Which Amphotericin for Neutropenic Fever?
Abstract & Commentary
Fungal infections are increasing in incidence in neutropenic patients. There are several causes for this, not the least of which is the fact that patients are living longer due to better prophylaxis against bacterial and viral infection. As a result, intensivists are more often faced with patients with neutropenic fever. High proportions of patients with persistent fever while neutropenic have occult fungal infection. The majority of these patients who develop pulmonary infiltrates require antifungal agents to resolve the pneumonia. The conventional treatment for persistent neutropenic fever is amphotericin B. Toxicity, especially nephrotoxicity, limits the dose of drug that can be given. Daily dosing usually is limited to 1.0 to 1.5 mg/kg. Several available lipid-based amphotericin B preparations are associated with fewer side effects and therefore can be dosed at higher daily levels. The National Institutes of Allergy and Infectious Diseases Mycoses Study Group conducted a randomized, double-blinded, multicenter trial to compare the efficacy and toxicities of liposomal amphotericin B (AmBisome*) with conventional amphotericin B in the empirical treatment of fever in persistently neutropenic patients. The study used well-recognized parameters for defining persistent neutropenic fever. Walsh and colleagues randomized a total of 687 patients in this study. The mean daily dose of each agent was amphotericin B, 0.6 mg/kg, and liposomal drug, 3.0 mg/kg. Durations of treatment were not significantly different in the two patient groups.
There were no significant differences in successful treatments between the groups (50% for liposomal amphotericin B, 49% for conventional amphotericin B). Neither antifungal prophylaxis nor growth factor use influenced success. In addition, there were no significant differences in survival (93% and 90%), resolution of fever (58% for each), or discontinuation of the drugs due to toxicity or lack of efficacy (14% and 19%). Toxicity was less common with the liposomal preparation compared to conventional amphotericin B. There was less frequent nephrotoxicity (creatinine more than twice the upper limits of normal; 19% and 34%), infusion-related fever (17% and 44%), chills or rigors (18% and 54%), and breakthrough fungal infection (3% and 8%) with the liposomal preparation. (Walsh TJ, et al. N Engl J Med 1999;340:764-771.)
Comment by Stephen W. Crawford, MD
Currently, there is only one published study that reports a superior outcome of a lipid-based amphotericin B compared to conventional amphotericin B in treatment of fungal infection in neutropenia (Leenders AC, et al. Br J Haematol 1998;103:205-212). However, all studies uniformly conclude that any of the three available lipid preparations cause fewer side effects, especially renal impairment. This NIAID study is important because of its size. However, it does not give us the definitive answer about whether to use conventional amphotericin B or a lipid-based version. Toxicity is less: not absent, but less. This alone does not warrant the significant additional cost of the liposomal amphotericin B. Outcome is not different in empirical treatment in neutropenic fever. In most cases, I believe we should use conventional amphotericin B for empirical treatment and consider alternative agents in the case of severe toxicity.
Should we use lipid-based amphotericin B in the case of proven (or highly suspected) invasive fungal infection? The answer is not yet in. It is clear from numerous studies that the critical determinant of successful outcome of invasive fungal infection in the neutropenic patient is the recovery of granulocyte numbers and function; the choice of antifungal agent may be of secondary importance. In addition, the mortality rate for neutropenic patients with proven or suspected invasive pulmonary aspergillosis is high and there are many competing causes of death in these patients. Demonstrating a benefit from any change in therapy will be difficult.
In general, I still advocate initiating treatment with conventional amphotericin B for most immunosuppressed patients with persistent neutropenic fever or suspected fungal infection. However, the immunosuppressed patient in the intensive care unit may present a specific case for starting with a lipid-based amphotericin B. The presence of other critical illness (particularly renal insufficiency) in such a patient may warrant assuming the additional cost of these drugs in an effort to limit as much as possible additional toxicity. This NIAID-sponsored study suggests that when we do not know the best way to cure, we should choose the way least likely to harm the patient.
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