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PRIORITY PRESS - ID Week - Infectious Diseases Society of America (IDSA)

San Francisco, California / October 2-6, 2013

San Francisco - Attributed to broader use of immunosuppressive therapies, the rising global incidence in invasive fungal infections overall and invasive aspergillosis (IA) specifically threatens a parallel rise in resistant species. This risk has intensified interest in promoting optimal treatment choices at optimal doses and durations. At ID Week, several presentations provided insight on both ineffective and effective treatment strategies. One counterintuitive finding, based on registry data, was that adding a second agent to the gold standard for IA does not improve cure rates among solid organ transplant patients. In a second study, the potential benefits of therapeutic drug monitoring were found frequently compromised by inappropriate technique. A third study of risk of adverse outcomes in patients with IA and renal insufficiency suggested that the presence of renal impairment was not a predictor of adverse outcome for first-line therapy, particularly when treatment is administered intravenously.

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

Monitoring Antifungal Susceptibility

Rapid initiation of the most appropriate antifungal agent in patients with invasive aspergillosis (IA) is a critical step for reducing the mortality associated with this infection. This is the reason that guidelines from the Infectious Diseases Society of America (IDSA) recommend first-line antifungal therapy for probable or possible IA in advance of confirmatory diagnostic studies (Walsh et al. Clin Infect Dis 2008;46:327-360). New epidemiologic data reinforce the order of guideline-based therapies, a step that may be even more important in the context of growing concern that failure to use antifungals optimally will generate resistant organisms in the future.

“Although the prevalence of resistance is low among fungal isolates for all of the antifungal agents, extended monitoring seems prudent because of the increasing rates of IA worldwide,” reported Dr. Mariana Castanheira, Senior Research Scientist, Molecular Studies Section, JMI Laboratories, North Liberty, Iowa. Presenting data at ID Week on 1,714 invasive fungal clinical isolates, including 107 IA species, Dr. Castanheira reported that minimum inhibitory concentrations (MICs) indicated acceptable susceptibility to both echinocandins and azoles, including voriconazole, which is identified as the primary therapy for several forms of IA in the IDSA guidelines.

In the study, susceptibility of all the isolates were tested against the azoles voriconazole, posaconazole, and fluconazole, as well as against the echinocandins anidulafungin, caspofungin, and micafungin. Fluconazole resistance to Candida species, such as C. tropicalis, was observed in isolates from five countries, including the United States, and rates for several other Candida isolates, such as C. glabrata, had increased relative to a previous survey by the same group. Among Candida species, susceptibility rates to echinocandins were 97.4% or higher. Voriconazole was active against all invasive candidiasis and aspergillosis, but, like other antifungals, did not provide uniform coverage of rare molds.

“It is important to monitor resistance because invasive fungal infections have become a major cause of morbidity and mortality among immunocompromised patients,” Dr. Castanheira observed. “Although our data suggest resistance rates remain low, the overall incidence of invasive fungal infections is increasing, and this may create pressure for resistant organisms to emerge.”

One way to combat resistance is to employ the optimal therapy in sufficient doses to achieve cure. In the evidence-based IDSA guidelines, voriconazole is identified as the primary therapy for pulmonary IA and several other IA types, such as IA of the central nervous system, but there are exceptions. This includes IA of the heart, where no primary antifungal has been identified, and allergic bronchopulmonary IA for which itraconazole is the first choice.

Solid Organ Transplantation: Mono vs Dual Therapy

An analysis of registry data suggests that intensifying therapy by combining voriconazole with an echinocandin in IA does not appear to be a valid strategy for improving outcome at least when IA develops after solid organ transplantation.

Due to the substantial rates of morbidity and mortality from IA in patients on immunosuppressive therapy following solid organ transplantation, therapy intensification is attractive. While prospective trials in this population are difficult to conduct because of the challenges of randomization and the control for the broad array of variables that affect outcome, the Prospective Antifungal Therapy (PATH) Alliance registry network, which involves 25 centres in both the United States and Canada, has allowed an assessment of the empiric use of voriconazole plus an echinocandin. The frequency with which this approach is employed is reinforced by the fact that 50 of 145 cases of IA in solid organ transplant received voriconazole plus an echinocandin in a registry that collected data over four years.

Using a primary composite outcome assessment of death or no response to therapy versus complete or partial response at 12 weeks of antifungal therapy, propensity scores were developed for the likelihood of combination therapy versus voriconazole alone to achieve efficacy. According to Dr. Shahid Husain, Division of Experimental Therapeutics – Infection & Immunity, Toronto General Research Institute, University of Toronto, the crude rates of a positive outcome at 12 weeks were 34% for the combination and 32% for monotherapy. This difference was not significant nor was a propensity-stratified difference to account for selection bias on factors reflecting risk of adverse outcome.

“Comparison of voriconazole plus echinocandin for therapy of IA in solid organ transplant using one of the largest cohorts of solid organ transplant patients available failed to detect an advantage over voriconazole monotherapy,” Dr. Husain reported.

TDM: Standardized Institutional Procedures Key

One strategy to improve outcomes in IA is to perform therapeutic drug monitoring, a step that remains of uncertain value as a routine tool even if this may be helpful when there is concern about drug-drug interactions or risk of adverse events. The IDSA guidelines suggest that measurement of serum levels “may be useful” to ensure adequate drug exposure, “especially” in progressive infection among patients on oral therapy, but routine analyses are not advocated. In typical practice, progressive disease does appear to be a common reason to evaluate serum levels, but a study presented at ID Week suggests analyses are often performed incorrectly.

“Voriconazole dose adjustments based on trough serum concentrations became common practice at our institution several years ago, but it is performed by clinical discretion,” reported Dr. Mildred Vicente, Pharmacy Services, University of Chicago School of Medicine, Chicago, Illinois. However, when this practice was evaluated more closely, it was found that “adjustments were commonly made on non-trough levels, which is inappropriate.”

In this study of 86 patients receiving voriconazole, 42 received therapeutic drug monitoring. Rates of therapeutic drug monitoring were significantly higher in those with hematologic malignancies and in those with a history of invasive fungal infections. The median duration of voriconazole was also significantly longer (8.5 vs. 4 days; P=0.03) in those who received drug monitoring. When a closer look at the timing of drug monitoring was taken, only 54% were conducted when drug levels were at their predicted trough, indicating that 46% of assessments were made on non-trough levels.

There may be value in evaluating serum concentrations to confirm that drug levels are in the therapeutic range when there is concern that infection is progressing or that a patient is experiencing an avoidable adverse event, but “institutions utilizing voriconazole therapeutic drug monitoring should establish standardized recommendations, including timing of the monitoring and what dose adjustments are appropriate based on the results,” Dr. Vicente concluded.

One reason to consider drug monitoring is in patients with renal insufficiency. In the IDSA guidelines regarding the use of intravenous (IV) voriconazole, caution is expressed about renal accumulation of the sulfobutyl-ether cyclodexterin vehicle, which is dependent on the kidney for elimination. However, a study of 63 patients with renal insufficiency receiving voriconazole for possible, probable, or confirmed IA found a nephrotoxicity rate of 3% for the IV formulation and 8% rate for the oral formulation. A logistic regression analysis did not associate nephrotoxicity with increased risk of mortality in either group.

Based on these data, “our study suggests that IV voriconazole use in patients with renal insufficiency appears to be safe compared with oral voriconazole use,” reported Dr. So-Youn Park, Department of Infectious Diseases, University of Ulsan College of Medicine, Seoul, South Korea. While these data do not preclude a value for therapeutic drug monitoring in patients with renal impairment, these data suggest a low overall risk of nephrotoxicity.

Conclusion

The rates of invasive fungal infections are expected to continue to rise as a product of increasing use of immunosuppressive therapies for a variety of disease states that are common in aging populations. Current surveillance of fungal isolates suggests that susceptibility to commonly used antifungal therapies remains high, but prudent use of these agents is considered to be a factor for sustained efficacy. Awareness and application of clinical guidelines, such as those issued by the IDSA, are instrumental to reducing the morbidity and mortality associated with IA and other severe fungal diseases.