title: 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.affiliation: Advanced Therapies Group, School of Dentistry, Cardiff University, Heath Park, Cardiff, United Kingdom The Welsh Centre for Burns and Plastic Surgery, Morriston Hospital, Swansea, United Kingdom e.a.p.azzopardi@swansea.ac.uk.
authors.forename: Ernest A
authors.initials: EA
authors.lastname: Azzopardi
authors.affiliation: Advanced Therapies Group, School of Dentistry, Cardiff University, Heath Park, Cardiff, United Kingdom.
authors.forename: Elaine L
authors.initials: EL
authors.lastname: Ferguson
authors.affiliation: Advanced Therapies Group, School of Dentistry, Cardiff University, Heath Park, Cardiff, United Kingdom.
authors.forename: David W
authors.initials: DW
authors.lastname: Thomas
mesh_terms: D040981:Acinetobacter baumannii / Q000187:drug effects / Q000254:growth & development; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D058491:Bacterial Load; D002056:Burns / Q000201:enzymology; D003091:Colistin / Q000494:pharmacology; D015169:Colony Count, Microbial; D004926:Escherichia coli / Q000187:drug effects; D006801:Humans; D008826:Microbial Sensitivity Tests / Q000379:methods*; D008954:Models, Biological; D011108:Polymers / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D015203:Reproducibility of Results; D014946:Wound Infection / Q000382:microbiology; D000516:alpha-Amylases / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D011108:Polymers; D000516:alpha-Amylases; D003091:Colistin