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Robust pharmacodynamic indices that align fluconazole dose or exposure with outcomes in invasive candidiasis due to Candida glabrata remain elusive. The purpose of this retrospective multicenter study was to evaluate a cohort of 127 patients with C. glabrata fungemia treated with fluconazole, using adjusted analyses to identify risk factors for 28-day death. No significant correlations were found between fluconazole area under the curve (AUC), AUC/MIC ratio, or MIC and survival. In multivariate logistic regression analyses, however, higher average fluconazole dose (odds ratio [OR], 1.006 [95% confidence interval [CI], 1.001 to 1.010]; P = 0.008), average fluconazole dose of ≥400 mg (OR, 3.965 [95% CI, 1.509 to 10.418]; P = 0.005), and higher fluconazole dose on day 1 of therapy (OR, 1.007 [95% CI, 1.002 to 1.011]; P = 0.002) were found to be independent predictors of 28-day survival. Additionally, the presence of a central venous catheter at the time of infection was found to be a significant risk factor for death. In conclusion, we found fluconazole dose to be an independent predictor of 28-day survival for patients with C. glabrata fungemia, with doses of ≥400 mg/day being associated with 28-day survival rates approaching 90%. These data indicate the use and efficacy of fluconazole in the treatment of this serious infection. Aggressive dosing appears to be necessary when fluconazole is used for the treatment of C. glabrata fungemia, irrespective of MIC., (Copyright © 2018 American Society for Microbiology.)

Objectives: We studied whether fluconazole or echinocandin treatment of Candida glabrata fungaemia results in superior outcomes., Methods: A multicentre, retrospective study was performed with 224 adult patients who received ≥ 5 days of therapy with either fluconazole or an echinocandin as their first antifungal treatment after collection of a blood culture that grew C. glabrata. The primary outcome was day 14 complete response., Results: Patients in the echinocandin group were generally more ill, both at baseline and at the time of the index culture. Day 14 complete response was obtained in 58/127 (46%) and 50/97 (52%) of the fluconazole and echinocandin patients, respectively (P=0.383). Logistic regression found intensive care unit admission to be associated with failure [OR 0.456 (0.217-0.957), P=0.038] and echinocandin therapy to be associated with day 14 complete response [OR 2.305 (1.124-4.727), P=0.023]. Twenty-eight day survival was similar between the fluconazole and echinocandin groups and logistic regression did not reveal antifungal therapy choice to be independently predictive of mortality. For patients treated with fluconazole, a dose:MIC ratio >12.5 (when compared with a ratio ≤ 12.5) was associated with a significantly higher day 14 complete response [4/20 (20%) ≤ 12.5 versus 50/102 (49%) >12.5, P=0.025]., Conclusions: Severity of illness and choice of antifungal predict response in patients with C. glabrata fungaemia. Antifungal choice, however, does not influence mortality. In addition, new CLSI C. glabrata fluconazole susceptibility breakpoints are predictive of response when fluconazole is dosed appropriately.

In recipients of hematopoietic stem cell transplants (HSCTs), the mortality associated with invasive fungal infections (IFIs) remains high, despite the introduction of broad-spectrum antifungal agents over the past 2 decades. Preventing exposure to fungal pathogens in this population is impossible; therefore, clinicians have focused on prophylactic use of antifungal agents to prevent IFIs in high-risk HSCT recipients. It is important to target antifungal prophylaxis by type of HSCT (autologous or allogeneic), local epidemiology, and risk factors for IFIs so that patients can receive the most appropriate agent while balancing costs and the risks of toxicity, and minimizing the development of resistance. To assist clinicians in weighing the pros and cons of currently available antifungal agents when choosing a suitable prophylactic regimen, we provide a review of several key prospective randomized trials that evaluated various antifungal agents for primary prophylaxis in adult HSCT recipients. In addition, we describe the epidemiology of and risk factors for IFIs in HSCT recipients, the difficulties in diagnosing IFIs, antifungal agents used for prophylaxis, and the goals of primary prophylaxis. Fluconazole remains the gold standard for primary prophylaxis in autologous HSCT recipients. For allogeneic HSCT recipients, the agent chosen for prophylaxis must be based on the patient's risk factors for IFIs. In low-risk patients, fluconazole is an appropriate agent to use for primary prophylaxis immediately after transplantation. However, in allogeneic HSCT recipients who develop complications, such as graft failure, graft-versus-host disease, or cytomegalovirus infection, prophylaxis with a mould-active agent should be used.

Background: Invasive candidiasis (IC) is associated with significant morbidity and mortality in critically ill patients. This, in conjunction with difficulties in diagnosis, underscores the need for novel treatment strategies based on the identification of significant risk factors for IC., Objective: To review the evidence surrounding the use of early antifungals in critically ill adult patients and to present concise and specific recommendations for different early treatment strategies for IC., Data Sources and Data Extraction: Pubmed search from 1966 to July 2008 using the search terms "antifungals, critical care, prophylaxis, preemptive therapy, and empiric therapy." Examined all relevant peer-reviewed original articles, meta-analyses, guidelines, consensus statements, and review articles., Conclusion: The use of early antifungal therapy should be reserved for patients with a high risk (10% to 15%) of developing IC. Despite a large number of articles published on this topic, there is no single predictive rule that can adequately forecast IC in critically ill patients. Until further prospective validation of existing data is completed, clinicians should assess patients on a case-by-case basis and determine the need for early antifungal treatment strategies based on frequent evaluations of risk factors and clinical status.

Although increasing numbers of hospital microbiology laboratories are performing antifungal susceptibility testing ( AST), its routine use is uncommon. The utility of AST is founded on the belief that susceptibility (or resistance) of an agent allows some prediction of clinical outcome. This review provides an overview of the development of antifungal susceptibility testing methodology, including wild-type minimum inhibitory concentration ( MIC) distributions, epidemiologic breakpoints, and Interpretive Clinical Breakpoints for antifungal agents. In addition, we examine the current clinical utility of AST and the clinical data support utilized in the development of clinical breakpoints ( CBP) for common pathogens causing invasive fungal infections. In the treatment of fungal infections, identifying consistent correlations between MICs - or susceptibility category - and clinical outcomes is an ongoing challenge, and current data sets are insufficient for many drugs and pathogens to enable the development, revision, or confirmation of CBPs. Antifungal susceptibility testing is of current value, but further research in many areas is needed before MICs are independently used to guide treatment decisions. [ABSTRACT FROM AUTHOR]

The magnitude of drug interactions between azole antifungals and immunosuppressants is drug and patient specific and depends on the potency of the azole inhibitor involved, the resulting plasma concentrations of each drug, the drug formulation, and interpatient variability. Many factors contribute to variability in the magnitude and clinical significance of drug interactions between an immunosuppressant such as cyclosporine, tacrolimus, or sirolimus and an antifungal agent such as ketoconazole, fluconazole, itraconazole, voriconazole, or posaconazole. By bringing similarities and differences among these agents and their potential interactions to clinicians' attention, they can appreciate and apply these findings in a individualized patient approach rather than follow only the one-size-fits-all dosing recommendations suggested in many tertiary references. Differences in metabolism and in the inhibitory potency of cytochrome P450 3A4 and P-glycoprotein influence the onset, magnitude, and resolution of drug interactions and their potential effect on clinical outcomes. Important issues are the route of administration and the decision to preemptively adjust dosages versus intensive monitoring with subsequent dosage adjustments. We provide recommendations for the concomitant use of these agents, including suggestions regarding contraindicated combinations, those best avoided, and those requiring close monitoring of drug dosages and plasma concentrations. [ABSTRACT FROM AUTHOR]

We have previously developed and published methods for conducting antifungal time-kill series. The purpose of this study was to evaluate the inter- and intra-laboratory reproducibility of results obtained using these methods. Seven sites were recruited for participation in this study. Each site conducted a series of time-kill experiments with fluconazole and amphotericin B against two isolates of Candida albicans and one isolate each of Candida glabrata and Candida tropicalis. Time-kill studies were conducted under the following conditions: RPMI 1640 served as a growth medium; cultures were incubated at 35 degrees Celsius with agitation; sampling volume was 30 microliters; and potato dextrose agar was used for solid media. A control, fluconazole at concentrations of 1, 10, and 20 micrograms/ml and amphotericin B at concentrations of 0.25, 1, and 2.5 micrograms/ml were run for each isolate. Experiments were conducted over 24 hours, with samples removed for colony determination at pre-determined time points. All experiments were performed in triplicate. Examination of intra- and inter-laboratory data suggest good reproducibility with respect to sampling methods and time-kill data for all four isolates. The percent agreement among centers with respect to classification of regimens as either fungitatic, fungicidal, or no effect at the various test concentrations was 90% for fluconazole and 93% for amphotericin B. Methods for conducting antifungal time-kill studies are reproducible among different laboratories when examined using fluconazole and amphotericin B against Candida species. [ABSTRACT FROM PUBLISHER]