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PRIORITY PRESS - Focus on Fungal Infections

New Orleans, Louisiana / March 3-5, 2010

In both placebo-control and active-control studies, prophylactic treatment with an azole antifungal agent significantly reduced the risk of fungal infections, including aspergillosis (N Engl J Med 2007;356:348-59). According to Dr. Ben de Pauw, Radboud University, Nijmegen Medical Center, The Netherlands, invasive aspergillosis (IA) treatment involves prophylactic or diagnosis-based pre-emptive therapy. However, prophylactic therapy runs the risk of becoming unnecessary, perhaps for days or weeks before laboratory results confirm or rule out fungal infection. Development of tests that could provide results more quickly create the potential for a new strategy, pre-emptive antifungal therapy. “Culture took two weeks and use of CT scans reduced that to one week,” remarked Dr. de Pauw. “With serology, we have an impression within a few days whether a patient has an invasive fungal infection.”

Recent studies have shown that a wait-and-see approach based on serial serology does not reduce the frequency of invasive fungal infections compared with empirical therapy but does reduce the use of antifungal therapy and results in a similar overall mortality (Clin Infect Dis 2005;41:1242-50, Clin Infect Dis 2009;48:1042-51, Bone Marrow Transpl 2009;41:553-61). “In this complex scheme, you can now say that we have pre-emptive therapy as an established new approach,” he told the audience, adding, “Empiric therapy will not be replaced, but its use will be reduced.”

Therapeutic Drug Monitoring

Clinical guidelines about managing the risk of IA (and other fungal infections) address therapeutic drug monitoring (TDM) of the azole antifungal agents, stated Paul G. Gubbins, PharmD, University of Arkansas, Little Rock. Individually, the agents have certain characteristics that complicate TDM decision-making. Examples include nonlinear, unpredictable pharmacokinetics (PK); variable absorption, which is influenced by factors such as gastric pH and food intake; extensive metabolism; and variable activity of the agent’s parent drug. Irrespective of the differences among agents, “the most important question is whether drug levels correlate with efficacy,” stated Dr. Gubbins.

Limitations seen in early studies of itraconazole TDM included use of capsules and bioassays, small numbers of patients and heterogeneous populations. Yet the data suggested that treatment failure correlated with low drug levels, indicated Dr. Gubbins. The studies also pointed toward a minimum concentration of 500 ng/mL (0.5 mg/L), a level below which poor outcomes start to occur.

One recent study examined the association between itraconazole concentrations and toxicity. Patients were treated with oral itraconazole for three weeks for an Aspergillus-related syndrome. The bioassay had a range of 0.5 to 25.6 mg/L and the drug dose was adjusted for concentrations <5 or >15 mg/L. “A concentration of 5 mg/L via bioassay was associated with a 26% probability of an adverse event,” reported Dr. Gubbins. “Higher concentrations were associated with progressively higher probability of toxicity. The results suggested a concentration of 17 mg/L measured by bioassay might be the appropriate upper limit for TDM.”

Human data include a briefing document submitted to the U.S. Food and Drug Administration showing only a weak association between treatment success and concentrations. Overall, the analysis showed no pharmacodynamic or PK relationship between drug levels and efficacy. “The therapeutic doses given in the dataset achieved concentrations in excess of the MICs for clinical isolates, so in the executive summary, there wasn’t too much enthusiasm for doing voriconazole TDM,” Dr. Gubbins told delegates.

Investigations into the association between voriconazole concentrations and toxicity also have suggested minimal utility for TDM in most cases, he continued. Elevated transaminase levels have been observed in clinical trials of voriconazole and most cases have been classified as mild or moderate. No specific threshold was consistently related to transaminase elevations, which are a class effect of the azole antifungal agents, Dr. Gubbins noted.

Some small patient series have demonstrated associations between increasing concentrations of voriconazole and an increased risk of central nervous system (CNS) adverse effects (Clin Infect Dis 2004;39:1241-4, Clin Infect Dis 2008;46:201-11). “Where there is new onset of encephalopathy or other CNS manifestations after initiating voriconazole, serum concentrations probably should be obtained and the drug discontinued until you can see what is causing the new symptoms and their relationship to voriconazole,” Dr. Gubbins suggested.

Inherent interpatient variability and voriconazole’s nonlinear PK have posed challenges to prediction of serum concentrations on the basis of a single measurement. If TDM is undertaken, serial sampling will be required, he explained. “Practically speaking, voriconazole TDM will not help reduce the risk of common adverse events, although attempts to correlate concentrations with outcomes are ongoing. TDM can be justified in select cases, so long as you realize that there is no valid therapeutic target.”

Data are insufficient at this point in time to decide whether routine TDM for posaconazole is warranted. Efforts to predict efficacy on the basis of concentrations are a work in progress, Dr. Gubbins indicated, and valid target concentrations have yet to be determined. Moreover, drug levels appear to be highly susceptible to food intake (particularly dietary fat), gastric pH and the rate of gastric emptying.

Role of Combination Therapy

According to Dr. Luis Ostrosky-Zeichner, University of Texas Health Science Center, Houston, the strategy to combine antifungal therapy to improve survival is very attractive. Though limited, emerging clinical evidence demonstrates that current agents can be used safely and effectively in combination. One example is anidulafungin and voriconazole, which is being evaluated in clinical and preclinical studies as combination therapy for IA (Antimicrob Agents Chemother 2009;53:5102-07, Expert Opin Investig Drug 2009;18:1393-404, Antimicrob Agents Chemother 2009;53:2382-91, Antimicrob Agents Chemother 2009;53:2005-13).

IDSA clinical guidelines currently recommend consideration of combination antifungal therapy in a limited number of settings, specifically CNS and cardiovascular infections (Clin Infect Dis 2009;48:503-35). “We currently have limited experience with combination therapy,” acknowledged Dr. Ostrosky-Zeichner, “but the evidence suggests [it] may be useful for select cases.”

Emerging Antifungal Therapies

According to Dr. Thomas Patterson, University of Texas Health Science Center, San Antonio, the arsenal for treating invasive fungal infections continues to expand. Advances in the azoles include a liquid formulation of itraconazole for oral gavage and spray-freezing liquid formulation for aerosolization. In fact, interest in aerosol therapy has increased with recognition of the changing nature of fungal infections in the lung. Changes in etiologic agents and the timing of infections have increased the imperative for prompt diagnosis. Advanced infection continues to be associated with poor outcomes, particularly in severely immunosuppressed patients and in those with disseminated and CNS infection.

The search for more effective therapy has resulted in new agents and combinations, Dr. Patterson continued, but therapies often have limitations related to drug interactions, systemic toxicities, PK and cost. In the setting of these confounders and limitations, the potential for aerosol therapy to prevent invasive fungal infections in high-risk patients has assumed new prominence.

Aerosolized voriconazole has shown promise for addressing some of the shortcomings of treatment for invasive fungal infections. In one recent study, three stratregies were compared for prevention of invasive infection by Aspergillus fumigatus (Antimicrob Agents Chemother 2009;53:2613-5): a control aerosol of sulfobutyl ether-b-cyclodextrin sodium (SBECD), intravenous voriconazole dissolved in SBECD or amphotericin B deoxycholate were randomized in a murine model. Pulmonary delivery of voriconazole and control was achieved by means of a 20-minute aerosolization using a nose-only dosing chamber (adapted to one animal) and micropump nebulizer. Aerosolized voriconazole significantly improved survival during treatment and after discontinuation compared with control and amphotericin B deoxycholate (P<0.01).

Another strategy that has attracted interest involves use of histone deacetylase (HDAC) inhibitors to enhance the sensitivity of fungi to azoles such as voriconazole. The rationale for using the agents together comes from observations that azoles deacetylate the promoter of transcription, resulting in downregulation of repression, or alternatively, upregulation of resistance genes. HDAC inhibitors may enhance fungi sensitivity to azoles by reducing azole-dependent upregulation of efflux pumps and reducing transcription of genes encoding ergosterol biosynthesis. Preliminary studies have shown as much as a 50% reduction in transcription with the combination of an azole and an HDAC inhibitor (Antimicrob Agents Chemother 2002;46:3532-9).

Summary

The ability to treat IA has improved substantially with emerging antifungal therapies and novel treatment strategies. Increasingly, the challenge to clinicians is to optimize the available therapy. Both prophylactic and empirical strategies have limitations, some of which have been addressed by the emergence of serology-based pre-emptive therapy. Although lower drug concentrations correlate with an increased risk of therapeutic failure, the role of TDM in the management of aspergillosis has yet to be defined.