Bachli, Esther B.

Schneemann, Markus

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CORRESPONDENCE • CID 2004:38 (15 January) • 3031 5 J A N U A R YCorrespondenceReduction ofNephrotoxicity Associatedwith Amphotericin BDeoxycholateSir—The most compelling argument forreplacing amphotericin B deoxycholate(AmBD) with lipid formulations of am-photericin B (LFABs), as proposed by Os-trosky-Zeisner et al. [1], is that it wouldlead to avoidance of AmBD-associatedtoxicities, among which nephrotoxicity isthe most costly and is associated with thegreatest morbidity. However, aggressivehydration and electrolyte correction (asnoted by Ostrosky-Zeisner et al. [1] andothers [2]), as well as administration viacontinuous infusion (which is not men-tioned by Ostrosky-Zeisner et al. [1], butwhich has been discussed elsewhere [3,4]), may significantly reduce the nephro-toxicity associated AmBD. These measureswere not systematically used in the com-parative trials that showed a reduction innephrotoxicity with use of LFABs insteadof AmBD [1]. Before the much morecostly LFABs are adopted for routine useinstead of AmBD, it would seem prudentto directly compare the nephrotoxicity ofLFABs with that of AmBD administeredin a maximally nephroprotective fashion.With respect to the various LFABs, Os-trosky-Zeisner et al. [1] advocate “morehead-to-head clinical trials with standard-ized protocols of infusion and toxicitymanagement…to clearly define which for-mulation is superior, if any” (p. 423). Per-haps AmBD should be included in suchstudies.James R. JohnsonVeterans Affairs Medical Center and Departmentof Medicine, University of Minnesota,Minneapolis, MinnesotaReferences1. Ostrosky-Zeichner L, Marr KA, Rex JH, CohenSH. Amphotericin B: time for a new “gold stan-dard.” Clin Infect Dis 2003; 37:415–25.2. Mayer J, Doubek M, Doubek J, Horky D,Scheer P, Stepanek M. Reduced nephrotoxicityof conventional amphotericin B therapy afterminimal nephroprotective measures: animalexperiments and clinical study. J Infect Dis2002; 186:379–88.3. Imhof A, Walter RB, Schaffner A. Continuousinfusion of escalated doses of amphotericin Bdeoxycholate: an open-label observationalstudy. Clin Infect Dis 2003; 36:943–51.4. Eriksson U, Seifert B, Schaffner A. Comparisonof effects of amphotericin B deoxycholate in-fused over 4 or 24 hours: randomised con-trolled trial. BMJ 2001; 322:579–82.Reprints or correspondence: Dr. James R. Johnson, InfectiousDiseases (111F), VA Medical Center, 1 Veterans Dr., Min-neapolis, MN 55417 (johns007@umn.edu).Clinical Infectious Diseases 2004; 38:303 2003 by the Infectious Diseases Society of America. Allrights reserved. 1058-4838/2004/3802-0020$15.00Continuous Infusionof Amphotericin BDeoxycholate: A Cost-Effective Gold Standardfor Therapy of InvasiveFungal Infections?Sir—Ostrosky-Zeichner et al. [1] reviewthe toxicity of amphotericin B deoxycho-late (AmBD) and recommend the newer,very expensive lipid formulations of am-photericin B (LFABs) as the new gold stan-dard for therapy of invasive fungalinfections. Their main concern is nephro-toxicity: up to 30% of patients developacute renal failure while receiving therapywith AmBD, according to Bates et al. [2].However, these investigators administeredAmBD during a 4-h period and did nothydrate the patients appropriately.Unfortunately, in their review, Os-trosky-Zeichner et al. [1] did not discussthe published studies carried out by A.Schaffner’s research group at our institu-tion [3–5]. Using 24-h continuous infu-sion of AmBD in treating ∼60 severelyimmunocompromised patients per year,we observe acute renal failure very rarely.This is because we combine antifungaltreatment with daily monitoring and ag-gressive correction of electrolyte levels andhydration. This observation has recentlybeen confirmed clinically and experimen-tally by another research group [6]. Evenin patients receiving high doses (i.e., 11mg/kg of AmBD in a 24-h continuous in-fusion) or receiving concomitant treat-ment with nephrotoxic ciclosporin A,treatment with AmBD very rarely leads toacute renal failure [4, 5].Equivalent doses of LFABs are ∼10times more expensive than doses ofAmBD. We currently save several hun-dreds of thousands of US dollars per yearby not using LFABs. We think it is pre-mature to establish LFABs as the gold stan-dard for therapy of invasive fungal in-fections. We ask for a study of cost-effectiveness comparing equivalent dosesof the new LFABs to 24-h continuous in-fusion of AmBD. Hospital managers andthose interested in cutting health care costsshould demand these studies before im-plementing costly new gold-standardtherapies.Markus Schneemann and Esther B. BachliDepartment of Medicine,University of Zu¨rich, SwitzerlandReferences1. Ostrosky-Zeichner L, Marr KA, Rex JH, CohenSH. Amphotericin B: time for a new “gold stan-dard.” Clin Infect Dis 2003; 37:415–25.2. Bates DW, Su L, Yu DT, et al. Mortality andcosts of acute renal failure associated with am-photericin B therapy. Clin Infect Dis 2001; 32:686–93.3. Eriksson U, Seifert B, Schaffner A. Comparisonof effects of amphotericin B deoxycholate in-fused over 4 or 24 hours: randomised con-trolled trial. BMJ 2001; 322:579–82.304 • CID 2004:38 (15 January) • CORRESPONDENCETable 1. Data on sales of amphotericin B (AmB) formulations in the United States, 2000.Type of AmB, brand nameQuantityper vial,mgCostper vial,aUS$Dailydose,bmgEstimatedno. of vialsper daily doseNo. ofvialsdistributedcNo. ofdosesadministereddEstimatedsales,c US$Estimatedcost perdose,e US$LFABsAmbisome (liposomal) 50 157 350 7 808,000 115,000 … …Abelcet (lipid-complex) 100 85 350 4 739,000 185,000 … …50 NA 350 7 22,200 3,000 … …Amphotec (colloidal dispersion) 100 NA 350 4 14,500 3,500 … …50 NA 350 7 2,800 500 … …Total … … … … 1,586,500 307,000 180,000,000 585AmBDFungizone 50 4.50 35 0.7 345,500 500,000 … …Amphotericin B 50 4.50 35 0.7 200,600 290,000 … …Amphocin 50 4.50 35 0.7 6,500 10,000 … …Total … … … … 552,600 800,000 3,300,000 4.50NOTE. AmBD, amphotericin B deoxycholate; LFABs, lipid formulations of amphotericin B; NA, not available.a Data on cost per vial provided by Jennifer Yi of Harbor-University of California Los Angeles Medical Center.b Data assumes a mean body mass of 70 kg and a daily dose of 0.5 mg/kg per day, for AmBD, and 5 mg/kg per day, for LFABs.c Data on no. of vials distributed and estimated sales provided by IMS Health (Fairfield, Connecticut).d No. of doses administered is calculated by dividing the number of vials distributed by the estimated number of vials used per daily dose.e The estimated cost per dose is calculated by dividing the estimated sales by the number of doses administered.4. Furrer K, Schaffner A, Vavricka SR, Halter J,Imhof A, Schanz U. Nephrotoxicity of cyclo-sporine A and amphotericin B-deoxycholate ascontinuous infusion in allogenic stem celltransplantation. Swiss Med Wkly 2002; 132:316–20.5. Imhof A, Walter RB, Schaffner A. Continuousinfusion of escalated doses of amphotericin Bdeoxycholate: an open-label observationalstudy. Clin Infect Dis 2003; 36:943–51.6. Mayer J, Doubek M, Doubek J, Horky D,Scheer P, Stepanek M. Reduced nephrotoxicityof conventional amphotericin B therapy afterminimal nephroprotective measures: animalexperiments and clinical study. J Infect Dis2002; 186:379–88.Reprints or correspondence: Dr. Markus Schneemann, Dept.of Medicine, Medical Clinic B, Ramistrasse 100, Zurich CH-8091, Switzerland (markus.schneemann@usz.ch).Clinical Infectious Diseases 2004; 38:303–4 2003 by the Infectious Diseases Society of America. Allrights reserved. 1058-4838/2004/3802-0021$15.00Amphotericin B: Is a Lipid-Formulation Gold StandardFeasible?Sir—We read with interest the article byOstrosky-Zeichner et al. [1] proposingthat lipid-based formulations of ampho-tericin B (LFABs) replace amphotericin Bdeoxycholate (AmBD) as the gold stan-dard for treatment of most invasive my-coses. On the basis of a review of com-parative efficacy, toxicity, and cost, webelieve AmBD remains a viable first-lineagent.Although the benefits of LFABs havebeen described in relation to secondary,microbiological end points in clinical trials[2, 3], primary end points have not dem-onstrated the superior efficacy of LFABsversus AmBD. In a randomized study ofpatients with histoplasmosis and AIDS,only 1 of 3 primary end points showed anapparent benefit of treatment with lipo-somal amphotericin rather than withAmBD [4]. The only outcome measure-ment that demonstrated the superiority oftreatment with liposomal amphotericinwas “clinical success,” which was a com-posite end point that included the require-ment that the patient be afebrile for 3 days.If any fever occurred during that time, in-cluding during drug infusion, the treat-ment was considered a clinical failure. Theapparent difference in the efficacy LFABsand AmBD may therefore have beencaused by a difference in infusion-relatedadverse events, rather than by a true dif-ference in efficacy.Moreover, AmBD-induced toxicitiesare usually treatable (e.g., infusion reac-tions) or reversible (e.g., anemia and az-otemia) if treatment with the drug is dis-continued in a timely manner [5–7].Patients who develop toxicities can begiven an LFAB, limiting the global impactof toxicity caused by the deoxycholateformulation.Finally, the cost of LFABs is prohibitive.In the year 2000, sales of LFABs in theUnited States were $180 million, versus$3.3 million for AmBD (table 1). Indeed,despite strictly enforced limitations ontheir use at our institution, LFABs havebeen the number one pharmacy cost foreach of the previous 5 years. Of the ∼1650drugs administered to patients at Harbor-UCLA Medical Center in 2001, LFABs ac-counted for 5% of all pharmacy costs.If LFABs became the new gold standard,the financial impact would be enormous.For example, if 75% of the doses of AmBDadministered in the United States in theyear 2000 had been administered asLFABs, the additional cost incurred wouldhave been approximately $240 million(75% of 550,000 doses  $580 in addi-tional cost per dose). Although some ofthe cost differential might be mitigated bysavings that result from a decrease in in-

Continuous Infusion of Amphotericin B Deoxycholate: A Cost-Effective Gold Standard for Therapy of Invasive Fungal Infections?

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