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PHYSICIAN PERSPECTIVE - Viewpoint based on presentations from the 26th International Congress of Chemotherapy and Infection AMMI Canada/CACMID Annual Conference

Toronto, Ontario / June 18-21, 2009

Reviewed and Edited by:

Donald Sheppard, MD, FRCPC

Assistant Professor, Department of Microbiology and Immunology, McGill University , Montreal, Quebec

In the debate over antifungal treatment strategies taking place here at the AMMI/CACMID conference, I argued in favour of “prudent practice.” I first suggested physicians ask themselves if there is a real clinical need for improved antifungal strategies. As demonstrated by the pivotal Herbrecht et al. study (N Engl J Med 2002;347(6):408-15), reconstitution of a patient’s immune system is the most important predictor of a successful outcome in invasive aspergillosis (IA). As such, the approximately 70% survival rate achieved with voriconazole in Herbrecht et al. suggests that survival rates in IA are already far superior than they once were and that there has been much progress in antifungal treatment (Figure 1). Yet even if we believe that there is room for improvement, we must still ask whether there is reason to think combination therapy would be more effective than monotherapy.

Figure 1.

The Case for Monotherapy

There are theoretical reasons to believe that combination therapy may be less effective than monotherapy. Consider the antifungal mechanism of action. Amphotericin B (AmB) works by attaching to ergosterol in cell membranes; inhibition of ergosterol synthesis is the mechanism by which azoles exert their antifungal effect. Therefore, the combination of AmB plus an azole has the potential for antagonism. This lack of synergy was demonstrated in a study of candidemia, where the success rates of 56% in the fluconazole/placebo group were not statistically different from the 69% seen in the fluconazole/AmB group (Clin Infect Dis 2003;36:1221-8). In vitro studies have also found evidence of a negative interaction when AmB is used in combination with an azole, while in a classically immunosuppressed animal model of invasive fungal disease (J Infect Dis 2006;194:1008-18), every outcome measure was worse in animals who received a combination of an azole plus liposomal AmB than animals receiving single-agent therapy. The addition of either AmB or micafungin to voriconazole yielded no additional benefit in neutropenic guinea pigs (Clin Microbiol Infect 2004;10:925-8), where the treatment effect was entirely accounted for by voriconazole alone.

I submit that I am skeptical of results from single-arm observational trials of salvage therapy in IA. With no control arm against which to compare success rates, overall efficacy in all of these observational studies typically approaches 50% regardless of the combination used, not an encouraging result.

A few comparative trials of combination vs. monotherapy have been performed, notably a study in organ transplant patients (Transplantation 2006;81:320-6) in which voriconazole plus caspofungin was compared to liposomal AmB. In this trial, there was a trend towards an improved outcome in favour of the combination arm as well as a significant advantage in favour of the combination arm in subgroups with Aspergillus fumigatus disease or renal failure. Nevertheless, it was unclear if outcomes in this trial would have been better if patients had been exposed to voriconazole alone. Further, although prospective, this study used a sequential design, with the monotherapy arm having been recruited before the combination therapy group. Thus it is also possible that the improved outcomes in the combination therapy arm may reflect better outcomes associated with other improvements in care. Indeed, a stepwise improvement in survival rates over time has been documented in a study by Upton et al. (Clin Infect Dis 2007;44:531-40).

Another comparison of micafungin monotherapy vs. micafungin plus other licensed antifungal therapy showed a survival advantage for the monotherapy arm but as an unrandomized trial, it was again subject to many biases, including the fact that sicker patients were more likely to receive the combination strategy, thereby skewing outcomes (J Infect Dis 2006;53(5):337-49).

A retrospective study of salvage posaconazole monotherapy compared to liposomal AmB plus an echinocandin showed that response and survival rates in the monotherapy arm were significantly better than those in the combination arm (Leukemia 2008;22:496-503).

These results may lead physicians to speculate whether the patients in these comparative studies on monotherapy received adequate doses of the drug, as outcomes are very likely to appear more promising when single agents are adequately dosed. In fact, recent evidence suggests that voriconazole drug levels may be low in up to 25% of recipients who receive standard recommended doses. Consequently, there is every reason to recommend therapeutic drug monitoring in patients receiving voriconazole, as is routinely done when prescribing gentamicin.

The only randomized, controlled trial in which a combination strategy did appear to lead to better outcomes was one in which investigators compared liposomal AmB and caspofungin to liposomal AmB alone (Cancer 2007; 110:2740-6). Once more carried out in the setting of IA, results did show significantly better response and survival rates for the combination arm. Nevertheless, as I pointed out during the debate, the dose of liposomal AmB used in this study was high and it is now known that high-dose liposomal AmB is associated with poorer outcomes. The magnitude of the benefit at 12 weeks in the combination arm—although statistically significant—was also at best quite modest and statistical significance was lost over time.

Furthermore, as Herbrecht et al. established, voriconazole is more effective than AmB in the treatment of IA—indeed, their landmark trial established voriconazole as the recommended strategy for pre-emptive and/or confirmed IA. Yet would patients receiving the combination of liposomal AmB and caspofungin in this randomized trial have done just as well if they had been treated upfront with first-line voriconazole or voriconazole plus an echinocandin, a more rational combination in this setting?

CNS Aspergillosis

Of all disseminated fungal disease, central nervous system (CNS) aspergillosis has the highest mortality rate, and older studies have suggested rates approaching 100%. The long-term cognitive effects from unchecked disease can also be significant: During infection, Aspergillus elaborates abundant lytic enzymes that digest lipids, proteins and everything in their wake, i.e. a patient’s neuronal network. Imaging studies are largely unhelpful in monitoring a patient’s progress once they develop CNS aspergillosis, while galactomannan testing is virtually useless in primary CNS disease. Thus, disease management of patients with primary CNS aspergillosis remains extremely challenging and treatment decisions are difficult at best.

In my own practice, if patients appear to be failing voriconazole, it is important to distinguish between failure due to intolerance and failure due to lack of efficacy. If drug reactions or interactions are problematic—e.g. if the patient has developed significant visual hallucinations—then switching to a different azole-based strategy is quite reasonable. If disease progression is the major problem, then it is important to determine if this is a consequence of inadequate drug delivery, in which case altering the dosage or delivery method may be appropriate. True primary drug resistance in this setting is not usually an issue but if the patient is receiving adequate levels of voriconazole and it is still ineffective, I avoid adding a second agent which I feel is tantamount to sequential monotherapy. I prefer to switch patients to two different classes of agents such as liposomal AmB and an echinocandin.

Combination Antifungal Strategies

My colleague, Dr. Kieren Marr, Director, Transplant and Oncology Infectious Diseases Program, Johns Hopkins University, Baltimore, Maryland, argued that there are a number of theoretical reasons why combinations of antimicrobial agents might be preferable to single-agent regimens. Combinations of antifungals may increase antimicrobial activity and decrease microbial resistance. Drug combinations also increase the spectrum of activity and two agents may have unique and complementary tissue distribution. For drugs with dose-dependent toxicities, using them in combination, such as AmB and 5-fluorocytosine in cryptococcal meningitis, increases cerebral spinal fluid sterilization rates and decreases cerebral spinal fluid opening pressures, both now considered surrogate markers of success in cryptococcal meningitis.

Citing the study of combination fluconazole plus AmB vs. fluconazole alone in candidemia (Clin Infect Dis 2003;36(10):1221-8), Dr. Marr felt that the combination strategy did decrease duration to clearance of positive cultures and outcomes were better when patients were stratified by APACHE II scores. However, the “real question,” she noted, was how to approach Aspergillus infections.

In vitro and animal studies indicate multiple azoles and the echinocandins have synergistic activity and kill Aspergillus species well together. Small observational studies in which the combination of AmB and caspofungin were used to treat aspergillosis also suggested responses with the combination strategy were considerably more promising than responses seen in historical controls. For example, 60% of patients with refractory infection in one of these studies (Cancer 2003;97:1025-32) had a favourable response—and 20% complete resolution—when caspofungin was added to AmB or liposomal AmB.

At the Fred Hutchinson Cancer Research Center in Seattle, Washington, Dr. Marr and colleagues started using combinations of antifungal agents in IA in an effort to improve patient outcomes. In their experience (Clin Infect Dis 2004;39:797-802), survival in patients with IA who received the combination of voriconazole and caspofungin as salvage therapy following initial treatment with AmB was significantly better at three months than patients who received voriconazole alone (Figure 2). At one year, survival rates between the two groups were not different, as Dr. Marr acknowledged. This study also used historical controls, and as such is subject to the same potential bias as seen with the studies in organ transplant patients, where overall patient survival has improved with time.

Nevertheless, fewer patients in the combination arm died of IA than in the monotherapy arm; deaths in the combination arm were predictable. Dr. Marr also felt that prevention of early death as was shown in this study was compelling enough to consider this particular combination of agents in the salvage setting of refractory IA, especially in very ill patients, as were those included in her analysis.

Regarding the difficult clinical challenge of CNS aspergillosis, Dr. Marr stated that persistent immunologic risk is the main reason for clinical failure in this setting. Failure may also result from an inability to deliver enough drug to the source of infection where it is needed; less likely might be the emergence of microbial resistance. If the patient had previously been treated with liposomal AmB plus caspofungin—as he had in this particular case history—animal data support the use of voriconazole in CNS disease. Some animal models of invasive aspergillosis suggest that liposomal AmB plus voriconazole leads to better outcomes (Antimicrob Agents Chemother 2005; 49:4867-75). However, an observational study of CNS invasive aspergillosis involving 81 patients (Blood 2005; 106:2641-5) found that 35% of patients achieved either a complete or partial response to treatment on voriconazole alone—a significantly better outcome compared with historical controls. In the same study, excision of CNS lesions was associated with improved survival on multifactorial analysis as well.

As Dr. Marr suggested, there are arguments both for and against combination therapy in invasive fungal disease. She stated that combination therapy is warranted in certain situations, although now, with the availability of echinocandins, probably not in candidiasis. Yet there is still a need for adequately powered, controlled clinical trials such as the important, phase III randomized trial now being carried out by the Mycoses Study Group (MSG 003) comparing voriconazole to voriconazole plus anidulafungin in the primary treatment of proven or probable IA.

Results from this study, expected by the end of 2010, will likely provide answers as to which strategy is more effective in terms of all-cause mortality measured at six weeks after initiation of study drug. Secondary outcome measures in MSG 003 include the rate of global response at six weeks, all-cause mortality at six weeks, all-cause mortality at 12 weeks, mortality due to IA at six weeks, time to death, and the safety and tolerability of the two regimens.

In the meantime, Dr. Marr told delegates that as long as physicians see that combination therapy is not leading to worse outcomes, its use is warranted in patients with progressive disease, as lack of evidence, as she suggested, is not necessarily ev
icacy.

Figure 2.

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