This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ASM journals
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Walsh, T. J.
Right arrow Articles by Anaissie, E. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Walsh, T. J.
Right arrow Articles by Anaissie, E. J.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, December 2001, p. 3487-3496, Vol. 45, No. 12
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.12.3487-3496.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Safety, Tolerance, and Pharmacokinetics of High-Dose Liposomal Amphotericin B (AmBisome) in Patients Infected with Aspergillus Species and Other Filamentous Fungi: Maximum Tolerated Dose Study

Thomas J. Walsh,1,* Jesse L. Goodman,2 Peter Pappas,3 Ihor Bekersky,4 Donald N. Buell,4 Maureen Roden,1 John Barrett,5 and Elias J. Anaissie6

Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute,1 and National Heart, Lung, and Blood Institute,5 Bethesda, Maryland; Division of Infectious Diseases, Department of Medicine, University of Minnesota School of Medicine, Minneapolis, Minnesota2; Division of Infectious Diseases, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama3; Fujisawa Healthcare, Inc., Deerfield, Illinois4; and Myeloma and Transplantation Research Center, Arkansas Cancer Research Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas6

Received 7 March 2001/Returned for modification 21 July 2001/Accepted 21 September 2001

We conducted a phase I-II study of the safety, tolerance, and plasma pharmacokinetics of liposomal amphotericin B (L-AMB; AmBisome) in order to determine its maximally tolerated dosage (MTD) in patients with infections due to Aspergillus spp. and other filamentous fungi. Dosage cohorts consisted of 7.5, 10.0, 12.5, and 15.0 mg/kg of body weight/day; a total of 44 patients were enrolled, of which 21 had a proven or probable infection (13 aspergillosis, 5 zygomycosis, 3 fusariosis). The MTD of L-AMB was at least 15 mg/kg/day. Infusion-related reactions of fever occurred in 8 (19%) and chills and/or rigors occurred in 5 (12%) of 43 patients. Three patients developed a syndrome of substernal chest tightness, dyspnea, and flank pain, which was relieved by diphenhydramine. Serum creatinine increased two times above baseline in 32% of the patients, but this was not dose related. Hepatotoxicity developed in one patient. Steady-state plasma pharmacokinetics were achieved by day 7. The maximum concentration of drug in plasma (Cmax) of L-AMB in the dosage cohorts of 7.5, 10.0, 12.5, and 15.0 mg/kg/day changed to 76, 120, 116, and 105 µg/ml, respectively, and the mean area under the concentration-time curve at 24 h (AUC24) changed to 692, 1,062, 860, and 554 µg · h/ml, respectively, while mean CL changed to 23, 18, 16, and 25 ml/h/kg, respectively. These data indicate that L-AMB follows dose-related changes in disposition processing (e.g., clearance) at dosages of >= 7.5 mg/kg/day. Because several extremely ill patients had early death, success was determined for both the modified intent-to-treat and evaluable (7 days of therapy) populations. Response rates (defined as complete response and partial response) were similar for proven and probable infections. Response and stabilization, respectively, were achieved in 36 and 16% of the patients in the modified intent-to-treat population (n = 43) and in 52 and 13% of the patients in the 7-day evaluable population (n = 31). These findings indicate that L-AMB at dosages as high as 15 mg/kg/day follows nonlinear saturation-like kinetics, is well tolerated, and can provide effective therapy for aspergillosis and other filamentous fungal infections.

* Corresponding author. Mailing address: Immunocompromised Host Section, National Cancer Institute, Building 10, Rm. 13N240, Bethesda, MD 20892. Phone: (301) 402-0023. Fax: (301) 402-0575. E-mail: walsht{at}mail.nih.gov.

Antimicrobial Agents and Chemotherapy, December 2001, p. 3487-3496, Vol. 45, No. 12
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.12.3487-3496.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Moriyama, B., Torabi-Parizi, P., Pratt, A. K., Henning, S. A., Pennick, G., Shea, Y. R., Roy Chowdhuri, S., Rinaldi, M. G., Barrett, A. J., Walsh, T. J. (2010). Pharmacokinetics of Liposomal Amphotericin B in Pleural Fluid. Antimicrob. Agents Chemother. 54: 1633-1635 [Abstract] [Full Text]  
  • Lewis, R. E., Albert, N. D., Liao, G., Hou, J., Prince, R. A., Kontoyiannis, D. P. (2010). Comparative Pharmacodynamics of Amphotericin B Lipid Complex and Liposomal Amphotericin B in a Murine Model of Pulmonary Mucormycosis. Antimicrob. Agents Chemother. 54: 1298-1304 [Abstract] [Full Text]  
  • Sundar, S., Chakravarty, J., Agarwal, D., Rai, M., Murray, H. W. (2010). Single-Dose Liposomal Amphotericin B for Visceral Leishmaniasis in India. NEJM 362: 504-512 [Abstract] [Full Text]  
  • Ellis, M., Bernsen, R., Ali-Zadeh, H., Kristensen, J., Hedstrom, U., Poughias, L., Bresnik, M., Al-Essa, A., A. Stevens, D. (2009). A safety and feasibility study comparing an intermittent high dose with a daily standard dose of liposomal amphotericin B for persistent neutropenic fever. J Med Microbiol 58: 1474-1485 [Abstract] [Full Text]  
  • Gubbins, P. O., Amsden, J. R., McConnell, S. A., Anaissie, E. J. (2009). Pharmacokinetics and Buccal Mucosal Concentrations of a 15 Milligram per Kilogram of Body Weight Total Dose of Liposomal Amphotericin B Administered as a Single Dose (15 mg/kg), Weekly Dose (7.5 mg/kg), or Daily Dose (1 mg/kg) in Peripheral Stem Cell Transplant Patients. Antimicrob. Agents Chemother. 53: 3664-3674 [Abstract] [Full Text]  
  • Andes, D., Pascual, A., Marchetti, O. (2009). Antifungal Therapeutic Drug Monitoring: Established and Emerging Indications. Antimicrob. Agents Chemother. 53: 24-34 [Full Text]  
  • Vallon-Eberhard, A., Makovitzki, A., Beauvais, A., Latge, J.-P., Jung, S., Shai, Y. (2008). Efficient Clearance of Aspergillus fumigatus in Murine Lungs by an Ultrashort Antimicrobial Lipopeptide, Palmitoyl-Lys-Ala-DAla-Lys. Antimicrob. Agents Chemother. 52: 3118-3126 [Abstract] [Full Text]  
  • Lewis, R. E., Liao, G., Hou, J., Chamilos, G., Prince, R. A., Kontoyiannis, D. P. (2007). Comparative Analysis of Amphotericin B Lipid Complex and Liposomal Amphotericin B Kinetics of Lung Accumulation and Fungal Clearance in a Murine Model of Acute Invasive Pulmonary Aspergillosis. Antimicrob. Agents Chemother. 51: 1253-1258 [Abstract] [Full Text]  
  • McLintock, L. A., Cook, G., Holyoake, T. L., Jones, B. L., Kinsey, S. E., Jackson, G. H. (2007). High loading dose AmBisome(R) is efficacious and well tolerated in the management of invasive fungal infection in hematology patients. haematol 92: 572-573 [Abstract] [Full Text]  
  • Olson, J. A., Adler-Moore, J. P., Schwartz, J., Jensen, G. M., Proffitt, R. T. (2006). Comparative Efficacies, Toxicities, and Tissue Concentrations of Amphotericin B Lipid Formulations in a Murine Pulmonary Aspergillosis Model. Antimicrob. Agents Chemother. 50: 2122-2131 [Abstract] [Full Text]  
  • Petraitis, V., Petraitiene, R., Solomon, J., Kelaher, A. M., Murray, H. A., Mya-San, C., Bhandary, A. K., Sein, T., Avila, N. A., Basevicius, A., Bacher, J., Walsh, T. J. (2006). Multidimensional Volumetric Imaging of Pulmonary Infiltrates for Measuring Therapeutic Response to Antifungal Therapy in Experimental Invasive Pulmonary Aspergillosis. Antimicrob. Agents Chemother. 50: 1510-1517 [Abstract] [Full Text]  
  • Hong, Y., Shaw, P. J., Nath, C. E., Yadav, S. P., Stephen, K. R., Earl, J. W., McLachlan, A. J. (2006). Population Pharmacokinetics of Liposomal Amphotericin B in Pediatric Patients with Malignant Diseases. Antimicrob. Agents Chemother. 50: 935-942 [Abstract] [Full Text]  
  • Andes, D., Safdar, N., Marchillo, K., Conklin, R. (2006). Pharmacokinetic-Pharmacodynamic Comparison of Amphotericin B (AMB) and Two Lipid-Associated AMB Preparations, Liposomal AMB and AMB Lipid Complex, in Murine Candidiasis Models. Antimicrob. Agents Chemother. 50: 674-684 [Abstract] [Full Text]  
  • Clemons, K. V., Espiritu, M., Parmar, R., Stevens, D. A. (2005). Comparative Efficacies of Conventional Amphotericin B, Liposomal Amphotericin B (AmBisome), Caspofungin, Micafungin, and Voriconazole Alone and in Combination against Experimental Murine Central Nervous System Aspergillosis. Antimicrob. Agents Chemother. 49: 4867-4875 [Abstract] [Full Text]  
  • Bicanic, T., Harrison, T. S. (2005). Cryptococcal meningitis. Br Med Bull 72: 99-118 [Abstract] [Full Text]  
  • Simitsopoulou, M., Roilides, E., Dotis, J., Dalakiouridou, M., Dudkova, F., Andreadou, E., Walsh, T. J. (2005). Differential Expression of Cytokines and Chemokines in Human Monocytes Induced by Lipid Formulations of Amphotericin B. Antimicrob. Agents Chemother. 49: 1397-1403 [Abstract] [Full Text]  
  • Kontoyiannis, D. P., Lewis, R. E., Tattevin, P., Bareau, B., Camus, C., Marty, F. M., Lowry, C. M., Schneemann, M., Imhof, A., Danaher, P. J., Jones, B. L., McLintock, L. A., Walsh, T. J., Donowitz, G. R., dePauw, B. E. (2005). Caspofungin versus liposomal amphotericin B for empirical therapy.. NEJM 352: 410-414 [Full Text]  
  • Offner, F., Krcmery, V., Boogaerts, M., Doyen, C., Engelhard, D., Ribaud, P., Cordonnier, C., de Pauw, B., Durrant, S., Marie, J.-P., Moreau, P., Guiot, H., Samonis, G., Sylvester, R., Herbrecht, R., the EORTC Invasive Fungal Infections Group, (2004). Liposomal Nystatin in Patients with Invasive Aspergillosis Refractory to or Intolerant of Amphotericin B. Antimicrob. Agents Chemother. 48: 4808-4812 [Abstract] [Full Text]  
  • Adler-Moore, J. P., Olson, J. A., Proffitt, R. T. (2004). Alternative dosing regimens of liposomal amphotericin B (AmBisome) effective in treating murine systemic candidiasis. J Antimicrob Chemother 54: 1096-1102 [Abstract] [Full Text]  
  • De Socio, G. V. L., Fiorio, M., Stagni, G. (2003). AmBisome administration for Candida albicans shunt infections. J Antimicrob Chemother 52: 1048-1049 [Full Text]  
  • Martin, M. T., Gavalda, J., Lopez, P., Gomis, X., Ramirez, J. L., Rodriguez, D., Len, O., Jordano, Q., Ruiz, I., Rosal, M., Almirante, B., Pahissa, A. (2003). Efficacy of high doses of liposomal amphotericin B in the treatment of experimental aspergillosis. J Antimicrob Chemother 52: 1032-1034 [Abstract] [Full Text]  
  • Ibrahim, A. S., Avanessian, V., Spellberg, B., Edwards, J. E. Jr. (2003). Liposomal Amphotericin B, and Not Amphotericin B Deoxycholate, Improves Survival of Diabetic Mice Infected with Rhizopus oryzae. Antimicrob. Agents Chemother. 47: 3343-3344 [Abstract] [Full Text]  
  • Gerbaud, E., Tamion, F., Girault, C., Clabault, K., Lepretre, S., Leroy, J., Bonmarchand, G. (2003). Persistent acute tubular toxicity after switch from conventional amphotericin B to liposomal amphotericin B (Ambisome). J Antimicrob Chemother 51: 473-475 [Full Text]  
  • Pacetti, S. A, Gelone, S. P (2003). Caspofungin Acetate for Treatment of Invasive Fungal Infections. The Annals of Pharmacotherapy 37: 90-98 [Abstract] [Full Text]  
  • Ortoneda, M., Capilla, J., Pastor, F. J., Pujol, I., Guarro, J. (2002). Efficacy of Liposomal Amphotericin B in Treatment of Systemic Murine Fusariosis. Antimicrob. Agents Chemother. 46: 2273-2275 [Abstract] [Full Text]  


Copyright © 2010 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»