Development and validation of an in vitro pharmacokinetic/pharmacodynamic model to test the antibacterial efficacy of antibiotic polymer conjugates.

Abstract

This study describes the use of a novel, two-compartment, static dialysis bag model to study the release, diffusion, and antibacterial activity of a novel, bioresponsive dextrin-colistin polymer conjugate against multidrug resistant (MDR) wild-type Acinetobacter baumannii. In this model, colistin sulfate, at its MIC, produced a rapid and extensive drop in viable bacterial counts (<2 log10 CFU/ml at 4 h); however, a marked recovery was observed thereafter, with regrowth equivalent to that of control by 48 h. In contrast, dextrin-colistin conjugate, at its MIC, suppressed bacterial growth for up to 48 h, with 3 log10 CFU/ml lower bacterial counts after 48 h than those of controls. Doubling the concentration of dextrin-colistin conjugate (to 2× MIC) led to an initial bacterial killing of 3 log10 CFU/ml at 8 h, with a similar regrowth profile to 1× MIC treatment thereafter. The addition of colistin sulfate (1× MIC) to dextrin-colistin conjugate (1× MIC) resulted in undetectable bacterial counts after 4 h, followed by suppressed bacterial growth (3.5 log10 CFU/ml lower than that of control at 48 h). Incubation of dextrin-colistin conjugates with infected wound exudate from a series of burn patients (n = 6) revealed an increasing concentration of unmasked colistin in the outer compartment (OC) over time (up to 86.3% of the initial dose at 48 h), confirming that colistin would be liberated from the conjugate by endogenous α-amylase within the wound environment. These studies confirm the utility of this model system to simulate the pharmacokinetics of colistin formation in humans administered dextrin-colistin conjugates and further supports the development of antibiotic polymer conjugates in the treatment of MDR infections.

• Authors: Ernest A Azzopardi, Elaine L Ferguson, David W Thomas
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 59 Issue 4 Pg. 1837-43 (Apr 2015) ISSN: 1098-6596 [Electronic] United States
• PMID: 25512401 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Chemical References

• Anti-Bacterial Agents
• Polymers
• alpha-Amylases
• Colistin

Topics

• Acinetobacter baumannii (drug effects, growth & development)
• Anti-Bacterial Agents (chemistry, pharmacokinetics, pharmacology)
• Bacterial Load
• Burns (enzymology)
• Colistin (pharmacology)
• Colony Count, Microbial
• Escherichia coli (drug effects)
• Humans
• Microbial Sensitivity Tests (methods)
• Models, Biological
• Polymers (chemistry, pharmacokinetics, pharmacology)
• Reproducibility of Results
• Wound Infection (microbiology)
• alpha-Amylases (metabolism)