Treatment of Invasive Aspergillosis: To Combine or Not to Combine?

Abstract & Commentary

Synopsis: A retrospective review found evidence indicating improved survival when voriconazole was used in combination with caspofungin than when voriconazole was used alone in the treatment of patients with invasive aspergillos failing therapy with amphotericin B.

Source: Marr KA, et al. Combination Antifungal Therapy For Invasive Aspergillosis. Clin Infect Dis. 2004; 39:797-802.

Marr and colleagues retrospectively evaluated the outcomes of salvage therapy in 47 patients with probable or proven invasive aspergillosis who failed treatment with amphotericin B. Eighty-seven percent had received a hematopoietic stem cell transplant, most of which were allogeneic. Seventeen patients had received amphotericin B deoxycholate as primary therapy, while 30 received either amphotericin B lipid complex or liposomal amphotericin B. Salvage therapy was initiated either because of progressive infection, intolerance, or renal dysfunction. From 1997 until February 2001, voriconazole alone was used for salvage (31 patients), while after that date, caspofungin was given together with voriconazole (16 patients). Progressive infection was the reason for salvage in 71% of the montherapy group and in 93% of those given combination therapy.

Overall, 3-month mortality after the diagnosis of aspergillosis, as well as after initiation of salvage therapy, was greater in those who received the combination with a hazard ratio (HR) of 0.43 (95% CI, 0.17-1.1; P = 0.50). Multivariate analysis also found that combination therapy was associated with lesser mortality than monotherapy (HR, 0.27; 95% CI, 0.09-0.78; P = .008). This apparent benefit was also present when only allogeneic stem cell recipients were considered. There was no evidence of greater toxicity with combination therapy.

Comment by Stan Deresinski, MD, FACP

Voriconazole has become the antifungal agent of choice for patients with invasive aspergillosis on the basis of a randomized trial demonstrating its association with improved survival, when compared to treatment with amphotericin B deoxycholate.1 Caspofungin has been demonstrated in a non-randomized trial to have efficacy as salvage therapy with this high lethality infection. In vitro evidence has demonstrated no antagonism, but has found frequent synergy between caspofungin and several other antifungals, including voriconazole.2 Caspofungin and voriconazole demonstrated apparent antimicrobial synergy in a rodent model of invasive aspergillosis, although the 100% survival with voriconazole alone could not be improved upon.3 Synergy has been demonstrated in experimental pulmonary aspergillosis between caspofungin and ravuconazole.4 In addition, there are no pharmacokinetic interactions between azole voriconazole and caspofungin, and no increase in toxicity appears to result from their use in combination. These characteristics have made the use of these drugs in combination in an attempt to improve survival in invasive aspergillosis a tempting prospect.

Others have reported their experience with the use of caspofungin with either voriconazole or amphotericin in patients with variable, and often, difficult to interpret results.2 In a retrospective study of patients with hematologic malignancy who had received salvage therapy for definite or probable invasive aspergillosis, the response rates for 38 patients who received an amphotericin B lipid formulation was 5%, while it was 20% for caspofungin recipients (n = 15), and 14% for those who received both drugs (n = 42) (P > 0.1).5 A review by the same group of patients who had received either posaconazole or caspofungin plus an amphotericin B lipid formulation for salvage therapy, found no significant difference in outcome.6

This single center study evaluated a very small number of patients and was retrospective, non-randomized, and non-concurrent. As indicated above, the limited experience reported from some other centers is not confirmatory of these results. Nonetheless, the study is highly provocative, and most of all, provides the rationale for a randomized clinical trial. Such a trial, however, is likely to be prohibitively costly in dollars and time because of the very large sample size required.

It must be remembered that the only thing we know about the treatment of invasive aspergillosis from randomized clinical trials, is that voriconazole is superior to amphotericin B deoxycholate as primary therapy. We do not know the relative efficacy of voriconazole vis a vis lipid formulations of amphotericin B, caspofungin, or even itraconazole. It is possible that one or the other of these are superior to voriconazole. Thus, there remains a great deal of work to be done.

The story, however, does not end at the issue of 2 drug combinations. In vitro synergy with caspofungin against Aspergillus spp. has been reported with sulfamethoxazole,7 flucytosine, flucytosine plus amphotericin, and with flucytosine plus voriconazole.8 Subinhibitory concentrations of amphotericin B have an additive effect against Aspergillus spp., when added to caspofungin together with either voriconazole or ravuconazole in vitro.9

The major downside to combination therapy of caspofungin with voriconazole is increased cost. We may never, unfortunately, have the randomized trial data necessary to conclusively resolve the issue of combination therapy for invasive aspergillosis. In the meantime, it is undeniable that the use of these drugs in combination should be considered in the therapy of patients with invasive aspergillosis failing amphotericin B. The data, however, provide us no insight with regard to the currently more common situation, salvage therapy in patients failing voriconazole monotherapy. To complicate matters further, some clinicians are using the combination of voriconazole and caspofungin for primary therapy as well. All of this is a demonstration that much current decision making in the management of patients with life-threatening fungal infections remains more an art than a science.

References

1. Herbrecht R, et al. Voriconazole vs Amphotericin B For Primary Therapy of Invasive Aspergillosis. N Engl J Med. 2002;347:408-415.

2. Deresinski SC, et al. Caspofungin. Clin Infect Dis. 2003;36:1445-1457.

3. Kirkpatrick WR, et al. Efficacy of Caspofungin Alone and in Combination With Voriconazole in a Guinea Pig Model of Invasive Aspergillosis. Antimicrob Agents Chemother. 2002;46:2564-2568.

4. Petraitis V, et al. Combination Therapy in Treatment of Experimental Pulmonary Aspergillosis: Synergistic Interaction Between An Antifungal Triazole and An Echinocandin. J Infect Dis. 2003;187:1834-1843.

5. Raad II, et al. Caspofungin, Amphotericin B Lipid Formulations or the Combination As Salvage Therapy For Invasive Aspergillosis in Patients With Hematologic Malignancy. 42nd Annual Meeting of the Infectious Disease Society of America, September 30-October 3, 2004, Boston, Massachusetts. Abstract 679.

6. Raad II, et al. Posaconazole Compared to Amphotericin B Lipid Formulations in Combination With Caspofungin As Salvage Therapy For Invasive Aspergillosis in Patients With Hematologic Malignancy. 44th ICAAC Meeting: Washington, DC, Oct 30-Nov 2, 2004, Abstract M-1035.

7. Yekutiel A, et al. In Vitro Activity of Caspofungin Combined With Sulfamethoxazole Against Clinical Isolates of Aspergillus spp. Antimicrob Agents Chemother. 2004;48:3279-3283.

8. Dannaoui E, et al. In Vitro Evaluation of Double and Triple Combinations of Antifungal Drugs Against Aspergillus fumigatus and Aspergillus terreus. Antimicrob Agents Chemother. 2004;48:970-978.

9. O’Shaughnessy EM, et al. Subinhibitory Concentrations of Amphotericin B Enhance the In Vitro Effect of Caspofungin Plus Voriconazole or Ravuconazole Combinations Against Aspergillus Species. 44th ICAAC Meeting: Washington, DC, Oct 30-Nov 2, 2004, Abstract M-249.

Stan Deresinski, MD, FACP, Clinical Professor of Medicine, Stanford; Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, is Editor for Infectious Disease Alert.