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PRIORITY PRESS - 23rd European Congress on Clinical Microbiology and Infectious Diseases

Berlin, Germany / April 27-30, 2013

Berlin - The absence of strategies to ensure adequate antifungal drug levels for the treatment of invasive aspergillosis (IA) and other serious fungal diseases appears to be a major source of poor outcomes, judging from a series of studies presented at ECCMID. Many centres have improved response to fungal infections with clinical pathways that accelerate the time to the most effective therapy, but few include mechanisms to ensure adequate drug levels. While adequate drug levels are important across fungal infections and therapeutic options, particular attention at ECCMID was directed at IA for which therapies have a narrow therapeutic range. In multiple sets of data presented, failure to maintain antifungal drug levels in the therapeutic range was found to be both common and a cause of poor clinical response. The data provide compelling support for routine therapeutic drug monitoring to address a readily reversible cause of treatment failure.

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

Pathways and Therapeutic Monitoring

The patterns of fungal infection and the order of efficacy of antifungal agents have been increasingly well defined, encouraging the development of clinical pathways to guide therapeutic decisions. Such pathways, outlined in published studies and customized for routine use at many institutions, are particularly reliable when the pathogen is known, but they also improve the likelihood of starting the best option when prophylactic, preemptive or empirical therapy is considered appropriate. New data on optimal treatment of invasive aspergillosis (IA) suggest that the greatest risk of treatment failure may not be produced by starting the wrong agent but from failing to confirm adequate drug levels.

“We now have an array of antifungal agents that we can apply in very specific settings to increase the likelihood of clinical cure while minimizing risk of toxicity, but we will not get far if the drug levels of agents we are using are not in the therapeutic range,” observed Dr. Monica Slavin, Head, Department of Infectious Diseases, Peter MacCallum Cancer Centre, Melbourne, Australia.

Although this remark was directed at antifungal therapies overall, this concern was reinforced by a series of drug monitoring studies presented at ECCMID that were conducted in patients with IA and other fungal infections for which azoles are commonly employed. These agents offer high rates of clinical cure but a narrow therapeutic window. At levels above the therapeutic range, patients risk neurotoxicity and other adverse events, but the more common problem is subtherapeutic blood levels where the risk includes progressive disease. A large database supports this claim.

“The data show that the serum concentrations of the azoles in the clinical setting are lower than those previously reported,” according to Dr. Nathan P. Wiederhold, Director, Fungal Testing Laboratory, University of Texas Health Science Center, San Antonio. “The variability in serum concentration was consistent across the triazoles with subtherapeutic dosages being much more common than supratherapeutic doses. These data make a strong case for therapeutic drug monitoring [TDM].”

Subtherapeutic Drug Levels Reported

The large database created by blood and cerebral spinal fluid (CSF) samples submitted for analysis to Dr. Wiederhold’s Fungal Testing Laboratory was queried regarding therapeutic concentrations of azoles. The analysis consisted of 14,536 samples from patients receiving voriconazole, 1386 from patients receiving posaconazole and 3105 from patients taking itraconazole. In all cases, the majority of samples showed drug levels outside of the recommended therapeutic range.

In the voriconazole samples, drug was undetectable in almost 15%, and >40% had serum levels under the recommended level of <1 mcg/mL. Moreover, >10% had serum levels above the recommended level of 5 mcg/mL. This left less than one-third of patients in the therapeutic range. In the posaconazole samples, 43% of blood concentrations were <0.7 mcg/mL. For itraconazole, 18% of serum samples were undetectable using a sensitive bioassay for evaluation.

In this study of consecutively submitted samples, “the frequency with which we saw low or undetectable concentrations of azoles is higher than that previously reported, although the variability in azole concentration has been identified by others,” Dr. Wiederhold reported. He noted that subtherapeutic dosing appeared to be particularly common in patients with underlying hematologic malignancies.

Due to recent fungal outbreaks affecting the central nervous system, “we also looked at CSF levels and found a similar range of levels with only a minority in the therapeutic range,” reported Dr. Wiederhold. While voriconazole was undetectable 11.4% of CSF samples, the proportion was 84.2% in the posaconazole group.

This was not an isolated report. Similar results were generated by a separate study conducted by investigators at the University of Graz in Austria. In this study, 221 trough voriconazole plasma concentrations were analyzed from 61 patients of whom 40 were being treated for hematologic malignancies and 21 were admitted to the intensive care unit for another cause. Of these patients, 20 were receiving voriconazole prophylaxis. The remaining patients were receiving treatment, primarily for IA.

“Voriconazole was below the target range, defined as 1.5 mg/L, in 124 or 56% of the 221 samples,” reported Dr. Martin Hoenigl, a clinical researcher in the Section of Infectious Diseases. In this study, the low levels of voriconazole were associated with clinical implications because “multivariate analysis revealed that concentrations in the therapeutic range were associated with a significantly greater likelihood of a clinical response [P<0.015].” Conversely, the odds ratio (OR) of failure were about 3 times greater with low concentrations.

Emphasizing the variability in blood levels, supratherapeutic doses, defined as >5.5 mg/L, were also identified in 18 (8%) of samples. Of the six cases of neurological side effects in the patients evaluated, all but one occurred in the supratherapeutic or upper end of the therapeutic range.

In Support of TDM

“This was a single-centre observational study, but it is consistent with other reports and it supports a published study that found TDM to both improve treatment response and to reduce drug discontinuations due to adverse events,” reported Dr. Hoenigl, referring to a randomized study in which response rates climbed from 57% to 81% in voriconazole patients on TDM relative to those who did not (Park et al. Clin Infect Dis 2012;55:1080-7).

The concern about subtherapeutic levels is particularly relevant for IA where azoles overall and voriconazole in particular have demonstrated high rates of efficacy when administered in the therapeutic range. Several guidelines, including those issued by the Infectious Diseases Society of America (IDSA) and the fourth European Congress of Infections in Leukemia (ECIL-4), identify voriconazole as the first-line therapy for IA based on a randomized study in which voriconazole demonstrated a survival advantage over amphotericin B (Herbrecht et al. N Engl J Med 2002;347:
408-15).

“Voriconazole is the gold standard in the treatment of IA, but it is associated with non-linear pharmacokinetics, which is the reason that TDM is an attractive strategy to improve outcomes,” reported Dr. Hoenigl, who said that his analysis indicates the problem may be greater in those given this agent for prophylaxis rather than treatment and for those with underlying hematologic malignancies. At his centre where pantoprazole is the most common proton pump inhibitor (PPI) administered, PPI use was also a risk factor for subtherapeutic levels.

By increasing the likelihood that patients receive an effective therapy for IA to increase cure rates, reduce toxicity and lower costs, one multicentre collaborative group of investigators presenting data at ECCMID advocated a “diagnostic-driven” (DD) strategy. Using a decision-analytic model based on published studies to test the strategy, the model predicted a 41% improvement in survival at lower costs. The DD was described as employing serum galactomannan (GM) antigen and Aspergillus polymerase chain reaction (PCR) testing in order to initiate targeted rather than empirical therapy.

“Although there were increased costs due to serum GM antigen and Aspergillus PCR testing, the total cost of the DD strategy was lower than with empirical therapy,” reported Dr. Rosemary A. Barnes, Department of Medical Microbiology, College of Medicine, University of Cardiff, UK. In addition to the difference in cost ($2773 vs. $3254), Dr. Barnes noted that a higher proportion of the infections were definitively diagnosed. Although the decision analysis did not suggest the DD approach would reduce mortality, the authors advocated this approach for its potential to lower cost and toxicity with the potential to improve outcomes.

Summary

Due to the importance of rapid initiation of first-line antifungal agents, clinical pathways are being increasingly employed to guide treatment, but new data suggest that ensuring adequate drug levels is an additional and critical step. This is particularly important for therapies employed in the treatment of IA due to variable pharmacokinetics. 

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