Development and Validation of an In Vitro Pharmacokinetic/Pharmacodynamic Model To Test the Antibacterial Efficacy of Antibiotic Polymer Conjugates

Abstract

bThis 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 log 10 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 log 10 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 log 10 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 log 10 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 ␣-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. In an attempt to meet the challenge of the global epidemic of antibiotic-resistant infections, treatment strategies are increasingly employing nanomedicine-based approaches, which have been used in the treatment of a number of human diseases with considerable success (1, 2). The adoption of these approaches as antimicrobial therapies has seen the preclinical development of novel agents, including antibiotic-bearing nanoparticles, liposomes, dendrimers, and polymer therapeutics (3, 4). These agents may offer potential benefits over conventional systemic delivery in minimizing toxicity and overcoming drug resistance by affording selective targeting of systemically delivered antibiotics to sites of infection and inflammation, thus maximizing local bioavailability of the chemotherapeutic agent (3, 5). The employment of polymer therapeutics, in which an antibiotic is covalently attached to a water-soluble polymer, may afford a number of important practical advantages, including increased solubility and bioavailability, decreased toxicity, and a chemically modifiable controlled-release system that can be truly customized (2, 4, 6).In this respect, we recently described a nanoantibiotic polymer therapeutic, based on dextrin conjugated to colistin, whereby colistin is controllably released from the co...

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