Changes in renal function after changes in antifungal drug therapy

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Amphotericin B, a broad-spectrum antifungal agent that has been available for more than 30 years, is still the drug of choice for many serious fungal infections.
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Changes in renal function after changes in antifungal drug therapy OLGA M. KLIBANOV, RALPH H. RAASCH, AND JOHN C. RUBLEIN Am J Health-Syst Pharm. 2004; 61:50-3

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mphotericin B, a broad-spectrum antifungal agent that has been available for more than 30 years, is still the drug of choice for many serious fungal infections. Amphotericin B deoxycholate is the conventional formulation of amphotericin B; however, multiple drug-related toxicities are associated with its use. Nephrotoxicity is a major amphotericin B-related complication and appears to be associated with higher cumulative doses, use of diuretics, abnormal serum creatinine (SCr) levels at baseline, and use of concomitant nephrotoxic drugs.1-4 Wingard et al.4 reviewed the medical records of 239 patients to determine the rates of nephrotoxicity, hemodialysis, and death following conventional amphotericin B therapy for aspergillosis. After a median of seven days of therapy, SCr levels doubled in 127 patients (53%). Hemodialysis was administered to 35 patients (15%). Concomitant administration of nephrotoxic agents (cyclosporine, tacrolimus, aminoglycosides) was associated with a greater likelihood of a need for hemodialysis. The overall mortality rate was 60%, and receiving hemodialysis and the use of nephrotoxic agents were the factors significantly associated with mortality. Bates et al.5 reported that, for 707 adult admissions in which amphotericin B was given, there were 212 episodes of acute renal failure (30%). The mortality rate was higher in patients who developed

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acute renal failure than in those who did not (54% versus 16%) (p = 0.001). Each patient with acute renal failure spent a mean of 8.2 days longer in the hospital and accounted for an adjusted increase in total costs of $29,823 (p < 0.001).5 Lipid formulations of amphotericin B, including liposomal amphotericin B, amphotericin B lipid complex, and amphotericin B colloidal dispersion, have been manufactured in attempts to circumvent amphotericin B-related toxicities.6 Studies of the efficacy and safety of lipid preparations of amphotericin B consistently found that the frequency of renal toxicity associated with the newer formulations was reduced by at least 50% compared with amphotericin B deoxycholate.7-10 The newer broad-spectrum antifungals caspofungin and voriconazole are also associated with less nephrotoxicity than amphotericin B.11-13 In patients with invasive aspergillosis, renal impairment (definition not provided) occurred in 19 (10%) of 185 patients randomized to amphotericin B, compared with 2 OLGA M. KLIBANOV, PHARM.D., is Clinical Assistant Professor, School of Pharmacy, Temple University, Philadelphia, PA; at the time of this study she was Infectious Diseases Specialty Resident, University of North Carolina Hospitals (UNC Hospitals), and Clinical Instructor, School of Pharmacy, University of North Carolina, Chapel Hill. R ALPH H. RAASCH, PHARM.D., FCCP, BCPS, is Associate Professor of Pharmacy, UNC School of Pharmacy. JOHN C. RUBLEIN, PHARM.D., BCPS, is

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(1%) of 194 patients randomized to voriconazole (p < 0.001).11 In 239 patients with invasive candidiasis, nephrotoxicity, defined as a doubling of the SCr concentration or an increase of at least 1 mg/dL, occurred significantly more often in patients receiving amphotericin B (24.8%) than in those given caspofungin (8.4%) (p = 0.02).12 Walsh et al.14 studied 556 patients who were intolerant of or refractory to conventional amphotericin B therapy and were then switched to amphotericin B colloidal dispersion. Renal dysfunction while receiving amphotericin B deoxycholate was defined as an increase in the SCr concentration to above 2.5 mg/dL. By the end of therapy with amphotericin B colloidal dispersion (median duration, 22 days; range, 1–510 days), SCr levels remained stable in 278 patients (50%), declined in 118 (21%), and increased in 132 (24%). SCr trends were not evaluated in 28 patients (5%) because the number of SCr values was insufficient. Overall, SCr levels declined for the entire sample, becoming significantly different from baseline levels by week 3, and continuing through week 6. Because of the toxicities associated with amphotericin B deoxycholate, many patients at our institution are switched to a lipid formulation of amphotericin B once an increase in serum creatinine is detected. The efClinical Specialist, Infectious Diseases, Department of Pharmacy, UNC Hospitals. Address correspondence to Dr. Klibanov at the Department of Pharmacy Practice, School of Pharmacy, Temple University, 3307 N. Broad Street, Philadelphia, PA 19140 ([email protected]). Copyright © 2004, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/04/0101-0050$06.00.

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fect on renal function of such a switch at our institution was unknown. Also unknown was the effect of switching patients from conventional amphotericin B to caspofungin or voriconazole. The purpose of this study was to quantify the change in SCr levels in patients who had renal toxicity with amphotericin B deoxycholate and were subsequently switched to lipid formulations of amphotericin B, caspofungin, or voriconazole. Secondary objectives included assessing the frequency of changes in antifungal therapy due to infusion-related reactions involving amphotericin B formulations, evaluating mycological cure rates in patients with documented fungal infections, and examining clinical cure rates based on radiologic and symptomatic resolution of findings, as documented in patients’ medical records. Methods. This study was based on a retrospective chart review at a 650bed tertiary care teaching institution. Approval from the institutional review board was obtained, and patients were identified through a pharmacy database for the period from January 1, 2002, to January 1, 2003. Hospitalized adults (≥18 years old) whose antifungal therapy was switched from amphotericin B deoxycholate to a lipid formulation of amphotericin B, caspofungin, or voriconazole were included. Data were obtained from computerized patient records and paper medical charts. Baseline data collected included patient demographics, laboratory test findings, and mycology culture results. Toxicity was evaluated by examining changes in SCr concentration, as well as administration of bolus infusions of fluids and amphotericin B premedications (acetaminophen, diphenhydramine, and meperidine). Clinical efficacy data included mycology culture data and documentation of symptomatic improvement. The study was designed to evaluate the null hypothesis that, after am-

photericin B deoxycholate-induced renal dysfunction occurs, switching therapy to alternative antifungals does not result in improvement in renal function. Data were analyzed with Microsoft Excel (Microsoft Corp., Redmond, WA). Descriptive statistics were used to evaluate measures of central tendency and variability. Student’s t test was used to compare SCr levels at baseline (before the initiation of amphotericin B deoxycholate therapy), at the time of discontinuation of amphotericin B deoxycholate therapy, and at the end of alternative antifungal therapy. Statistical power was calculated to detect a 50% change in SCr concentration, and α was set at 0.05. A sample size of 18 patients was determined to be necessary to assess the primary endpoint with at least 90% power. Results. A total of 78 patients were started on amphotericin B deoxycholate during the period from January 1, 2002, to January 1, 2003. Therapy was changed to alternative antifungal agents in 38 (49%) of the patients. Because of unavailability of completed paper charts and time restrictions, data for only 25 patients were evaluated. The mean ± S.D. age of the patients was 48.6 ± 11.5 years, and the most common underlying condition was hematologic malignancy (11 patients [44%]) (Table 1). Eleven patients were located in the intensive care unit (ICU) when therapy was initiated, and 10 patients (40%) received other nephrotoxic agents concomitantly with amphotericin B deoxycholate. The most common indications for the initiation of amphotericin B therapy were febrile neutropenia and cryptococcal meningitis (Table 2). Documented mycology data were available for 13 patients (52%) at or after the start of therapy. Therapy with amphotericin B deoxycholate. All 25 patients were treated with amphotericin B deoxycholate initially at a mean ± S.D. daily dose of 0.8 ± 0.2 mg/kg. Bolus

infusions of 0.9% sodium chloride injection and amphotericin B premedications were administered to 24 patients. Therapy was changed because of increases in SCr levels in all 25 patients. The median duration of treatment with amphotericin B deoxycholate before switching to alternative antifungals was 3 days (range, 1–17 days), and the median total dose received was 210 mg (range, 40–595 mg). The mean ± S.D. SCr concentration at baseline was 0.84 ± 0.25 mg/dL, and the mean ± S.D. peak SCr concentration before therapy was switched was 1.73 ± 0.45 mg/dL (p < 0.001). Hemodialysis was deemed necessary in 6 patients (24%). Three patients chose not to have hemodialysis and subsequently died. The median duration of dialysis in the other 3 patients was 13 days (range, 12–18 days). Alternative antifungal therapy. Therapy was switched to amphotericin B lipid complex in 18 patients (72%). A formulary change was made at our institution in the fall of 2002, at which time liposomal amphotericin B replaced amphotericin B lipid complex. Only 1 of the 25 patients received liposomal amphotericin B as alternative antifungal therapy. Two patients received caspofungin as alternative therapy, and 1 patient received oral voriconazole. Three patients received a variety of antifungals during the period of alternative therapy: 2 patients received amphotericin B lipid complex followed by voriconazole and 1 patient received amphotericin B lipid complex followed by caspofungin. The median duration of alternative antifungal therapy was 7 days (range, 2–45 days). Evaluation of toxicity. Only 5 of the 25 patients (20%) had an improvement in renal function while receiving alternative antifungals, with a mean ± S.D. decrease in SCr concentration of 37% ± 15% (range, 24–61%). The mean ± S.D. SCr concentration at the end of alternative

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Table 1.

Patient Characteristics at Baseline (n = 25) Characteristic

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Mean ± S.D. age (yr) Male:Female Mean ± S.D. baseline serum creatinine conc. (mg/dL) Underlying condition, no. (%) pts. Hematologic malignancy AIDS Diabetes mellitus Other Neutropenia (absolute neutrophil count,