Reports

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PRIORITY PRESS - 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)

Chicago, Illinois / September 17-20, 2011

Chicago - Prophylactic and empirical therapy with first-line antifungal agents is becoming increasingly dependent on therapeutic drug monitoring (TDM). The efficacy relationship between drug exposure and cure, particularly in the context of rapidly progressive, life-threatening infections, was the focus of numerous studies at this year’s ICAAC. It included a study that demonstrated relatively tight correlations for drug exposure and infection control in the treatment of resistant invasive pulmonary aspergillosis. Understanding TDM in regard to the urgent need to achieve a complete response is particularly important for empiric therapies, when the pathogen is unknown, or in prophylactic strategies, when the goal is to prevent clinical infection.

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

Early detection or prevention of fungal infections plays a critical role in reducing morbidity and mortality in hospitalized patients. Even though currently available antifungal agents are effective when administered promptly in adequate doses, it is important to recognize the need to adjust doses to avoid treating at sub-therapeutic levels. A study designed to evaluate voriconazole adjustments in invasive pulmonary aspergillosis (IPA) is an example. Recognized as a first-line agent after providing highly significant improvement in survival when compared to amphotericin B in a pivotal trial almost 10 years ago (Herbrecht et al. N Engl J Med 2002;347:408-15), voriconazole is likely to retain this role as long as dose adjustments are made to ensure that the therapeutic drug range is achieved in each patient.

Overcoming Higher MICs

“Isolates of Aspergillus fumigatus that require higher voriconazole minimum inhibitory concentrations (MICs) are being increasingly seen worldwide, but our study suggests that a routine method for monitoring breakpoints means that these are not a barrier to the persistent and predictable efficacy of this agent,” reported Dr. Susan J. Howard, Division of Infectious Diseases, University of Manchester, UK. Using a novel dynamic in vitro model of the human alveolus, Dr. Howard reported that there was a tight relationship between increased drug exposure and inhibition of fungal growth as MICs climbed from 0.5 to 16.0 mg/L.

In this model using multiple strains, fungal growth and the antifungal effect of voriconazole were estimated using circulation galactomannan (GM) concentrations. A mathematical pharmacokinetics (PK)/pharmacodynamics (PD) model provided an ability to link the area under the curve (AUC):MIC and trough concentrations:MIC with circulating GM concentrations. While Monte Carlo simulations suggested that standard doses were effective in most patients with a strain that required an MIC =1.0 mg/L, greater MICs “could be overcome with elevated drug exposures,” Dr. Howard told delegates.

Therapeutic Drug Monitoring and Novel Treatment Strategies

The importance of therapeutic drug monitoring (TDM) is especially pronounced in prophylactic or empiric therapy because it can be employed both to ensure adequate drug exposure in the context of known MICs for likely pathogens and provide protection against adverse events by ensuring that the selected agent remains within its therapeutic window of tolerability. This permits the most potent agents to be used with a low risk of adverse events, an advantage relevant not only to currently available antifungal agents but also to agents in development, such as E1210.

Data presented here at ICAAC on E1210 attracted attention because it represents a new therapeutic class. “So far, E1210 has been associated with excellent potency in in vitro studies with good inhibition of isolates cross-resistant to all of the triazoles,” stated Dr. Mariana Castanheira, JMI Laboratories, North Liberty, Iowa. Although the clinical analyses of E1210 with TDM have not been reported, Dr. Castanheira indicated that defining ways to monitor efficacy on standardized methodology, whether or not TDM is the tool, is critical to prevention or management of evolving pathogen types and resistance characteristics.

Here at ICAAC, several studies were presented on the novel first-in-class, broad-spectrum antifungal agent that inhibits the inositol acylation step in fungal glycophosphatidylinositol (GP) biosynthesis. This mechanism results in impaired cell wall growth and inhibition of fungal cells to biological substrates. In the study presented by Dr. Castanheira, 78 isolates of Aspergillus species with varying degrees of resistance were tested for relative susceptibility to 3 currently available triazoles (voriconazole, itraconazole and posaconazole) and the 3 echinocandins (anidulafungin, caspofungin and micafungin) as well as E1210.

While the study, which included 4 Aspergillus species, generated a broad range of results, Dr. Castanheira reported that E1210 at a dose expected to be used in further clinical development was the most effective or one of the most effective for all resistant strains. According to Dr. Castanheira, a new antifungal with a novel mechanism of action would be important if, as projected, rates of resistant fungal infections continue to climb.

Combination Antifungal Therapy for Increasing Resistance

Another strategy that also shows substantial promise is the use of combination antifungal agents. Again, TDM may be important in guiding doses of both agents into their therapeutic window. In a study that evaluated a combination of anidulafungin and voriconazole in an experimental model of invasive aspergillosis (IA), the MICs of each agent were critical to survival even in the combination. Compared to monotherapy with either agent, which did not offer consistent survival, the addition of a low dose of anidulafungin to a higher dose of voriconazole, or the reverse, produced 100% survival.

“The combination of anidulafungin and voriconazole was therapeutically effective in this model. It was particularly more effective than voriconazole or anidulafungin monotherapy when infection was caused by azole-resistant Aspergillosis fumigatus isolates,” reported the study’s senior author Dr. Adam R. Jeans, Department of Infectious Diseases, University of Manchester.

Again, when TDM is employed it offers an opportunity both to ensure that adequate levels of the antifungal agent are reaching the infection and to reduce the risk of adverse events. In a retrospective study undertaken at a hospital where TDM has been used since 2002 for monitoring antifungal treatment, a retrospective study was undertaken of all patients who had been treated for IA to identify risk of neurotoxicity. Over a 3-year period, all 80 of the patients in this analysis had received voriconazole, the first-line treatment at the centre for IA. The conclusion was reached that blood levels of 5.5 mg/L represent a safety threshold for neurotoxic symptoms, such as confusion or hallucinations.

“When we specifically evaluated just those patients treated in 2010, 0 out of 16 patients with a voriconazole level <5.5 mg/L vs. 3 of 9 with greater levels developed neurotoxicity,” reported Dr. Christophe Padoin, Therapeutic Drug Monitoring and Pharmacokinetics Laboratory, CHU Avicenne, Bobigny, France. “All symptoms disappeared when the dosage was reduced or voriconazole was discontinued.”

Isothermal Microcalorimetry

While TDM is currently the most widely used method of monitoring drug levels for efficacy and safety, alternative strategies are in development. One reported here at ICAAC involved isothermal microcalorimetry. This tool measures growth-related heat production of pathogens exposed to antifungal therapy. Interestingly, different classes of antifungal agents affect the heat growth in different ways, but each appears to be reproducibly measured. The concept was tested in Aspergillus species.

“Amphotericin B and azoles delayed the heat production in a concentration-dependent manner whereas caspofungin modified the heat profile; both correlated well with MIC values,” reported Dr. Ulrika Furustrand Tafin, University Hospital, Lausanne, Switzerland. Dr. Tafin added that the the median detection time was 4.1 hours although it ranged up to 15.4 hours. Although clinical use of this tool may be some distance off, Dr. Tafin predicted a more immediate use in testing of new antifungals and antifungal therapies in combination.

Summary

Fungal infections can be a devastating complication for hospitalized patients, particularly those who are immunocompromised. Consequently, strategies for prophylaxis or rapid implementation of empiric therapy are commonly employed to reduce morbidity and mortality. With the urgency in life-threatening infections, effective antifungal targeted dosing is becoming increasingly important for treatment success and for preserving the efficacy of first-line agents. TDM provides the opportunity not only to ensure that the adequate dose is being administered but also to avoid excessive doses associated with adverse events. This is particularly important when attempting to administer the most potent agents, when the pathogen is unknown or when prophylaxis is the goal. Recent studies suggest progress in the development of antifungal therapies with novel mechanisms of agents as well as in development of new strategies to gauge infection susceptibility. One more readily available strategy may be simply combination antifungal therapy in which independent mechanisms of action can be used to defeat infections at relatively low doses.