Newer combination antifungal therapies for invasive aspergillosis

Medical Mycology April 2011, 49(Suppl. 1), S77–S81 Review Article Newer combination antifungal therapies for invasive aspergillosis Optimal therapy for invasive aspergillosis is unknown, and many clinicians have attempted to utilize a combination antifungal approach to improve outcomes. However, while numerous in vitro studies, animal models, and clinical reports suggest the possibility that combination antifungal therapy might offer improved results, there is no definitive accepted strategy. The currently available antifungals used in various combination approaches have not demonstrated clear improvement over monotherapy. The current classes of drugs targeting the cell wall and cell membrane may need adjunctive agents focused on separate cellular pathways, such as cell stress response or cellular signaling, to maximize efficacy. The calcineurin and the Hsp90 pathways are two such untouched arenas in which targeted manipulation may lead to great advances against aspergillosis. Keywords aspergillosis, Aspergillus, combination, antifungal, calcineurin Introduction In the last decade, there has been a surge of development of newer antifungals for invasive aspergillosis (IA), creating new hope for treatment and increasing the permutations of new potential combination therapies. Drawing from other infectious diseases such as HIV, tuberculosis, and cryptococcal meningitis [1], combination therapy for IA seems plausible to optimize therapy. Although no controlled clinical trial supports its use and the efficacy of combination therapy for IA has not been conclusively established [2], clinicians are desperately seeking new strategies to improve outcomes. However, the existing antifungal classes have not shown tremendous advances beyond the use of voriconazole monotherapy compared to amphotericin B. While the advent of voriconazole [3] therapy has greatly improved Received 23 February 2010; Received in final revised from 19 May 2010; Accepted 4 June 2010 Correspondence: William J. Steinbach, Box 3499, Division of Pediatric Infectious Diseases, Duke University Medical Center, Durham, NC 27710, USA. Tel: ⫹1 919 681 1504; fax: ⫹1 919 684 8902; E-mail: © 2011 ISHAM survival, it has been difficult to make further advances. Nearly every possible combination of the existing agents, including mixing different classes of drugs to better attack diverse targets, has been tested in vitro and some in vivo. Despite these efforts, little progress has been made on the combination antifungal front to optimize the possible clinical benefit from the combination approach. There are several foreseeable advantages to combination antifungal therapy, i.e., a widened spectrum and potency of drug activity, more rapid antifungal effect, synergy, lowered dosing of toxic drugs, and a reduced risk of antifungal resistance [4]. While each individual antifungal agent has limitations, combinations might prove more effective, as seen with the now standard highlyactive anti-retroviral therapy used with HIV patients. Utilizing agents with different mechanisms of action is a hallmark in current medical therapies in numerous medical disciplines, but of course one has to be cautious of some combinations as they may be antagonistic or clinically indifferent with additive side effects. More is not necessarily better, but the current antifungal approach is clearly not optimal as patients continue to die from IA in increasing numbers. DOI: 10.3109/13693786.2010.499374 WILLIAM J. STEINBACH*†, PRAVEEN R. JUVVADI*, JARROD R. FORTWENDEL*† & LUISE E. ROGG* *Department of Pediatrics, Division of Pediatric Infectious Diseases, and †Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina S78 Steinbach et al. Brief review of important animal model data on combination antifungal therapy Brief review of important clinical data on combination antifungal therapy The largest analysis of combination therapy of IA reviewed the management of 6,281 total cases from 1966–2001. The 249 clinical cases evaluated comprised a total of 23 different antifungal combinations, including 16 unique double antifungal and seven triple antifungal regimens. A total of 64% of patients showed improvement, with mortality from IA at 34%. While a response rate of 64% is encouraging, there are obvious limitations to a retrospective review. Additionally, this exhaustive study is now dated as the older combination used are not employed by contemporary clinicians with a much larger arsenal of available antifungal agents. In a prospective, open study, patients with proven or probable IA received either a combination of standard dose (3 mg/kg/day) liposomal amphotericin B and caspofungin versus high-dose liposomal amphotericin B (10 mg/kg/day) monotherapy [8]. There were significantly more favorable overall responses (10/15) and survival (100%) in the combination group compared with the highdose monotherapy group (4/15; 80% survival). This study implied that two agents using different mechanisms of action (cell membrane and cell wall) are preferred over even a larger dose of a proven agent. However, using the principle of two mechanistically different agents, the antifungal combination of a triazole ⫹ echinocandin, most commonly voriconazole ⫹ caspofungin, © 2011 ISHAM, Medical Mycology, 49(Suppl. 1), S77–S81 Studying combination antifungal therapy in animal models of IA has historically been problematic for numerous reasons. The primary objective for studying infection in animals is to adequately and appropriately mimic human disease. However, many studies have used relatively artificial means of generating invasive disease such as intravenously administering an Aspergillus inoculum at high concentrations, which may limit extrapolation to clinical disease. Additional issues with antifungal testing in animals center on relevant dosing, as for instance most studies have not measured serum or tissue azole levels to ensure adequate exposure and consistent levels that would be obtained in a patient. The most often quoted in vivo combination antifungal animal model investigation examined voriconazole ⫹ caspofungin [5]. In this immunosuppressed guinea pig model of intravenously inoculated invasive aspergillosis, treatment with amphotericin B or caspofungin (1 mg/kg/d or 2.5 mg/kg/d) resulted in 30–50% mortality. However, treatment with voriconazole or voriconazole plus either of the indicated caspofungin doses resulted in no mortality (0/12 in all experimental arms). Although this report ignited excitement, this guinea pig model actually showed no difference in mortality or mean times of survival in the combination therapy arm compared to voriconazole monotherapy. Semi-quantitative organ cultures of fungal burden (CFU/gram of tissue) with respect to the liver, lung, kidney, and brain in the combinations were better than untreated controls (P ⬍ 0.0025), but there are no reports of any difference between the combination (...truncated)