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Abstract & Commentary
Synopsis: Both simultaneous and sequential administration of fluconazole and amphotericin B were antagonistic against Candida albicans in vitro and in an animal model of infection.
Source: Louie A, et al. Impact of the order of initiation of fluconazole and amphotericin B in sequential or combination therapy on killing of Candida albicans in vitro and in a rabbit model of endocarditis and pyelonephritis. Antimicrob Agents Chemother. 2001;45:485-494.
Is treatment of serious fungal infections with a combination of amphotericin B and an azole antifungal reasonable? Is the use of these drugs in sequence effective?
Louie and colleagues in Albany, NY, evaluated the interaction, sequentially or combinationally, of fluconazole and amphotericin B on 4 strains of Candida albicans both in vitro and in vivo. Amphotericin B was rapidly fungicidal against each strain in vitro, while fluconazole was only fungistatic (MICs 0.125 mg/mL-0.25 mg/mL for both antifungals).
When the strains were incubated in vitro with the 2 drugs simultaneously, fluconazole had no effect when the amphotericin B concentration was 1.0 mg/mL or more but was antagonistic at a lower concentration. When incubated initially with fluconazole with the subsequent addition of amphotericin B, antagonism resulted; only fungistasis, similar to that seen with fluconazole alone, was detected. This induced resistance was transient with its duration increasing with the duration of preincubation with fluconazole; after 18 hours of preincubation, the effect lasted for 6 to more than 40 hours. Preincubation for only 2-6 hours had no effect.
These findings were reflected in the results seen in rabbit models of C albicans pyelonephritis and of endocarditis. These experiments were not designed to detect differences in mortality, and none were found. Rapid sterilization of kidneys and cardiac vegetations resulted from the administration of amphotericin B alone or from the administration of amphotericin B alone for 24 hours followed by the addition of fluconazole. Clearance of organisms was, however, significantly slower in animals given the 2 drugs simultaneously or when amphotericin was added to existing fluconazole therapy. Fluconazole alone and fluconazole followed by the addition of amphotericin B were the least active regimens.
Comment by Stan Deresinski, MD, FACP
This in vitro and in vivo animal model study indicates that the simultaneous administration of amphotericin B and fluconazole is less effective than amphotericin alone and no more effective than fluconazole alone. This antagonistic interaction, if true in the clinical setting, means that the only effect of the combination is the loss of efficacy of amphotericin B, along with retention of its toxicity.
Furthermore, these data suggest that the commonly used approach of initiating treatment with amphotericin B and then, after clinical improvement occurs and/or susceptibility data are available, changing to fluconazole therapy, is safe. The opposite does not appear to be the case however; starting with fluconazole and then switching to amphotericin B may lead to antifungal antagonism that can persist for as long as 72 hours.
These results are consistent with some, but not all, prior reports. Vazquez and colleagues previously reported that pretreatment of C albicans and C tropicalis with either fluconazole or itraconazole isolates resulted in resistance to amphotericin B that persisted for several days.1 Others have also reported that azoles inhibited the fungistatic activity of amphotericin B with simultaneous incubation against C albicans when both drugs were used at subinhibitory concentrations.2 However, while preincubation with high concentrations of the lipophilic azoles (miconazole, ketoconazole, and itraconazole) resulted in antagonism, this was not the case with the more hydrophilic fluconazole. Consistent with the in vivo results reported by Louie et al, another group has previously demonstrated that both sequential and combination treatment with itraconazole and amphotericin B were antagonistic in a murine model of invasive C albicans infection.3
In vitro antagonism between amphotericin B and azoles against Aspergillus fumigatus has also been observed.4-6 Exposure of isolates of A fumigatus, both in vitro and in a murine model, led to lack of subsequent response to amphotericin B.6 Some investigators, however, have failed to find evidence of antagonism with simultaneous in vitro exposure.7
Assuming that these results are applicable to the treatment of human infection, several potential therapeutic implications emerge. The combination of amphotericin B and an azole is not an effective approach to the therapy of invasive Candida or Aspergillus infections. Similarly, switching from an azole to amphotericin B may lead to a window period during which antifungal antagonism is present. This practice is less uncommon than one might think when one considers the use of azoles for prophylaxis in immunocompromised patients at risk of fungal infections. Such patients are routinely given amphotericin when fungal infections break through their prophylaxis.
1. Vazquez JA, et al. Stable phenotypic resistance of Candida species to amphotericin B conferred by preexposure to subinhibitory levels of azoles. J Clin Microbiol. 1998;36:2690-2695.
2. Scheven M, Schwegler F. Antagonistic interactions between amphotericin B with yeasts depend on azole lipophilia for special test conditions in vitro. Antimicrob Agents Chemother. 1995;39:1779-1783.
3. Sugar AM, Liu XP. Interactions of itraconazole with amphotericin B in the treatment of murine invasive candidiasis. J Infect Dis. 1998;177:1660-1663.
4. Kontoyiannis DP, et al. Itraconazole-amphhotericin B antagonism in Aspergillus fumigatus: An E-test-based strategy. Antimicrob Agents Chemother. 2000;44: 2915-2918.
5. Schmitt HJ, et al. Combination therapy in a model of pulmonary aspergillosis. Mycoses. 1991;34:281-285.
6. Schaffner A, Bohler A. Amphotericin B refractory aspergillosis after itraconazole: Evidence for significant antagonism. Mycoses. 1993;36:421-424.
7. Denning DW, et al. In vitro susceptibility and synergy studies of Aspergillus species to conventional and new agents. Diagn Microbiol Infect Dis. 1992;15:21-34.