Correspondence
Liposomal Amphotericin B for Fever and Neutropenia
N Engl J Med 1999; 341:1152-1155October 7, 1999
- Article
To the Editor:
In their study of liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia (March 11 issue),1 Walsh et al. report that liposomal amphotericin B was associated with fewer breakthrough fungal infections than conventional amphotericin B. We think that the design of this randomized trial was not adequate because the dose of conventional amphotericin B (0.6 mg per kilogram of body weight per day) that was used does not reflect widely used standards of care. Most institutions in Europe and the United States would agree that treatment of this patient population requires a dose of at least 1.0 mg of conventional amphotericin B per kilogram per day to avoid breakthrough fungal infections. In fact, the rate of proved breakthrough fungal infections in the group given conventional amphotericin B is rather high (7.8 percent) and appears to be due to the low dose of conventional amphotericin B chosen.
We performed a retrospective analysis of 138 patients who underwent autologous peripheral-blood stem-cell transplantation at our institution between 1995 and 1997. The primary diagnosis was non-Hodgkin's lymphoma (30 percent of patients), followed by breast cancer (25 percent), multiple myeloma (16 percent), chronic myelogenous leukemia (10 percent), and other hematologic cancers (19 percent). Antibiotics and antiviral agents were used according to standard criteria. Patients who had persistent fever and neutropenia were treated with a standard dose of 1.0 mg of conventional amphotericin B per kilogram per day. Proved breakthrough fungal infections occurred in only four patients (2.9 percent). In three patients, candida was isolated from blood cultures, and in one patient, aspergillus was isolated from the sinuses. Thus, in this high-risk population, the rate of proved breakthrough fungal infections during treatment with conventional amphotericin B was very similar to the rate reported by Walsh et al. among patients treated with liposomal amphotericin B (3.2 percent). It therefore appears very likely that if Walsh et al. had used a “normal” dose of 1.0 mg of conventional amphotericin B per kilogram per day, there would not have been a significant difference in the rate of proved breakthrough fungal infections between the two treatment groups.
1 ReferencesThomas Fischer, M.D.
Gudula Heußel, M.D.
Christoph Huber, M.D.
Johannes Gutenberg University, 55131 Mainz, Germany1
Walsh TJ ,Finberg RW ,Arndt C , et al. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. N Engl J Med 1999;340:764-771
Full Text | Web of Science | Medline
To the Editor:
The result of the study by Walsh et al. has been the licensing of liposomal amphotericin B (AmBisome, NeXstar, Boulder, Colo.) at a dose of 3 mg per kilogram per day for the management of antibiotic-resistant fever of unexplained origin. In fact, the results of an earlier European study suggest that a lower daily dose of 1 mg per kilogram may be adequate.1 Substantial experience at our own institution suggests that the lower dose is adequate for patients with fever that is not responsive to antibiotics, especially now that we have more reliable methods of assessing the probability of invasive fungal infection.2-4 Our practice is to use conventional amphotericin B initially but to switch to the liposomal form if the patient's creatinine clearance falls below 70 ml per minute. Patients who are receiving two or more nephrotoxic drugs concurrently are given liposomal amphotericin B from the start.
The study by Walsh et al. may serve to demonstrate the importance of changing to treatment with liposomal amphotericin B rather than continuing treatment with an inadequate dose of the conventional form. They reported that during the final three days of therapy, 27 percent of patients in the conventional amphotericin B group were receiving a reduced dose of the drug (0.3 mg per kilogram per day), as compared with 15 percent of those receiving liposomal amphotericin B (1.5 mg per kilogram per day). This high percentage might explain the significant difference between groups in the incidence of breakthrough fungal infections.
4 ReferencesH. Grant Prentice, M.B., F.R.C.P.
Christopher C. Kibbler, F.R.C.P.
Royal Free Hospital, London NW3 2QG, United Kingdom1
Prentice HG ,Hann IM ,Herbrecht R , et al. A randomized comparison of liposomal versus conventional amphotericin B for the treatment of pyrexia of unknown origin in neutropenic patients. Br J Haematol 1997;98:711-718
CrossRef | Web of Science | Medline2
Einsele H ,Hebart H ,Roller G , et al. Detection and identification of fungal pathogens in blood by using molecular probes. J Clin Microbiol 1997;35:1353-1360
Web of Science | Medline3
Verweij PE ,Latge JP ,Rijs AJ , et al. Comparison of antigen detection and PCR assay using bronchoalveolar lavage fluid for diagnosing invasive pulmonary aspergillosis in patients receiving treatment for hematological malignancies. J Clin Microbiol 1995;33:3150-3153
Web of Science | Medline4
Berger LA . Imaging in the diagnosis of infections in immunocompromised patients. Curr Opin Infect Dis 1998;11:431-436
CrossRef | Web of Science | Medline
To the Editor:
In the study by Walsh et al., 66 percent of patients who received conventional amphotericin B tolerated the drug without evidence of renal dysfunction. Multiple studies have shown that salt loading can reduce the incidence of nephrotoxicity induced by amphotericin B.1-4 It is not clear whether Walsh et al. used salt loading in the patients who were treated with conventional amphotericin B. The rise of salt loading would have significantly increased the number of patients who were able to tolerate conventional amphotericin B without evidence of renal dysfunction. The benefit of liposomal amphotericin B over conventional amphotericin B with appropriate salt loading is therefore unclear. . . .
4 ReferencesMinalkumar A. Patel, M.D.
Kelley Curtis, R.P.H., M.B.A.
James H. Maguire, M.D.
Brigham and Women's Hospital, Boston, MA 021151
Llanos A ,Cieza J ,Bernardo J , et al. Effect of salt supplementation on amphotericin B nephrotoxicity. Kidney Int 1991;40:302-308
CrossRef | Web of Science | Medline2
Anderson CM . Sodium chloride treatment of amphotericin B nephrotoxicity: standard of care? West J Med 1995;162:313-317
Medline3
Stein RS ,Alexander JA . Sodium protects against nephrotoxicity in patients receiving amphotericin B. Am J Med Sci 1989;298:299-304
CrossRef | Web of Science | Medline4
Heidemann HT ,Gerkens JF ,Spickard WA ,Jackson EK ,Branch RA . Amphotericin B nephrotoxicity in humans decreased by salt repletion. Am J Med 1983;75:476-481
CrossRef | Web of Science | Medline
To the Editor:
Walsh and colleagues explored two strategies to reduce the incidence of invasive fungal infections among patients with neutropenia. In the study population, candida infections occurred in 37 patients; 22 were present at base line and 15 were breakthrough infections. Of these 37 infections, only 4 were caused by Candida krusei or C. glabrata, species that are frequently resistant to fluconazole. Although fluconazole prophylaxis was permitted before entry into the study, it would appear that it was used infrequently. Had fluconazole been given prophylactically, it is likely that very few candida infections would have occurred in this study population and the need for either liposomal or conventional amphotericin B would have been reduced substantially. Thus, an alternative strategy to reduce candida infections among patients with neutropenia is fluconazole prophylaxis, an approach that is associated with lower costs and an excellent safety profile.
Among patients receiving fluconazole prophylaxis, persistent fever is uncommonly associated with documented fungal infection. In the study by Goodman and colleagues,1 fungal infection was noted in only 1 percent of patients receiving fluconazole prophylaxis who were given amphotericin B empirically, as compared with 18 percent of those in the placebo group who were given amphotericin B empirically. Indeed, the need for an empirical trial of amphotericin B (or liposomal amphotericin B) for fever alone in the absence of other signs of fungal infection is highly questionable as a means of controlling candida infections in patients who are receiving fluconazole prophylaxis. . . .
1 ReferencesJohn R. Wingard, M.D.
University of Florida, Gainesville, FL 32610-02771
Goodman JL ,Winston DJ ,Greenfield RA , et al. A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. N Engl J Med 1992;326:845-851
Full Text | Web of Science | Medline
To the Editor:
Walsh and colleagues have nicely shown that liposomal amphotericin B is as effective as and less toxic than conventional amphotericin B when used for empirical therapy in patients who have neutropenia and fever. The key next question is at what cost? It would be helpful to see a formal cost–benefit analysis of this issue. For a simple cost analysis, I assumed that the mean weight of their patients (which was not given) was 65 kg, I used the same mean doses and durations of therapy as in the study, and I used an average wholesale price of $34.58 per 100 mg for conventional amphotericin B and $376 per 100 mg for the liposomal form.1 According to my calculations, the cost of a course of conventional amphotericin B is $138.91 ([65 kg × 0.6 mg/kg × 10.3 days] ÷ 100 mg × $34.58), as compared with a cost of $7,918.56 for a course of liposomal amphotericin B ([65 kg × 3.0 mg/kg × 10.8 days]÷100 mg × $376). These calculations include only the cost of the drugs. Since the rates of survival and resolution of fever were almost identical with these two preparations, it would seem that the real issue is whether the lower incidence of infusion-related toxicity and nephrotoxicity associated with liposomal preparation is worth the more than $7,700 in increased costs associated with this drug.
1 ReferencesRobert Rakita, M.D.
Virginia Mason Medical Center, Seattle, WA 98111To the Editor:
Dr. Walsh and colleagues must be commended on their extremely well-designed study of liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. We participated in a similar multicenter, randomized study comparing amphotericin B–liquid complex with conventional amphotericin B for empirical antifungal therapy in patients with fever and neutropenia. Despite objections from the investigators, this study was prematurely discontinued by the sponsor, the Liposome Company, Princeton, New Jersey. Nevertheless, an analysis of the patients at the University of California at Los Angeles who participated in this study showed no differences in the incidence of nephrotoxicity (defined as a doubling of the base-line serum creatinine concentration), fever, or chills among patients receiving amphotericin B–lipid complex as compared with patients treated with conventional amphotericin B. The clinical responses in the two groups were also similar. Another randomized study recently found that the efficacy of amphotericin B colloidal dispersion was similar to that of conventional amphotericin B for empirical antifungal therapy in febrile patients with neutropenia.1 Amphotericin B colloidal dispersion was associated with less renal dysfunction but more infusion-related hypoxia and chills. Thus, the beneficial effects of liposomal amphotericin B reported by Dr. Walsh and colleagues may not be applicable to other lipid-associated formulations of amphotericin B.
The primary factor prohibiting the routine use of liposomal amphotericin B in patients with neutropenia at our center and many other medical centers is the extremely high cost. It is surprising that Walsh and colleagues did not mention the cost of liposomal amphotericin B. An analysis comparing the cost effectiveness of liposomal amphotericin B and conventional amphotericin B in their patients would be helpful. . . .
1 ReferencesDrew J. Winston, M.D.
Gary J. Schiller, M.D.
Mary C. Territo, M.D.
UCLA Center for the Health Sciences, Los Angeles, CA 900951
White MH ,Bowden RA ,Sandler ES , et al. Randomized, double-blind clinical trial of amphotericin B colloidal dispersion vs. amphotericin B in the empirical treatment of fever and neutropenia. Clin Infect Dis 1998;27:296-302
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Our study of empirical antifungal therapy was carefully designed to reflect the standards of care at all 32 participating centers. Most institutions were already using conventional amphotericin B at an initial dose of 0.6 mg per kilogram per day, which is consistent with that of the original placebo-controlled clinical trials.1 The increased risk of nephrotoxicity at a dose of 1.0 mg per kilogram per day may pertain more to patients with proved fungal infection. To reflect patterns of clinical practice, we allowed the dose of the study drug to be adjusted in patients with evidence of infection. Protocol-defined guidelines were provided to increase the daily dose of conventional amphotericin B to intermediate levels of 0.9 mg per kilogram or to high levels of 1.2 mg per kilogram.
In our study, the frequency of breakthrough fungal infections of 7.8 percent may be related to our patients' higher risk of fungal infections as a result of their more protracted neutropenia (e.g., in patients with acute leukemia and recipients of allogeneic bone marrow transplants), which is in contrast to the shorter duration of neutropenia observed in recipients of peripheral-blood stem-cell transplants.
Drs. Prentice and Kibbler underscore the importance of new approaches that merit further investigation in high-risk patients. Our blinded study design allowed us to reduce the dose of the study drugs on the basis of toxicity. That appropriate doses of conventional amphotericin B could not be administered to some patients by the end of the study is evidence of the limitation of this compound.
With respect to the query of Patel et al. about salt loading, we can say that this approach was permitted according to routine institutional practice. Most institutions used salt loading. The administration of sodium was prospectively monitored, and its use was found to be similar in both groups.
Dr. Wingard is incorrect in suggesting that fluconazole was used infrequently. Forty-six percent of the patients enrolled in this study were recipients of bone marrow transplants, in whom fluconazole prophylaxis is widely used. Overall, 46 percent of patients received antifungal prophylaxis. Since the publication of the initial studies of fluconazole prophylaxis in recipients of bone marrow transplants, there have been increasing reports of fluconazole resistance in C. albicans and other candida species.2 Twelve of the 15 episodes of breakthrough fungemia in our study were due to candida species other than C. albicans. Empirical antifungal therapy with amphotericin B is a standard of care for patients who have fever and neutropenia.3,4
Dr. Rakita and Dr. Winston and colleagues raise the important issue of cost. A recent pharmacoeconomic analysis of our study found that the occurrence of nephrotoxicity significantly increased hospital costs.5 The higher acquisition cost of liposomal amphotericin B counterbalances the cost of nephrotoxicity once the cost of the drug is no higher than $85 per 50-mg vial, or approximately $340 for a dose of 3 mg per kilogram per day for a 70-kg adult. The cost of new forms of technology is best assessed not on the basis of acquisition cost alone but according to the effect on the total costs of hospitalization.
5 ReferencesThomas J. Walsh, M.D.
National Cancer Institute, Bethesda, MD 20892Carola Arndt, M.D.
Mayo Clinic, Rochester, MN 55905William Dismukes, M.D.
University of Alabama, Birmingham, AL 352941
Walsh TJ ,Lee J ,Lecciones J , et al. Empirical therapy with amphotericin B in febrile granulocytopenic patients. Rev Infect Dis 1991;13:496-503
CrossRef | Medline2
Nguyen MH ,Peacock JE Jr ,Morris AJ , et al. The changing face of candidemia: emergence of non-Candida albicans species and antifungal resistance. Am J Med 1996;100:617-623
CrossRef | Web of Science | Medline3
Hughes WT ,Armstrong D ,Bodey GP , et al. 1997 Guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever. Clin Infect Dis 1997;25:551-573
CrossRef | Web of Science | Medline4
Wingard J, Hiemenz J, Anaissie E, et al. Randomized, double-blind multicenter study of AmBisome versus Abelcet for empirical antifungal therapy. Presented at Focus on Fungal Infections 9, San Diego, Calif., March 17–19, 1999. abstract.
5
Hiemenz JW, Cagnoni P, Tong K. A cost effectiveness study comparing AmBisome (liposomal amphotericin B) versus amphotericin B deoxycholate in the empirical treatment of persistently febrile neutropenic patients. Presented at Focus on Fungal Infections 8, Orlando, Fla., March 4–6, 1998. abstract.
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