JAC Advance Access originally published online on May 30, 2007
Journal of Antimicrobial Chemotherapy 2007 60(1):180-182; doi:10.1093/jac/dkm147
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Correspondence |
Amphotericin B deoxycholate: no significant advantage of a 24 h over a 6 h infusion schedule
Department of Haematology and Oncology, University Hospital, 93042 Regensburg, Germany
* Corresponding author. Tel/Fax: +49-941-944-5538; E-mail: stefan.krause{at}klinik.uni-r.de
Keywords: continuous infusion , nephrotoxicity , antifungals , antimycotic , empirical antifungal therapy
In a publication in this journal, Peleg and Woods1 described a retrospective analysis demonstrating reduced toxicity and improved survival in neutropenic patients receiving amphotericin B deoxycholate (AmB) by continuous infusion. AmB is a broad-spectrum antimycotic drug widely used for the therapy of fungal infections or therapy-resistant fever during neutropenia. During AmB therapy, severe side effects may occur, including nephrotoxicity and acute reactions with fever and chills. These side effects are one reason why AmB is increasingly replaced by newer drugs and new (liposomal) preparations of amphotericin B; however, the latter are all of considerably higher costs. Therefore, attempts were made to decrease AmB toxicity by modified application schemes. In 2001, Eriksson et al.2 reported that application of AmB by continuous infusion considerably decreased its toxicity and similar effects were reported by Peleg and Woods.1
Here, we report that a similar positive effect of continuous AmB infusions could not be reproduced in our institution. Similar to Peleg and Woods, we performed a retrospective analysis of AmB therapy before and after a switch of our AmB infusion regimen to continuous infusions. The major endpoint of our analysis was toxicity according to common toxicity criteria (CTC). Further endpoints were duration of AmB infusions and switch to second-line antimycotics versus defervescence and death. On the basis of the results of Eriksson et al.,2 we adopted a 24 h infusion schedule in July 2001. Before this change in patient management, AmB was infused over 6 h. The 6 h schedule had been optimized beforehand in an attempt to minimize side effects of AmB. Regular supportive therapy included paracetamol (acetaminophen, 500 mg), pentoxyfylline (600 mg), dimethindene (4 mg, an H1 blocker) and 0.9% NaCl (500 mL) before start of infusion of AmB as well as a second infusion of 0.9% NaCl (500 mL) and two additional doses of pentoxyfylline (600 mg) after AmB infusion. Potassium and magnesium were substituted as indicated by regular serum controls. In the 24 h schedule, 0.9% NaCl (1000 mL/24 h) was infused as in the 6 h schedule, but paracetamol, dimethindene and pentoxyfylline were not routinely administered. Substitution of potassium and magnesium were started from the first day of AmB and dose-adjusted as needed. AmB was applied at a dose of 1 mg/kg body weight per day in both schedules.
To be eligible for our retrospective analysis presented here, patients had to be at a high risk of fungal infection, i.e. they were subjected to allogeneic stem cell transplantation or to aggressive cytostatic treatment leading to an expected duration of neutropenia [absolute neutrophil count (ANC) < 0.5/nL] of more than 10 days. Treatment had to be started in the 12 months before or in the 12 months after the change of our AmB schedule from 6 h infusion to continuous infusion. Two hundred and twenty treatment episodes of 105 patients were screened. Six chemotherapy treatment cycles were counted together with the preceding chemotherapy cycle as one treatment, because patients were already on overlapping AmB initiated during the preceding neutropenic episode, leaving 214 treatment cycles for analysis. In 56 patients, during 67 of the ensuing neutropenic episodes, AmB was initiated because of suspected fungal infection. Six ‘pilot patients’ were treated with 24 h AmB in the first part of the study period (before July 2001) and one patient was treated by 6 h AmB after July 2001. In six patients, AmB treatment was started, stopped due to defervescence or switched to second-line antimycotic treatment, and re-instated a second time during the same chemotherapy cycle. In these patients, only the first AmB treatment was analysed for this report.
Many cases had to be considered ‘possible’ fungal infection according to the definitions of Ascioglu et al.3 or had only pulmonary infiltrates as the single criterion for a possible fungal infection; however, all patients with fever and pulmonary infiltrates are routinely treated with broad-spectrum antifungals in our institution.4 Most patients were treated without definite suspicion of fungal infection because of fever persisting for more than 72–96 h despite antibacterial therapy. AmB was initiated more frequently during the second part of our observation period, i.e. after the summer of 2001. This may not reflect a real increase in the systemic fungal infections, but rather a greater alertness of treating physicians for this condition and a higher number of CT scans leading to more frequent detection of pulmonary infiltrates.
There was no significant difference in patient characteristics (age, chemotherapy versus transplantation) between the 6 h and the 24 h cohort. Actual duration of leucopenia was slightly longer in the 24 h cohort (median 19 versus 15 days), but this difference was not statistically significant (P = 0.08, Mann–Whitney test). Side effects and overall results did not differ significantly between the 6 h and the 24 h treatment schedules. Renal impairment as well as acute reactions occurred in roughly the same percentage of patients (Table 1). Acute side effects of our 6 h cohort have probably been lower than described by others because of the regular use of acetaminophen, pentoxyfylline and dimethindene, whereas these drugs could be safely omitted in the 24 h group. Both groups were treated by saline infusions and by substitution of potassium and magnesium as recommended; nevertheless, in both cohorts, at least mild renal impairment developed in half of the patients. A switch to second-line antimycotics was also performed at the same percentage in both patient cohorts, either due to persisting fever or due to side effects. Mean duration of AmB therapy was slightly longer with 24 h infusions than with 6 h infusions (median 10.5 versus 7 days on AmB), because renal impairment on average developed slightly more slowly in the 24 h infusion cohort, but this trend was not significant (P = 0.44, Mann–Whitney test). The 4 week survival rate was not significantly different (P = 0.43, Fisher's exact test). Overall, no difference in outcome was observed.
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Taken together, at least in our hands, continuous infusion of AmB turned out to be feasible. It had the advantage of being well tolerated regarding acute side effects without the need for pre-medication except electrolyte solutions, and the number of days on AmB therapy was slightly increased when compared with 6 h infusions. However, continuous infusions did not eliminate the nephrotoxicity that is frequently induced by this drug and did not change the outcome in our cohort. The problem of nephrotoxicity can be avoided by alternative preparations of amphotericin B than AmB deoxycholate or by newer antifungals,5 but at considerably higher drug expenses.
This study was supported by an unrestricted grant form Gilead Sciences.
S. W. K. has received travel expenses from Gilead Sciences and speaker's fees from Ortho Biotech.
References
1
Peleg AY, Woods ML. Continuous and 4 h infusion of amphotericin B: a comparative study involving high-risk haematology patients. J Antimicrob Chemother (2004) 54:803–8.
2
Eriksson U, Seifert B, Schaffner A. Comparison of effects of amphotericin B deoxycholate infused over 4 or 24 hours: randomised controlled trial. BMJ (2001) 322:579–82.
3 Ascioglu S, Rex JH, de Pauw B, et al. Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clin Infect Dis (2002) 34:7–14.[CrossRef][Web of Science][Medline]
4 Maschmeyer G, Link H, Hiddemann W, et al. Pulmonary infiltrations in febrile patients with neutropenia. Risk factors and outcome under empirical antimicrobial therapy in a randomized multicenter study. Cancer (1994) 73:2296–304.[CrossRef][Web of Science][Medline]
5 Girois SB, Chapuis F, Decullier E, et al. Adverse effects of antifungal therapies in invasive fungal infections: review meta-analysis. Eur J Clin Microbiol Infect Dis (2006) 25:138–49.[CrossRef][Web of Science][Medline]
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