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Therapeutic Drug Monitoring and Other Contemporary Issues in Antifungal Therapy

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 49th Annual Meeting of the Infectious Diseases Society of America

Boston, Massachusetts / October 20-23, 2011

Boston - Fungal infections have become more frequent and now represent the fourth most common source of bloodstream infection, causing substantial morbidity and mortality and driving up health resources and costs. In an effort to maximize the benefits of currently available antifungal therapies, therapeutic drug monitoring (TDM) has emerged as a key issue in management of invasive fungal infections. TDM can provide valuable information for clinical decision-making, particularly in the use of prophylactic and empiric therapy and in the management of rapidly progressing, life-threatening infections. Presentations here at IDSA provided clinically relevant information about the potential value of TDM in minimizing variation in serum drug concentrations and preventing treatment-related adverse events. Data also revealed shortcomings of current approaches to treating fungal infections, including frequent switching with conventional first-line agents and a substantial proportion of patients who receive no antifungal therapy.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

Recognition of the value of therapeutic drug monitoring (TDM) goes back a decade or more, when a pivotal clinical trial showed that monitoring and appropriate adjustment of voriconazole serum levels was associated with significant improvement in survival in patients with invasive aspergillosis, as compared with amphotericin B (Herbrecht et al. N Engl J Med 2002;347:408-15). Since then, studies have shown that voriconazole serum levels can vary, even with recommended dosing. Moreover, low serum levels of the antifungal agent have been associated with lack of treatment response and elevated levels with an increased incidence of adverse events, reported Dr. Rachel Rivera, University of Texas, San Antonio, here at IDSA.

In an effort to encourage TDM in all patients treated for at least 7 days, Dr. Rivera and colleagues reviewed medical records at their institution and identified all patients who received voriconazole for ≥7 days from January 2010 to February 2011. Investigators then developed a plan to improve the rate. Steps included direct discussion with clinicians and clinical pharmacists; development of a voriconazole treatment algorithm that included TDM; and integration of automatic ordering of TDM into the electronic medical records of patients who are prescribed the antifungal agent for 7 days or longer.

In the period prior to implementation of the plan, only one-third of patients treated with the antifungal had undergone TDM. The intervention started in October 2010, and from then until February 2011, the TDM rate increased to 86% (P<0.001 vs. pre-intervention period). Of the TDM values obtained, 32% were <1 mg/mL, 56% were within the recommended therapeutic range of 1 to 6 mg/mL, and 12% exceeded 6 mg/mL. “The variability of the voriconazole levels obtained emphasizes the importance of TDM,” Dr. Rivera and colleagues concluded.

Minimizing Risk of Adverse Events

Here at IDSA, South Korean investigators reported study data that further emphasized the value of TDM in minimizing the risk of adverse events with voriconazole. Dr. Wan Beom Park, Seoul National University, and colleagues randomized 90 patients who were prescribed the antifungal to TDM, standard dosing and follow-up. Among patients in the TDM group, the voriconazole level was determined after 4 days of treatment, and the dose was adjusted as necessary to maintain a level within the range of 1 to 5.5 mg/L. In the antifungal group, 38% of measured drug levels exceeded the target and 12% fell below the target. The incidence of treatment-related adverse events and serious adverse events did not differ between the TDM and standard-dosing group. However, only 1 (2%) patient in the TDM group discontinued because of adverse events, as compared with 8 (17%) in the control group (P=0.030).

Dr. Park and colleagues speculated that the lack of difference in adverse events could indicate that many of these occurred early in the course of treatment, before the serum level was measured and the dose adjusted.

Timing of Therapy

The relationship between timing of antifungal therapy and subsequent clinical outcomes has attracted considerable interest in recent years, particularly as use of prophylactic and pre-emptive (empiric) therapy has increased. Two different studies discussed here at IDSA showed a significant association between the timing of treatment and in-hospital mortality. 

The larger of the 2 studies (N=230) showed that increased delay from the time of a positive culture to the start of treatment was associated with increased mortality (Garey et al. Clin Infect Dis 2006;43:25-31). Patients who started antifungal therapy on day 0 had the lowest mortality (15%), increasing to 24% for initiation of antifungal therapy on day 1, 37% on day 2 and 41% for initiation on day 3 or later (P=0.0009 for trend). The second study (N=157) showed that initiation of antifungal therapy ≥12 hours from a first positive culture doubled the odds of in-hospital mortality, as compared with patients who began treatment sooner (Morrell et al. Antimicrob Agents Chemother 2005;49:3640-5).

Aside from those 2 studies, limited evidence has been added to the knowledge base about the relationship between timing of antifungal therapy and subsequent clinical outcomes, noted Dr. Thy Le, Temple University, Philadelphia, Pennsylvania. To that end, he and colleagues retrospectively reviewed medical records of all patients with culture-proven candidemia during 2003 to 2010. They excluded patients who had hospital stays <48 hours or who had received antifungal therapy within the previous 30 days. The final analysis included 186 patients, of whom 125 survived to hospital discharge.

Investigators examined both the timing and the appropriateness of antifungal therapy. Time to initiation of therapy spanned from <24 hours to >96 hours. Unexpectedly, patients who received appropriate therapy within 24 hours did no better than patients treated later. However, examination of demographic and clinical characteristics revealed significant differences between patients who survived and those who did not. Patients who died in hospital were older (63 vs. 53 years old, P<0.001), more infirm (Charlson score 4 vs. 2, P=0.004), more ill (APACHE II score 25.9 vs. 13.0, P<0.001) and were more likely to have a history of recent antibiotic therapy (100% vs. 85.6%, P=0.002).

All patients received 1 of 2 antifungal drugs, one of which was associated with a twofold greater mortality risk (65.6% vs. 34.4%, P=0.008).

In univariate and multivariate analysis, only the APACHE II score emerged as an independent predictor for the 3 outcomes of interest: clinical cure and microbiologic cure, as well as mortality. According to Dr. Le, the inconsistency of the results with those from previous studies indicate that “further analysis or studies are needed to determine the importance of time to appropriate antifungal therapy in general hospital populations.”

Treatment Sequence and Switching

Though not specifically related to timing of therapy, another IDSA presentation provided insights to 2 other issues that have the potential to influence outcomes: initial treatment and switching from the initial antifungal to another agent. The analysis involved 1652 patients treated for culture-proven candidemia from 2005 to 2010. Patients were identified from a commercial database with clinical records from 141 hospitals in the US.

The analysis yielded findings that raised questions about current approaches to antifungal therapy, according to Rolin Wade, RPh, MS, Cerner LifeSciences, Beverly Hills, California. Noteworthy observations included: fewer than 25% of patients had a diagnosis of invasive candidiasis; 22% of patients received no antifungal therapy; and 39% switched to a different therapy or mode of administration within 48 hours. “Current treatment patterns raise concerns regarding initial treatment strategies for management of serious and commonly fatal inpatient Candida infection,” Mr. Wade concluded.

Exploring Combination Therapy

Clinical guidelines for treatment of invasive candidiasis call for monotherapy with an antifungal. Considerable interest has arisen over the potential value of combined antifungal therapy with an azole and an echinocandin. One drug currently under evaluation in a trial of combination therapy is the new-generation echinocandin anidulafungin, which is being studied with voriconazole. Here at IDSA, investigators in a multicentre European trial reported findings from an open-label evaluation of anidulafungin in patients with candidemia or invasive candidiasis following abdominal surgery.

The retrospective analysis included 90 patients who were post-abdominal surgery and 80 who had candidemia or invasive candidiasis unrelated to abdominal surgery. Response rates did not differ significantly between groups at the end of intravenous therapy, at the end of all therapy or at 2 and 6 weeks’ post-therapy, reported Dr. Philippe Montravers, Hôpital Bichat-Claude Bernard, Paris, France. Adverse event rates were 10.6% in the patients who had abdominal surgery and 20.4% in those who did not have prior abdominal surgery.  



















 



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