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Cited by 116Antifungal resistance and susceptibilityFungal Infections and StudiesAntibiotics Pharmacokinetics and Efficacy

Pharmacokinetic-pharmacodynamic comparison of amphotericin B (AMB) and two lipid-associated AMB preparations, liposomal AMB and AMB lipid complex, in murine candidiasis models

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Andes, D., Safdar, N., Marchillo, K., Conklin, R.·2006·Antimicrobial Agents and Chemotherapy
DOI 10.1128/aac.50.2.674-684.2006PMC PMC1366906
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Abstract

It is generally accepted that the lipid formulations of amphotericin B (AMB) are not as potent as conventional AMB on a milligram-per-kilogram basis. We used a neutropenic murine disseminated candidiasis model to compare the in vivo potencies of AMB, liposomal AMB (L-AMB), and AMB lipid complex (ABLC) pharmacodynamically. The pharmacokinetics of the antifungals were examined in serum and in three organs commonly seeded in disseminated candidiasis (kidneys, liver, and lung). Both single-dose time-kill studies and multiple-dosing-regimen studies were used with each of the compounds. Determinations of the numbers of CFU in the kidneys were performed following the administration of three escalating single doses of the polyenes at various times over 48 h. The areas under the time-kill curves (AUTKs) for each dose level of the drugs were compared by analysis of variance (ANOVA). In the multiple-dosing-regimen studies with five Candida isolates, AMB, L-AMB, and ABLC were administered daily for 72 h. The organism burdens in the mouse kidneys were similarly used as the treatment end point. Additional multiple regimen-dosing-studies were performed with a single Candida albicans isolate, and the microbiologic outcomes in four internal organs (kidneys, liver, spleen, and lung) were examined at the end of therapy (48 h). The relationship between the dose and the drug exposure expressed by the pharmacokinetics of the dosing regimens in serum and organ tissue were analyzed by using a maximum-effect model. ANOVA was used to compare the drug exposures necessary to achieve the 25% effective dose (ED 25 ), ED 50 , ED 75 , and 1 log 10 killing. Comparison of AUTKs suggested that AMB was 4.3- to 5.9-fold more potent than either ABLC or L-AMB. The time-kill curves for both lipid formulations were very similar. In the multiple-dosing-regimen studies, AMB was 5.0- to 8.0-fold more potent than each of the lipid formulations against five Candida isolates in the kidneys. Similar differences in potency (5.1- to 7.2-fold) were observed in the other end organs. The difference in pharmacokinetics in serum accounted for much of the difference in potency between AMB and ABLC (ratio of serum ABLC area under the curve of effective doses to serum AMB area under the curve of effective doses, 1.2). The differences in the kinetics in the various end organs between AMB and L-AMB were better at explaining the disparate potencies at these infection sites (ratio of organ L-AMB area under the curve of effective doses to organ AMB area under the curve of effective doses, 1.1).

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  • In vitro and in vivo pharmacodynamic studies have observed increased killing of Candida species as amphotericin B concentration is escalated multiple times higher than the MIC.

    “In vitro and in vivo PD studies have observed increased killing of Candida species as the concentration of amphotericin B is escalated multiple times higher than the MIC.”

    From Fungal Sepsis: Optimizing Antifungal Therapy in the Critical Care Setting (2011) · cites this paper as [120]

  • For lipid formulations of amphotericin B, the Cmax/MIC target needed for efficacy is approximately 5 times larger than for amphotericin B.

    “These investigations have demonstrated similar pharmacodynamic characteristics; however, for lipid preparations the C max /MIC target needed for efficacy is approximately 5 times larger than for amphotericin B.”

    From Fungal Sepsis: Optimizing Antifungal Therapy in the Critical Care Setting (2011) · cites this paper as [120]

  • The Cmax/MIC target associated with maximal efficacy for amphotericin B in experimental models is 2 to 4.

    “The concentration relative to the MIC associated with maximal efficacy in experimental models is a C max /MIC of 2 to 4.”

    From Fungal Sepsis: Optimizing Antifungal Therapy in the Critical Care Setting (2011) · cites this paper as [120]

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Research works printed but not linked: 3

  1. [11]Craig, W. A. 1998. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin. Infect. Dis. 26:1-12. [DOI] [PubMed] [Google Scholar]
  2. [19]Pfaller, M. A., D. J. Diekema, and M. G. Rinaldi. 2005. Antifungal drugs: mechanisms of action, drug resistance, susceptibility testing, and assays of activity in biological fluids, p. 226-265. In V. Lorian (ed.), Antibiotics in laboratory medicine, 5th ed. Lippincott Williams & Wilkins, Philadelphia, Pa.
  3. [22]van Etten, E. W., M. Otte-Lambillion, W. van Vianen, M. T. ten Kate, and A. J. Bakker-Woudenberg. 1995. Biodistribution of liposomal amphotericin B and amphotericin B desoxycholate in uninfected immunocompetent and leukopenic mice with C. albicans. J. Antimicrob. Agents 35:509-519. [DOI] [PubMed] [Google Scholar]

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Authors
Andes, D., Safdar, N., Marchillo, K., & Conklin, R.
Affiliations
  • University of Wisconsin–Madison (US)
  • Departments of Medicine
Corresponding author
Andes, D.
ORCID
Venue
Antimicrobial Agents and Chemotherapy
Publisher
American Society for Microbiology
Published
2006-02
Volume
50
Issue
2
Pages
674-684
ISSN
  • 0066-4804 (ISSN-L)
  • 1098-6596
DOI
10.1128/aac.50.2.674-684.2006
PMC
PMC1366906
OpenAlex
W2130470240
Cited by
116
References
27
Citations by year
2026: 4 · 2025: 4 · 2024: 4 · 2023: 3 · 2022: 5 · 2021: 6 · 2020: 4 · 2019: 5 · 2018: 1 · 2017: 7 · 2016: 7 · 2015: 5 · 2014: 10 · 2013: 4 · 2012: 3
FWCI
5.99
Type
journal article
Language
en
Open access
Licence
journals.asm.org/non-commercial-tdm-license (tdm)
Locations
  • Antimicrobial Agents and Chemotherapy (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
  • Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
  • Health Sciences › Medicine › Pharmacology › Antibiotics Pharmacokinetics and Efficacy
Keywords
amphotericin B, liposomal amphotericin B, amphotericin B lipid complex, pharmacokinetics, pharmacodynamics, systemic candidiasis, Candida albicans, time-kill kinetics, neutropenic mice, dose-response relationship, renal candidiasis
MeSH terms
Amphotericin B, Animals, Antifungal Agents, Candida, Candidiasis, Disease Models, Animal, Female, Lipids, Liposomes, Mice, Inbred ICR, Area Under Curve, Mice

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