Development of the invasive candidiasis discharge [I Can discharge] model: a mixed methods analysis.

Patients with invasive candidiasis (IC) have complex medical and infectious disease problems that often require continued care after discharge. This study aimed to assess echinocandin use at hospital discharge and develop a transition of care (TOC) model to facilitate discharge for patients with IC. This was a mixed method study design that used epidemiologic assessment to better understand echinocandin use at hospital discharge TOC. Using grounded theory methodology focused on patients given echinocandins during their last day of hospitalization, a TOC model for patients with IC, the invasive candidiasis [I Can] discharge model was developed to better understand discharge barriers. A total of 33% (1405/4211) echinocandin courses were continued until the last day of hospitalization. Of 536 patients chosen for in-depth review, 220 (41%) were discharged home, 109 (20%) were transferred, and 207 (39%) died prior to discharge. Almost half (46%, 151/329) of patients discharged alive received outpatient echinocandin therapy. Independent predictors for outpatient echinocandin use were osteomyelitis (OR, 4.1; 95% CI, 1.1-15.7; p = 0.04), other deep-seated infection (OR, 4.4; 95% CI, 1.7-12.0; p = 0.003), and non-home discharge location (OR, 3.9, 95% CI, 2.0-7.7; p < 0.001). The I Can discharge model was developed encompassing four distinct themes which was used to identify potential barriers to discharge. Significant echinocadin use occurs at hospital discharge TOC. The I Can discharge model may help clinical, policy, and research decision-making processes to facilitate smoother and earlier hospital discharges.

Adjuvant ß-Lactam Therapy Combined with Vancomycin for Methicillin-Resistant Staphylococcus aureus Bacteremia: Does ß-Lactam Class Matter?

We analyzed the impact of vancomycin (VAN) combined with adjuvant ß-lactam therapy (Combo) on persistent (≥5 days) methicillin-resistant Staphylococcus aureus bacteremia versus VAN alone by using pooled data from two previously published observational studies (n = 156). Combo was inversely associated with persistent bacteremia (adjusted odds ratio, 0.460; 95% confidence interval, 0.229 to 0.923). Acute kidney injury was more common with Combo than with VAN (18.9% and 7.6%, respectively; P = 0.062).

Drosophila melanogaster as a model to study virulence and azole treatment of the emerging pathogen Candida auris.

OBJECTIVES: Candida auris is an emerging, often MDR, yeast pathogen. Efficient animal models are needed to study its pathogenicity and treatment. Therefore, we developed a C. auris fruit fly infection model. METHODS: TollI-RXA/Tollr632 female flies were infected with 10 different C. auris strains from the CDC Antimicrobial Resistance bank panel. We used three clinical Candida albicans strains as controls. For drug protection assays, fly survival was assessed along with measurement of fungal burden (cfu/g tissue) and histopathology in C. auris-infected flies fed with fluconazole- or posaconazole-containing food. RESULTS: Despite slower in vitro growth, all 10 C. auris isolates caused significantly greater mortality than C. albicans in infected flies, with >80% of C. auris-infected flies dying by day 7 post-infection (versus 67% with C. albicans, P < 0.001-0.005). Comparison of C. auris isolates from different geographical clades revealed more rapid in vitro growth of South American isolates and greater virulence in infected flies, whereas the aggregative capacity of C. auris strains had minimal impact on their growth and pathogenicity. Survival protection and decreased fungal burden of fluconazole- or posaconazole-fed flies infected with two C. auris strains were in line with the isolates' disparate in vitro azole susceptibility. High reproducibility of survival curves for both non-treated and antifungal-treated infected flies was seen, with coefficients of variation of 0.00-0.31 for 7 day mortality. CONCLUSIONS: Toll-deficient flies could provide a fast, reliable and inexpensive model to study pathogenesis and drug activity in C. auris candidiasis.

Overtreatment of Asymptomatic Candiduria among Hospitalized Patients: a Multi-institutional Study.

Candiduria is common in hospitalized patients, and asymptomatic candiduria contributes to antifungal overuse. The guidelines for management of asymptomatic candiduria do not recommend antifungal use, but rather the elimination of predisposing factors. It is unknown whether these recommendations are being followed. The primary objective of this study was to characterize candiduria management among hospitalized patients. This was a retrospective cohort study of a random sample of 305 hospitalized patients with candiduria at four U.S. medical centers from January 2010 to December 2013. Patients were classified as asymptomatic or symptomatic based on established criteria, and data were collected by chart review. Infectious Diseases Society of America (IDSA) treatment guideline adherence and its association with clinical outcomes, including candiduria recurrence (short- and long-term) and 30-day readmission, were assessed. Eighty percent of patients were classified as having asymptomatic candiduria. Overall, 143 (47%) patients were not managed according to recommended guidelines, including 105/243 (43%) in the asymptomatic candiduria group and 38/62 (61%) in the symptomatic group (P = 0.01). Discordance among asymptomatic patients was driven by overtreatment with an antifungal (98/105 [93%]). Thirty-three percent of patients with asymptomatic candiduria not managed according to the guidelines were treated for over 7 days, and 5% received over 14 days of therapy. Fluconazole was the most commonly used empirical antifungal among asymptomatic candiduria patients (96%), followed by micafungin (4%). Asymptomatic candiduria patients not managed according to the guidelines had a trend toward higher 30-day readmission (35% versus 26%, P = 0.27). Inappropriate management of candiduria among hospitalized patients was high, leading to overtreatment with antifungal therapy.

In Vitro Evaluation of BacT/Alert FA Blood Culture Bottles and T2Candida Assay for Detection of Candida in the Presence of Antifungals.

The T2Candida assay is a novel, non-culture-based assay for the diagnosis of candidemia directly from whole blood. The impact of antifungals on the performance of the T2Candida assay and blood culture bottles has not been well described. In this study, the performance of the T2Candida assay was compared to that of blood culture in detecting Candida spp. in spiked blood cultures with or without the presence of antifungals. Clinical bloodstream isolates of Candida spp. were inoculated into human whole blood at low (1 to 5 cells/ml) and high (10 to 50 cells/ml) concentrations with or without the presence of caspofungin and fluconazole. Time to detection (TTD) was assessed for prepared samples using BacT/Alert FA aerobic blood culture bottles or the T2Candida assay. In the absence of antifungals, T2Candida assay sensitivity was comparable to that of blood culture at both the low inoculum and the high inoculum (95% versus 97.5% and 100% versus 100%, respectively) and the assay had an average TTD that was significantly shorter (5.1 h versus 27.2 to 30 h, respectively). Neither caspofungin nor fluconazole was observed to impact the sensitivity or TTD of the T2Candida assay, while fluconazole reduced the overall blood culture sensitivity by 7.5% to 12.5% (at the low inoculum and high inoculum, respectively) and significantly increased the TTD of Candida albicans, C. tropicalis, and C. parapsilosis by 14.8 to 67 h. Neither caspofungin nor fluconazole impacted the performance of the T2Candida assay in vitro, and the assay may be useful for the diagnosis of candidemia in patients receiving antifungal therapy.

Innate inflammatory response and immunopharmacologic activity of micafungin, caspofungin, and voriconazole against wild-type and FKS mutant Candida glabrata isolates.

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 ß-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.

Host factors and clinical outcomes of Candida colonization in critically ill patients.

This study aimed to describe factors and outcomes associated with Candida colonization of critically ill patients. This was a cross-sectional study conducted over 2 weeks in the intensive care unit (ICU) of a tertiary care hospital at the Texas Medical Center, Houston, TX. All Candida samples were prospectively collected with demographic and clinical data collected retrospectively. We examined 48 patients, 32 (67%) were colonized with Candida spp; 25 (52.1%) patients were isolated with Candida albicans and 18 (37.5%) were isolated with a non-albicans species, mostly commonly Candida glabrata. A multivariate analysis identified proton pump inhibitor administration at admission to ICU [odds ratio 5.66; 95% confidence interval 1.12-28.5] as associated with colonization. Patients colonized with Candida had a significantly longer length of ICU and hospital stays (7.6 ± 6.6 vs. 4.2 ± 2.6 days, P = 0.01 and 14.9 ± 12.9 vs. 7.5 ± 6.7 days, P = 0.02, respectively). Clonality testing between C. albicans and C. glabrata strains identified indistinguishable strains among the patient cohort. These data provide additional information on Candida colonization in critically ill patients.

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.

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.

Micafungin pharmacodynamics predict clinical outcomes in hospitalized patients with candidemia caused by certain Candida species.

STUDY OBJECTIVE: Echinocandins are guideline-preferred therapies for invasive candidiasis (IC). Fixed dosing of echinocandins is commonly used despite variations in body mass index and echinocandin susceptibility. The purpose of this study was to evaluate clinical outcomes of micafungin based on population-predicted pharmacokinetic/pharmacodynamic (PK/PD) factors and susceptibility. DESIGN AND SETTING: Candida isolate results were screened from bloodstream or intraabdominal cultures of hospitalized patients admitted to a quaternary-care teaching hospital. Patients with a first episode of IC who received micafungin for at least 48 h were included. Patients with mixed cultures or Candida species with no minimum inhibitory concentration (MIC) differences were excluded. Breakpoints for micafungin MIC and area under the curve (AUC)/MIC ratio were calculated using classification and regression tree (CART) analysis and related to clinical outcomes. Primary efficacy outcome was candida-contributable mortality, defined as mortality within 28 days of positive culture with concomitant micafungin treatment failure; secondary outcome was micafungin treatment failure within 28 days, MAIN RESULTS: Seventy-two patients were included of whom 15 (21%) had Candida-contributable mortality and 34 (47%) experienced micafungin treatment failure. C. albicans and C. tropicalis did not have differing MICs and these patients were excluded from the study. Mortality using a CART-derived MIC breakpoint of ≥1.0 mg/L was 38% compared to 9% in patients infected with lower MIC strains (p = 0.003). Patients with a CART-derived AUC/MIC value >138.5 had a mortality rate of 9% compared to 41% for patients with AUC/MIC values below the breakpoint (p = 0.0013). Results were similar for treatment failure rates, and both were confirmed using multivariable models. CONCLUSIONS: CART-derived micafungin MIC and AUC/MIC breakpoints predicted patient mortality and treatment failure for certain Candida species. These results support the need for further PK/PD studies to optimize echinocandin dosing and improve patient outcomes.

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.

A Vancomycin HPLC Assay for Use in Gut Microbiome Research.

The human microbiome project has revolutionized our understanding of the interaction between commensal microbes and human health. By far, the biggest perturbation of the microbiome involves use of broad-spectrum antibiotics excreted in the gut. Thus, pharmacodynamics of microbiome changes in relation to drug exposure pharmacokinetics is an emerging field. However, reproducibility studies are necessary to develop the field. A simple and fast high-performance liquid chromatography-photodiode array detector (HPLC) method was validated for quantitative fecal vancomycin analysis. Reproducibility of results were tested based on sample storage time, homogeneity of antibiotic within stool, and concentration consistency after lyophilization. The HPLC method enabled the complete elution of vancomycin within ~4.2 min on the reversed-phase C18 column under the isocratic elution mode, with excellent recovery (85% to 110%) over a 4-log, quantitative range (0.4-100 µg/mL). Relative standard derivations (RSD) of intra-day and inter-day results ranged from 0.4% to 5.4%. Using sample stool aliquots of various weights consistently demonstrated similar vancomycin concentrations (mean RSD: 6%; range: 2-16%). After correcting for water concentrations, vancomycin concentrations obtained after lyophilization were similar to the concentrations obtained from the original samples (RSD less than 10%). These methodologies establish sample condition standards for a quantitative HPLC to enable vancomycin pharmacokinetic studies with the human microbiome. IMPORTANCE Research on antibiotic effect on the gut microbiome is an emerging field with standardization of research methods needed. In this study, a simple and fast high-performance liquid chromatography method was validated for quantitative fecal vancomycin analysis. Reproducibility of results were tested to standardize storage time, homogeneity of antibiotic within stool, and concentration consistency after lyophilization. These methodologies establish sample condition standards for a quantitative HPLC to enable vancomycin pharmacokinetic studies with the human microbiome.

Clumping Morphology Influences Virulence Uncoupled from Echinocandin Resistance in Candida glabrata.

Here, we report two paired sets of an index wild-type Candida glabrata bloodstream isolate and subsequent echinocandin-resistant FKS mutant. One paired set exhibited a higher proportion of clumping cells and was more virulent in the invertebrate host Galleria mellonella than the other paired set. No virulence difference between the paired index and FKS strains was observed. These findings imply a potential link of clumping morphology with virulence in C. glabrata that is uncoupled from FKS-mediated echinocandin resistance. IMPORTANCE Candida glabrata is a leading cause of invasive candidiasis. In contrast to other species, it has a high propensity for developing resistance to echinocandins, which are the first-line treatment. Unlike the dimorphic Candida albicans which can grow invasive filamentous hyphae, C. glabrata lacks this ability. Here, we report a link between virulence and clumping cell morphology in two different sets of clinical C. glabrata strains obtained from patients failing echinocandin therapy. One set of paired strains (echinocandin-susceptible and subsequent resistant mutant) had a high proportion of clumping cells in the population and were significantly more virulent than another set which had fewer clumping cells. Additionally, we corroborate that echinocandin resistance does not impart a significant fitness cost. Our findings suggest that clumping morphology may be an important but previously underestimated virulence factor for C. glabrata and also aid our understand for the high prevalence of resistance observed in this species.

Comparative in vitro pharmacodynamic analysis of isavuconazole, voriconazole, and posaconazole against clinical isolates of aspergillosis, mucormycosis, fusariosis, and phaeohyphomycosis.

We compared the in vitro pharmacodynamics of isavuconazole, voriconazole, and posaconazole against 92 clinical isolates from documented cases of invasive aspergillosis, mucormycosis, fusariosis, and phaeohyphomycosis. Whereas inhibitory and fungicidal concentrations of these triazoles were predictably similar with the exception of Mucorales, isavuconazole appeared to have improved pharmacodynamics against Fusarium solani.

Prevalence and predictors of spontaneous bacterial peritonitis due to ceftriaxone-resistant organisms at a large tertiary centre in the USA.

OBJECTIVES: The epidemiology of spontaneous bacterial peritonitis (SBP) due to ceftriaxone-resistant organisms has not been well studied in the USA. The primary objective of this study was to assess the prevalence and predictors of ceftriaxone-resistant SBP at a large US tertiary-care centre. METHODS: This 1:1:4 case-case-control study included 141 adults with liver cirrhosis admitted from November 2011 to March 2016. Case group 1 were patients with SBP with a ceftriaxone-resistant organism (n=21). Case group 2 were patients with SBP with a ceftriaxone-susceptible organism (n=26). The control group were patients without SBP (n=94). Multiple logistic regression analysis was used to identify predictors of ceftriaxone-resistant SBP. RESULTS: Fifty isolates were identified from 47 patients with culture-positive SBP (case groups 1 and 2). Of these 50 isolates, 32 (64%) were Gram-negatives [mostly Enterobacteriaceae (91%)], 15 (30%) were Gram-positives and 3 (6%) were Candida spp. The prevalence of ceftriaxone resistance in patients with culture-positive SBP was 45% (21/47). The most common ceftriaxone-resistant organisms were ESBL-producing Enterobacteriaceae (45%). Independent predictors of ceftriaxone-resistant SBP included duration of ß-lactam therapy in the past 90days (aOR=1.07, 95% CI 1.01-1.13) and recent invasive gastrointestinal procedure (aOR=12.47, 95% CI 2.74-56.67). CONCLUSIONS: The prevalence of ceftriaxone-resistant SBP was significant at a US tertiary centre. Local epidemiological data and identification of risk factors associated with ceftriaxone-resistant SBP, e.g. increased usage of previous ß-lactam therapy and invasive gastrointestinal procedure, may help clinicians identify patients requiring alternative empirical antibiotics.

Rezafungin (CD101), a next-generation echinocandin: A systematic literature review and assessment of possible place in therapy.

OBJECTIVES: Rezafungin (CD101) is a novel echinocandin currently under development. The purpose of this study was to perform a systematic literature review of published evidence on rezafungin and an antimicrobial stewardship audit of real-world use of echinocandins to determine areas of unmet medical needs and potential places in therapy for rezafungin. METHODS: The systematic literature review identified 8 peer-reviewed manuscripts and 19 separate abstracts. A stewardship audit was performed on hospitalised patients receiving echinocandins to better understand potential future areas of use for rezafungin. RESULTS: Rezafungin is a cyclic hexapeptide with a lipophilic tail derived from anidulafungin, with a choline moiety at the C5 ornithine position resulting in increased in vitro and in vivo stability compared with other echinocandins. Microbiological data showed similar susceptibility and resistance development between rezafungin and other echinocandins. Rezafungin has a long half-life (80h) and a favourable safety profile that allows for high doses (up to 400mg) given once weekly. A phase 2 study is ongoing. The antimicrobial stewardship audit of echinocandin identified several areas of possible use for rezafungin, including patients receiving daily echinocandins for >7 days, patients who remained in the hospital to complete a full course of daily echinocandin therapy, and patients who required an echinocandin scheduled via an infusion clinic after discharge. CONCLUSION: Rezafungin is a novel echinocandin currently in phase 2 studies, differentiated by a long half-life that allows once-weekly dosing and a safety profile that allows higher doses. Several potential areas of use for rezafungin were identified.

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

STUDY OBJECTIVE: To determine whether early administration of adjuvant ß-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. DESIGN: Retrospective, multicenter cohort study. SETTING: Five academic or community hospitals throughout the United States. PATIENTS: Adults with MRSA bloodstream infections treated with vancomycin (≥ 72 hrs) with or without an intravenous ß-lactam (≥ 48 hrs) initiated within 24 hours of initiating vancomycin. MEASUREMENTS AND MAIN RESULTS: The primary outcome was clinical failure, a composite endpoint including 30-day mortality, persistent bacteremia (≥ 7 days), bacteremia relapse, or change in antibiotic therapy during treatment due to clinical worsening. A multivariable logistic regression examined the impact of patient-, treatment-, and pathogen-level characteristics on clinical failure. A total of 201 patients were evaluated of whom 97 (48.3%) met the criteria for study inclusion; 40 (41.2%) in STAN and 57 (58.8%) in COMBO groups. Among patients in the STAN and COMBO groups, 30% and 24.6% experienced clinical failure, respectively (p=0.552). The median (interquartile range) duration of bacteremia in the STAN and COMBO groups was 4 days (2.5-6.5) and 3 days (2-5), respectively (p=0.048). In a multivariable analysis, receipt of COMBO therapy was inversely associated with clinical failure (adjusted odds ratio [aOR] 0.237, 95% confidence interval [CI] [0.057-0.982]; p=0.047). Other independent predictors of clinical failure included complicated bacteremia (aOR 6.856, 95% CI [1.641-28.649]; p=0.008) and antibiotic therapy not continued at discharge (aOR 45.404, 95% CI [9.383-219.714]; p<0.001). CONCLUSIONS: Receipt of COMBO therapy did not decrease the rate of clinical failure but was associated with expedited bacteremia clearance. Early adjuvant ß-lactam therapy deserves continued evaluation and clinical consideration.

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.

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.