Double-blind randomized study of the effect of infusion rates on toxicity of amphotericin B

Abstract

Results of a double-blind randomized non-crossover study of rapid (45 min) versus slow (4 h) infusion of amphotericin B administered to 20 patients with proven or suspected fungal infection are reported. Toxicity was higher in the rapid infusion group than it was in the slow infusion group (mean total 7-day chill score, 173 ± 276 versus 20 ± 30 [P < 0.01]; mean total 7-day dosage of meperidine required to abate rigors, 180 ± 133 versus 58 ± 78 mg [P < 0.05]; and mean maximum total 7-day pulse rise, 225 ± 64 versus 135 ± 56 beats per min [P < 0.02], respectively). When analyzed on a daily basis, the mean chill score, meperidine dosage, and pulse rise were also higher; and in addition, nausea and vomiting (5 of 11 patients who received a rapid infusion versus 0 of 9 patients who received a slow infusion [P < 0.01]) appeared to be more common in those who received amphotericin B rapidly. The daily analysis approach proved that tolerance to these side effects developed with each subsequent infusion day, and by day 7 the incidence and severity were the same. This development of tolerance was signfficant for the mean chill score in the rapid infusion group (P < 0.05) and for the proportion of patients with chills (P < 0.005 for the slow infusion group; P < 0.05 for the rapid infusion group). A decrease in creatinine clearance to >51% of the baseline value was seen in two patients in each group. There were five deaths (four in the rapid infusion group, 1 in the slow infusion group) within 1 month, but none was clearly related to the amphotericin B infusion. The mean time to defervescence was similar for each group (10.8 ± 4.1 days in the slow infusion group versus 9.9 ± 5 days in the rapid infusion group). A rapid infusion regimen for amphotericin B cannot be recommended, at least during the first 5 to 7 days of treatment.Amphotericin B is an antimycotic polyene antibiotic that is commonly used for the treatment of proven or suspected severe fungal infections. Its administration requires intravenous access and, conventionally, a 6-h-daily infusion for days, weeks, or months, depending on the nature of the fungal infection. The prolonged infusion time consumes excessive patient and nursing time, but it is said (9) to be necessary to minimize the formidable toxicity of amphotericin B, which includes rigors, hypotension, renal toxicity, and cardiac dysrhythmias. Occasional anecdotal reports (11) and studies (2, 5) have suggested no increase in toxic side effects if amphotericin B is administered over a much shorter period. The present study compares the toxicities of rapid versus slow amphotericin B infusion rates when it is given to patients with proven or suspected fungal infections. MATERIALS AND METHODSTwenty patients with suspected or proven severe fungal infections were randomly ascribed by a computer-generated code held by the Department of Pharmacy Services, King Faisal Specialist Hospital and Research Centre, to receive amphotericin B over either 45 min (rapid infusion) or 4 h (slow infusion). Patients were recru...

Safety and effectiveness of amphotericin B deoxycholate for the treatment of visceral leishmaniasis in Uganda

“…There is some evidence that a relatively slow infusion of AmB (4 h v. 45 min) reduces the occurrence of infusion-related adverse effects (Ellis et al, 1992). Although the administration of AmB by continuous infusion over 24 h appears to reduce nephrotoxicity (Eriksson et al, 2001), such long infusions were not feasible at Amudat Hospital.…”

Continuously infused amphotericin B deoxycholate for primary treatment of invasive fungal disease in acute myeloid leukaemia

“…But importantly, we administer D‐AmB as a 24‐hour continuous infusion (24 h‐D‐AmB) to allow better tolerability and longer treatment duration . Slow infusion rates are known to lead to fewer side effects and less toxicity than 4‐hour infusions . We here report the safety and efficacy of D‐AmB given as a 24‐hour continuous infusion in patients with acute myeloid leukaemia (AML) and severe prolonged neutropenia following myeloablative chemotherapy.…”

Continuous versus Conventional Infusion of Amphotericin B Deoxycholate: A Meta-Analysis

“…[23], [24] A meta-analysis on the adverse events of the antifungal agents used against IFIs has shown that AmB deoxycholate is the most nephrotoxic AmB formulation, while the lipid formulations are less nephrotoxic. [25] Several lines of evidence from pharmacokinetic and non-comparative clinical studies have suggested that continuous infusion of AmB deoxycholate might reduce the nephrotoxicity of the drug [26], [27], [28].…”