains

Journal of Clinical Microbiology ◽

10.1128/jcm.37.9.2781-2788.1999 ◽

1999 ◽

Vol 37 (9) ◽

pp. 2781-2788 ◽

Cited By ~ 31

Author(s):

Tomasz A. Łe˛ski ◽

Marek Gniadkowski ◽

Anna Skoczyńska ◽

Elz˙bieta Stefaniuk ◽

Krzysztof Trzciński ◽

...

Keyword(s):

Resistance Mechanisms ◽

Hospital Environment ◽

Coagulase Negative Staphylococci ◽

Large Hospital ◽

Methicillin Resistant ◽

Inappropriate Use ◽

Clonal Spread ◽

High Level ◽

Almost All ◽

Level Resistance

An outbreak of mupirocin-resistant (MuR) staphylococci was investigated in two wards of a large hospital in Warsaw, Poland. Fifty-three MuR isolates of Staphylococcus aureus, S. epidermidis, S. haemolyticus, S. xylosus, and S. capitis were identified over a 17-month survey which was carried out after introduction of the drug for the treatment of skin infections. The isolates were collected from patients with infections, environmental samples, and carriers; they constituted 19.5% of all staphylococcal isolates identified in the two wards during that time. Almost all the MuR isolates were also resistant to methicillin (methicillin-resistant S. aureus and methicillin-resistant coagulase-negative staphylococci). Seven of the outbreak isolates expressed a low-level-resistance phenotype (MuL), whereas the remaining majority of isolates were found to be highly resistant to mupirocin (MuH). The mupA gene, responsible for the MuH phenotype, has been assigned to three different polymorphic loci among the strains in the collection analyzed. The predominant polymorph, polymorph I (characterized by a mupA-containingEcoRI DNA fragment of about 16 kb), was located on a specific plasmid which was widely distributed among the entire staphylococcal population. All MuR S. aureus isolates were found to represent a single epidemic strain, which was clonally disseminated in both wards. The S. epidermidis population was much more diverse; however, at least four clusters of closely related isolates were identified, which suggested that some strains of this species were also clonally spread in the hospital environment. Six isolates of S. epidermidis were demonstrated to express the MuL and MuH resistance mechanisms simultaneously, and this is the first identification of such dual MuR phenotype-bearing strains. The outbreak was attributed to a high level and inappropriate use of mupirocin, and as a result the dermatological formulation of the drug has been removed from the hospital formulary.

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Distribution and frequency of strains of Neisseria gonorrhoeae with plasmid-mediated, high-level resistance to tetracycline (TRNG) in the United States

Gonococci and Meningococci ◽

10.1007/978-94-009-1383-7_21 ◽

1988 ◽

pp. 125-129 ◽

Cited By ~ 1

Author(s):

J. S. Knapp ◽

J. M. Zenilman ◽

J. W. Biddle ◽

G. Perkins ◽

W. E. Dewitt ◽

...

Keyword(s):

United States ◽

Neisseria Gonorrhoeae ◽

The United States ◽

High Level ◽

Level Resistance

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Twenty Years of the SENTRY Antifungal Surveillance Program: Results for Candida Species From 1997–2016

Open Forum Infectious Diseases ◽

10.1093/ofid/ofy358 ◽

2019 ◽

Vol 6 (Supplement_1) ◽

pp. S79-S94 ◽

Cited By ~ 109

Author(s):

Michael A Pfaller ◽

Daniel J Diekema ◽

John D Turnidge ◽

Mariana Castanheira ◽

Ronald N Jones

Keyword(s):

Candida Glabrata ◽

Hot Spot ◽

Bloodstream Infections ◽

The United States ◽

Asia Pacific ◽

Steady Increase ◽

Surveillance Program ◽

Candida Auris ◽

Medical Centers ◽

Clinical Breakpoints

AbstractBackgroundThe emergence of antifungal resistance threatens effective treatment of invasive fungal infection (IFI). Invasive candidiasis is the most common health care–associated IFI. We evaluated the activity of fluconazole (FLU) against 20 788 invasive isolates of Candida (37 species) collected from 135 medical centers in 39 countries (1997–2016). The activity of anidulafungin, caspofungin, and micafungin (MCF) was evaluated against 15 308 isolates worldwide (2006–2016).MethodsSpecies identification was accomplished using phenotypic (1997–2001), genotypic, and proteomic methods (2006–2016). All isolates were tested using reference methods and clinical breakpoints published in the Clinical and Laboratory Standards Institute documents.ResultsA decrease in the isolation of Candida albicans and an increase in the isolation of Candida glabrata and Candida parapsilosis were observed over time. Candida glabrata was the most common non–C. albicans species detected in all geographic regions except for Latin America, where C. parapsilosis and Candida tropicalis were more common. Six Candida auris isolates were detected: 1 each in 2009, 2013, 2014, and 2015 and 2 in 2016; all were from nosocomial bloodstream infections and were FLU-resistant (R). The highest rates of FLU-R isolates were seen in C. glabrata from North America (NA; 10.6%) and in C. tropicalis from the Asia-Pacific region (9.2%). A steady increase in isolation of C. glabrata and resistance to FLU was detected over 20 years in the United States. Echinocandin-R (EC-R) ranged from 3.5% for C. glabrata to 0.1% for C. albicans and C. parapsilosis. Resistance to MCF was highest among C. glabrata (2.8%) and C. tropicalis (1.3%) from NA. Mutations on FKS hot spot (HS) regions were detected among 70 EC-R isolates (51/70 were C. glabrata). Most isolates harboring FKS HS mutations were resistant to 2 or more ECs.ConclusionsEC-R and FLU-R remain uncommon among contemporary Candida isolates; however, a slow and steady emergence of resistance to both antifungal classes was observed in C. glabrata and C. tropicalis isolates.

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Fks1 and Fks2 Are Functionally Redundant but Differentially Regulated in Candida glabrata: Implications for Echinocandin Resistance

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00813-12 ◽

2012 ◽

Vol 56 (12) ◽

pp. 6304-6309 ◽

Cited By ~ 62

Author(s):

Santosh K. Katiyar ◽

Ana Alastruey-Izquierdo ◽

Kelley R. Healey ◽

Michael E. Johnson ◽

David S. Perlin ◽

...

Keyword(s):

Candida Glabrata ◽

Transcriptional Control ◽

Mutational Analysis ◽

Hot Spot ◽

Normal Growth ◽

Integral Membrane Protein ◽

Content Type ◽

Echinocandin Resistance ◽

High Level ◽

The Impact

ABSTRACTThe echinocandins caspofungin, micafungin, and anidulafungin, inhibitors of cell wall β-1,3-glucan synthesis, were recently elevated to first-line agents for treating infections due to the azole-refractory yeastCandida glabrata. InCandida albicans, echinocandin resistance is strictly associated with mutations in Fks1, a large integral membrane protein and putative β-1,3-glucan synthase, while mutations in both Fks1 and its paralog Fks2 (but not Fks3) have been associated with resistance inC. glabrata. To further explore their function, regulation, and role in resistance,C. glabratafksgenes were disrupted and subjected to mutational analysis, and their differential regulation was explored. Anfks1Δfks2Δ double disruptant was not able to be generated; otherwise, all three single and remaining two double disruptants displayed normal growth and echinocandin susceptibility, indicating Fks1-Fks2 redundancy. Selection on echinocandin-containing medium for resistant mutants was dependent on strain background: onlyfks1Δ andfks1Δfks3Δ strains consistently yielded mutants exhibiting high-level resistance, all with Fks2 hot spot 1 mutations. Thus, Fks1-Fks2 redundancy attenuates the rate of resistance; further analysis showed that it also attenuates the impact of resistance-conferring mutations. Growth of thefks1Δ and, especially,fks1Δfks3Δ strains was specifically susceptible to the calcineurin inhibitor FK506. Relatedly, FK506 addition or calcineurin geneCMP2disruption specifically reversed Fks2-mediated resistance of laboratory mutants and clinical isolates. RNA analysis suggests that transcriptional control is not the sole mechanism by which calcineurin modulates Fks2 activity.

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Role of FKS Mutations in Candida glabrata: MIC Values, Echinocandin Resistance, and Multidrug Resistance

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03255-14 ◽

2014 ◽

Vol 58 (8) ◽

pp. 4690-4696 ◽

Cited By ~ 127

Author(s):

Cau D. Pham ◽

Naureen Iqbal ◽

Carol B. Bolden ◽

Randall J. Kuykendall ◽

Lee H. Harrison ◽

...

Keyword(s):

Candida Glabrata ◽

Susceptibility Testing ◽

Hot Spot ◽

Case Reports ◽

Multidrug Resistant ◽

High Rate ◽

Primary Therapy ◽

Content Type ◽

Major Mechanism ◽

Echinocandin Resistance

ABSTRACTCandida glabratais the second leading cause of candidemia in U.S. hospitals. Current guidelines suggest that an echinocandin be used as the primary therapy for the treatment ofC. glabratadisease due to the high rate of resistance to fluconazole. Recent case reports indicate thatC. glabrataresistance to echinocandins may be increasing. We performed susceptibility testing on 1,380 isolates ofC. glabratacollected between 2008 and 2013 from four U.S. cities, Atlanta, Baltimore, Knoxville, and Portland. Our analysis showed that 3.1%, 3.3%, and 3.6% of the isolates were resistant to anidulafungin, caspofungin, and micafungin, respectively. We screened 1,032 of these isolates, including all 77 that had either a resistant or intermediate MIC value with respect to at least one echinocandin, for mutations in the hot spot regions ofFKS1andFKS2, the major mechanism of echinocandin resistance. Fifty-one isolates were identified with hot spot mutations, 16 inFKS1and 35 inFKS2. All of the isolates with anFKSmutation except one were resistant to at least one echinocandin by susceptibility testing. Of the isolates resistant to at least one echinocandin, 36% were also resistant to fluconazole. Echinocandin resistance among U.S.C. glabrataisolates is a concern, especially in light of the fact that one-third of those isolates may be multidrug resistant. Further monitoring of U.S.C. glabrataisolates for echinocandin resistance is warranted.

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Salmonella enterica Burden in Harvest-Ready Cattle Populations from the Southern High Plains of the United States

Applied and Environmental Microbiology ◽

10.1128/aem.02076-07 ◽

2007 ◽

Vol 74 (2) ◽

pp. 345-351 ◽

Cited By ~ 37

Author(s):

David J. Kunze ◽

Guy H. Loneragan ◽

Tammy M. Platt ◽

Mark F. Miller ◽

Thomas E. Besser ◽

...

Keyword(s):

United States ◽

Salmonella Enterica ◽

The United States ◽

Most Probable Number ◽

High Plains ◽

Antimicrobial Drugs ◽

Probable Number ◽

At Risk Populations ◽

High Level ◽

Level Resistance

ABSTRACT Our objectives were to quantify the Salmonella enterica burdens in harvest-ready cattle and to identify specific at-risk populations of cattle most likely to harbor multiply resistant S. enterica. Hide swabs were collected in abattoirs from three cohorts of cattle (feedlot origin cattle that had achieved desirable harvest characteristics and dairy- and beef-type cows harvested because of poor productivity). Feces were collected from two cohorts housed in feedlots (cattle that had achieved desirable harvest characteristics and animals identified for salvage recovery because of poor productivity). Facilities were visited on four occasions over a 12-month period. Salmonella enterica isolates were recovered, and organisms were quantified using standard microbiological methodologies. Susceptibility to antimicrobial drugs and serotype were determined for one S. enterica isolate per sample. Salmonella enterica was recovered from 55.6% of 1,681 samples. The prevalences on hides and in feces were 69.6% and 30.3%, respectively. The concentrations of S. enterica organisms averaged (as determined by the most probable number technique) 1.82 log10/100 cm2 of hides and 0.75 log10/g of feces. None of the isolates recovered from cattle that had achieved desirable harvest characteristics were resistant to four or more drugs. For isolates recovered from animals with poor productivity characteristics, 6.5% were resistant to four or more drugs. Twenty-two serovars were identified, with the most common being Salmonella enterica serovar Anatum (25.5%), Salmonella enterica serovar Montevideo (22.2%), and Salmonella enterica serovar Cerro (12.5%). High-level resistance, i.e., resistance to four or more drugs, was clustered within a few relatively uncommon serovars. These results demonstrate that even though S. enterica isolates are readily recoverable from harvest-ready cattle, multiply resistant variants are rare and are associated with specific serovars in cattle harvested because of poor productivity characteristics.

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High diversity of vancomycin-resistant Enterococcus faecium isolated in Southern Brazil

10.7287/peerj.preprints.27817 ◽

2019 ◽

Author(s):

Renata O Soares ◽

Gabriela R Cunha ◽

Vinicius P Perez ◽

Jussara L Siqueira ◽

Gustavo E Sambrano ◽

...

Keyword(s):

Profile Analysis ◽

Southern Brazil ◽

Porto Alegre ◽

Vancomycin Resistant Enterococci ◽

Antimicrobial Susceptibility Profile ◽

Vancomycin Resistant ◽

Clonal Spread ◽

High Level ◽

Relationship Of ◽

Level Resistance

Background. Vancomycin-resistant enterococci (VRE) are common in some hospital settings and their clonal spread has been described in different regions of the world. We determined the antimicrobial susceptibility profile and the clonal relationship of VRE isolates recovered from inpatients at three general hospitals of Porto Alegre, Brazil. Results. Ninety-four VRE were characterized as Enterococcus faecium and exhibited resistance to teicoplanin, ampicillin, ciprofloxacin, and susceptibility to linezolid, quinupristin-dalfopristin and daptomycin. High level resistance to gentamicin was detected in 13.8% of them. All VREfm harbored vanA gene, while 85.1% and 94.7% harbored respectively esp and acm virulence genes. PFGE profile analysis revealed 23 clonal types including 79 isolates, while 15 isolates exhibited unique pattern type, showing a polyclonal distribution of VREfm in Southern Brazil. Conclusion. These findings contribute to the local understanding regarding the characteristics of the circulating VREs in the region.

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