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

Azzopardi, Ernest A. ORCID: https://orcid.org/0000-0002-4511-0954, Ferguson, Elaine L. ORCID: https://orcid.org/0000-0002-0125-0234 and Thomas, David W. ORCID: https://orcid.org/0000-0001-7319-5820 2015. Development and validation of an in vitro pharmacokinetic/pharmacodynamic model to test the antibacterial efficacy of antibiotic polymer conjugates. Antimicrobial Agents and Chemotherapy 59 (4) , pp. 1837-1843. 10.1128/AAC.03708-14

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Dentistry Systems Immunity Research Institute (SIURI)
Subjects:	R Medicine > RK Dentistry
Additional Information:	Published online 15/12/14.
Publisher:	American Society for Microbiology
ISSN:	0066-4804
Date of Acceptance:	7 December 2014
Last Modified:	15 Jan 2023 14:39
URI:	https://orca.cardiff.ac.uk/id/eprint/68622

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