Nicholas D. Beyda

FKS Mutant Candida glabrata: Risk Factors and Outcomes in Patients With Candidemia

BACKGROUND Echinocandins are recommended for Candia glabrata candidemia. Mutations in the FKS1 and FKS2 genes are associated with echinocandin resistance. Few studies have assessed risk factors for FKS mutant isolates and outcomes in patients receiving micafungin treatment. METHODS Patients with C. glabrata bloodstream infection admitted to a large, tertiary care hospital between 2009 and 2012 were included in this study. For each isolate, FKS1 and FKS2 genes were sequenced to identify mutations. Risk factors for FKS mutations and treatment outcomes in patients receiving an echinocandin were assessed using multivariate logistic regression. RESULTS Seventy-two patients were included in the study of which 13 (18%) had an FKS mutant isolate. The only significant predictor for FKS mutations was prior echinocandin exposure (odds ratio [OR], 19.9; 95% confidence interval [CI], 4.7-84.7; P ≤ .01). Treatment failure occurred in 17 (30%) of 57 patients who received an echinocandin and was more common in patients with FKS mutants (6 of 10; 60%) compared with non-FKS mutants (11 of 47; 23%). Underlying gastrointestinal disorder (OR, 4.7; 95% CI, 1.1-20.9; P = .04) and prior echinocandin exposure (OR, 8.3; 95% CI, 1.7-40.4; P ≤ .01) were independent predictors of echinocandin treatment failure. Treatment response and echinocandin minimum inhibitory concentrations varied among specific FKS mutations. CONCLUSIONS FKS mutations were identified in 18% of 72 patients with C. glabrata candidemia. Common risk factors for FKS mutant isolates included previous echinocandin exposure, which also influenced response rates.

Echinocandin Resistance in Candida Species: Mechanisms of Reduced Susceptibility and Therapeutic Approaches:

OBJECTIVE: To summarize published data regarding mechanisms of reduced echinocandin susceptibility in Candida spp., the impact of echinocandin resistance on the fitness and virulence of Candida isolates, and current and future treatment approaches. DATA SOURCES: A search of MEDLINE databases (1966-September 2011) was conducted. STUDY SELECTION AND DATA EXTRACTION: Databases were searched using the terms echinocandin, resistance, and Candida. Citations from publications were reviewed for additional references. DATA SYNTHESIS: Echinocandins have in vitro activity against most Candida spp. and are first-line agents in the treatment of candidemia. However, case reports describing echinocandin treatment failure due to resistant isolates have been published. Reduced echinocandin susceptibility has been shown to occur via 3 main mechanisms: (1) adaptive stress responses, which result in elevated cell wall chitin content and paradoxical growth in vitro at supra minimum inhibitory concentrations (MICs); (2) acquired FKS mutations, which confer reduced glucan synthase sensitivity, elevated MICs, and are associated with clinical failure; and (3) intrinsic FKS mutations, which are naturally occurring mutations in C. parapsilosis and C. guilliermondii, which confer elevated MIC levels but a lower level of reduced glucan synthase sensitivity compared with acquired FKS mutations. Some FKS mutants have been shown to have significantly reduced fitness and virulence versus wild type isolates and may contribute to the low incidence of echinocandin resistance reported in large surveillance studies. Treatment strategies evaluated for FKS mutants include echinocandin dose escalation and combination with agents such as calcineurin inhibitors, HSP90 inhibitors, and chitin synthase inhibitors. CONCLUSIONS: While the incidence of echinocandin resistance in Candida spp. is low, it can present a significant therapeutic challenge, especially in multidrug-resistant Candida isolates. Dose escalation is unlikely to be effective in treating FKS mutant isolates, and significant adverse effects limit the clinical use of agents evaluated as combination therapy. Patients with infections failing to respond to echinocandin therapy should undergo susceptibility testing and be treated with an alternative antifungal agent if possible.

Comparison of the T2Dx instrument with T2Candida assay and automated blood culture in the detection of Candida species using seeded blood samples.

As a delay in the diagnosis and treatment of candidemia is associated with increased mortality and healthcare costs, a more rapid method of detection is urgently needed. The T2Candida assay is a new rapid diagnostic test, which uses T2 magnetic resonance technology to identify Candida spp. directly from whole blood in approximately 3 hours. In this study, the performance of the BACTEC 9050 using Aerobic Plus/F blood culture bottles was compared to that of the T2Candida assay run on the T2Dx Instrument for detection of Candida albicans, Candida tropicalis, Candida parapsilosis, Candida glabrata, and Candida krusei, in seeded blood samples at concentrations between 3.1 and 11 CFU/mL. The BACTEC 9050 detected Candida growth in 100% of bottles (n = 20 replicates) within 5 days for all species (63.23 ± 30.27 hours), with the exception of Candida glabrata (0%). The T2Candida assay had a 100% detection rate for each species (n = 13-20 replicates) within 3 hours including C. glabrata. The sensitivity and specificity of the T2Candida assay were 1 and 0.978, respectively.

Clinical Practice Patterns in Hospitalized Patients at Risk for Invasive Candidiasis Role of Antifungal Stewardship Programs in an Era of Rapid Diagnostics

Background: Rapid diagnostic tests for Candida are becoming available that may supplement traditional microbiological identification. Objective: Assess clinical practice patterns in patients with or at risk of candidiasis who may benefit from the use of rapid diagnostic tests. Methods: This was a prospective cohort study of patients with candidemia or receiving systemic antifungals conducted at a university-affiliated tertiary care hospital. Time to initiation of therapy, Candida species, time to identification, and indications for antifungal use were assessed. Results: A total of 162 patients with candidemia aged 58 ± 17 years were identified. Average time to yeast identification yeast was 2.2 ± 1.3 days and varied by Candida species (range = 0.6-7.9 days). Average time for patient to start antifungal therapy was 3.5 ± 2.1 days. In Monte Carlo simulations, average time to initiation of antifungal therapy was 0.6 ± 0.2 days for T2Candida, 2.6 ± 1.3 days for PNA-FISH (fluorescence in situ hybridization using peptide nucleic acid probes), and 2.5 ± 1.4 days for MALDI-TOF (matrix-assisted laser desorption/ionization time of flight). Use of T2Candida on the day of the blood culture collection resulted in 3136 to 6078 fewer doses of echinocandins annually per 5000 patients. Conclusion: Many interventions are possible for antifungal stewardship programs to improve care of patients at risk for systemic candidiasis, including rapid identification of yeast species and limiting unnecessary antifungal agents. Technology enabling rapid diagnosis of Candida will be paramount to appropriate, cost-effective treatment of patients with or at risk for candidiasis.

Treatment of Candida famata bloodstream infections: case series and review of the literature

OBJECTIVES Candida famata (also known as Debaryomyces hansenii and Torulopsis candida) is a commensal yeast found in cheese, dairy products and the environment. C. famata accounts for 0.2%-2% of invasive candidiasis. The purpose of this study was to provide an overview of the treatment of C. famata bloodstream infections. METHODS The clinical course of two hospitalized patients who developed C. famata fungaemia within 2 weeks of each other was summarized along with available data regarding in vitro susceptibility patterns, genotyping and clinical outcomes of these cases compared with the published literature. RESULTS AND CONCLUSIONS C. famata appears to exhibit reduced susceptibility to echinocandins and azoles, particularly in the setting of prior antifungal exposure. The removal of indwelling central venous catheters and prompt initiation of therapy with liposomal amphotericin B is recommended for successful treatment of C. famata fungaemia, particularly in immunocompromised patients. These cases also help provide justification for routine antifungal susceptibility testing in patients with candidaemia to guide optimal antifungal therapy.

Assessment of treatment patterns and patient outcomes before vs after implementation of a severity-based Clostridium difficile infection treatment policy

BACKGROUND National guidelines recommend oral vancomycin for severe Clostridium difficile infection (CDI) based on results from recent clinical trials demonstrating improved clinical outcomes. However, real-world data to support these clinical trials are scant. AIM To compare treatment patterns and patient outcomes of those treated for CDI before and after implementation of a severity-based CDI treatment policy at a tertiary teaching hospital. METHODS This study evaluated adult patients with a positive C. difficile toxin before and after implementation of a policy where patients with severe CDI given metronidazole were switched to oral vancomycin unless contra-indicated. Patients were stratified according to disease severity using a modified published severity score. Treatment patterns based on CDI severity and rates of refractory CDI were assessed. FINDINGS In total, 256 patients with CDI (mean age 66 years, standard deviation 17, 52% female) were evaluated (before implementation: N = 144; after implementation: N = 112). Use of oral vancomycin for severe CDI increased significantly from 14% (N = 8) to 91% (N = 48) following implementation of the policy (P < 0.0001). Refractory disease in patients with severe CDI decreased significantly from 37% to 15% following implementation of the policy (P = 0.035). No significant differences were noted among patients with mild to moderate CDI. CONCLUSION A severity-based CDI treatment policy at a tertiary teaching hospital increased the use of oral vancomycin and was associated with decreased rates of refractory CDI.

Echinocandin Use in Hospitalized Patients: A Multi-institutional Study

Background:The echinocandin antifungals are recommended as initial therapy in hospitalized patients with candidemia. Contemporary usage rates and indication for use of echinocandins have not been studied in the United States. The purpose of this study was to evaluate echinocandin usage patterns in community and academic teaching hospitals over time and to evaluate dose, duration of therapy and indications for use. Methods:This study used hospital pharmacy databases from academic and community hospitals to collect information on adult inpatients given systemic antifungal agents from 2008 to 2012. Patient medical information was also obtained from randomly selected patients given an echinocandin over the same time period. Results:Echinocandin use was determined for 4 academic and 34 community hospitals. A significant increase in echinocandin use was observed in academic and community hospitals during the time period (P < 0.001). Two hundred forty-two randomly selected patients receiving an echinocandin were retrospectively reviewed. Indications for echinocandin use did not change during the time period and included empiric therapy in a high-risk patient without subsequent mycologic confirmation from a normally sterile site (55%), systemic candidiasis (43%) and prophylactic (2%). Fifty-six percent of patients had at least 1 anatomic site of mycologic growth; most commonly urine only (14%), respiratory only (12%) or blood only (7%). In patients with candidemia, the hospital treatment course with an echinocandin averaged 8.4 ± 7.9 days (range, 1–35 days). Conclusions:This study provides useful benchmark data on antifungal use and indications for use that could be used for antifungal stewardship program comparisons.

Early Administration of Adjuvant β-Lactam Therapy in Combination with Vancomycin among Patients with Methicillin-Resistant Staphylococcus aureus Bloodstream Infection: A Retrospective, Multicenter Analysis

To determine whether early administration of adjuvant β‐lactam in combination with vancomycin (COMBO) affects clinical outcomes compared to standard vancomycin therapy alone (STAN) among patients with methicillin‐resistant Staphylococcus aureus (MRSA) bloodstream infection.

Innate Inflammatory Response and Immunopharmacologic Activity of Micafungin, Caspofungin, and Voriconazole against Wild-Type and FKS Mutant Candida glabrata Isolates

ABSTRACT The direct or indirect interactions that antifungals have with the host immune response may play a significant role in defining their activity in vivo. However, the impact that acquired antifungal resistance has on the immunopharmacologic activity of antifungals is not well described. We assessed the immunopharmacologic activity of caspofungin, micafungin, and voriconazole among isolates of Candida glabrata with or without FKS-mediated echinocandin resistance. Clinical bloodstream isolates of C. glabrata from patients who did (n = 5) or did not (n = 3) develop persistent candidemia and who did (n = 2) or did not (n = 11) harbor FKS gene mutations were included. A cell-based assay was used to compare differences in macrophage activation among isolates when grown in the presence or absence of subinhibitory concentrations of caspofungin, micafungin, or voriconazole. In the absence of antifungals, macrophage activation was significantly lower for index C. glabrata isolates obtained from persistent candidemia patients than for those from nonpersistent patients (33% versus 79% increase over negative controls, respectively; P < 0.01). Growth of isolates possessing wild-type FKS genes in subinhibitory concentrations of micafungin or caspofungin, but not voriconazole, significantly increased macrophage inflammatory responses compared to untreated controls (1.25- to 2.75-fold increase, P < 0.01). For isolates harboring the FKS2 hot spot 1 (HS1) S663P mutation, however, a significant increase was observed only with micafungin treatment (1.75-fold increase versus negative control, P < 0.01). Macrophage activation correlated with the level of unmasking of β-glucan in the cell wall. The diminished macrophage inflammatory response to isolates that caused persistent candidemia and differential immunopharmacologic activity of echinocandins among FKS mutants suggest that certain strains of C. glabrata may have a higher propensity for immunoevasion and development of antifungal resistance during treatment.

The Utility of Rapid Microbiological and Molecular Techniques in Optimizing Antimicrobial Therapy

Early treatment of bloodstream infections with appropriate, definitive antimicrobial therapy has proven to reduce mortality, length of hospital stay, and healthcare costs. Culture-based testing methods require up to five days for final pathogen identification and susceptibility reporting, forcing use of broad spectrum empiric therapy. Recently, multiple rapid microbiological and molecular testing methods have been developed that reduce the time to identify the pathogen and susceptibility, allowing optimal antimicrobial therapy to be prescribed earlier. Real-time polymerase chain reaction and gene microarray have been described in literature, yet only peptide nucleic acid fluorescent in-situ hybridization has published data justifying its use based on clinical outcomes and cost savings. Target enriched multiplex polymerase chain reaction was developed to identify both the pathogen and multiple genes associated with resistance from blood within 6 hours and this methodology was studied in our hospital to assess effectiveness at optimizing antimicrobials in staphylococcal bloodstream infections.