Continuous Amphotericin Infusion

Abstract & Commentary

Synopsis: Amphotericin B deoxycholate was administered by continuous infusion in doses as high as 2 mg/kg/d with acceptable toxicity. But is this the right approach?

Source: Imhof A, et al. Continuous infusion of escalated doses of amphotericin B deoxycholate: An open-label observational study. Clin Infect Dis. 2003;36:943-951.

Imhof and colleagues evaluated the possibility that continuous infusion of amphotericin B deoxycholate might allow administration of higher doses without a parallel increase in toxicity. After an initial dose of 1 mg/kg administered over 24 hours, the daily dose was gradually escalated to 1.5 mg/kg/d, 1.75 mg/kg/d, or 2 mg/kg/d. Dose escalation proved possible in 28 of 33 patients. The median duration of amphotericin therapy was 16 days (range, 7-72 days).

Eighteen percent of 727 administrations involving 17 patients (52%) were associated with infusion-related toxicity. A decrease in creatinine clearance was observed in 27 (82%) patients, and a greater than 50% decrease was seen in 5 of these patients. Nonetheless, this adverse effect was dose limiting in only 1 patient, and none required dialysis. One patient developed respiratory decompensation thought to be related to volume overload, and 1 patient had grade 3 hepatotoxicity.

Twenty-four patients were alive at the end of treatment. While death had been deemed unrelated to fungal infection in the other 9, evidence of invasive fungal infection was found at postmortem examination in 3 of these patients.

Comment by Stan Deresinski, MD, FACP

This group of investigators previously compared the continuous infusion of amphotericin B deoxycholate to its administration over 4 hours each day in a randomized trial.1 They concluded that the former mode of delivery was associated with a reduced risk of both infusion-related adverse events and of nephrotoxicity. In the current study, they concluded that "continuous infusion of amphotericin B deoxycholate escalated to 2.0 mg/kg/d seems not to cause additional impairment of vital organ functions and to be well tolerated by most patients."

This investigation was, however, not randomized, making it difficult to know what the relative toxicity of amphotericin B at these dose levels would be relative to a shorter infusion. The goal of antimicrobial therapy is, however, not to administer the maximally tolerated dose of drug but to control or eradicate infection. One cannot discern from this study whether the approach taken by Imhof et al is associated with improved outcomes, since this was not studied and since the study design did not include randomization to a standard approach to amphotericin administration. Since current evidence favors the notion that the antifungal effect of amphotericin is concentration-dependent, rather than time-dependent, and that amphotericin has a prolonged post-antifungal effect, there is reason to suspect that better outcomes might not result from this strategy.2, 3

With drugs that have concentration-dependent antimicrobial effects, the accepted strategy is to maximize peak serum concentrations. The switch to once-daily administration of aminoglycosides from the past practice of repeated intermittent administrations is an example of exploitation of concentration-dependent killing. Thus, even if continuous infusion does allow administration of higher doses of amphotericin B, it is not clear to me what the point of this approach is.

Dr. Derenski is Clinical Professor of Medicine, Stanford; Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center.

References

1. Eriksson U, Seifert B, Schaffner A. Comparison of effects of amphotericin B deoxycholate infused over 4 or 24 hours: Randomized controlled trial. BMJ. 2001; 322:579-582.

2. Groll AH, et al. Antifungal pharmacodynamics: Concentration-effect relationships in vitro and in vivo. Pharmacotherapy. 2001;21:133S-148S.

3. Andes D. In vivo pharmacodynamics of antifungal drugs in treatment of candidiasis. Antimicrob Agents Chemother. 2003;47:1179-1186.