Mathematical modeling to characterize the inoculum effect.
Killing by beta-lactams is well known to be reduced against a dense bacterial population, commonly known as the inoculum effect. However, the underlying mechanism of this phenomenon is not well understood. We proposed a semi-mechanistic mathematical model to account for the reduced in vitro killing observed. Time-kill studies were performed with 4 baseline inocula (ranging from approximately 1 × 10(5) to 1 × 10(8) CFU/ml) of Escherichia coli ATCC 25922 (MIC, 2 mg/liter). Constant but escalating piperacillin concentrations used ranged from 0.25× to 256× MIC. Serial samples were taken over 24 h to quantify viable bacterial burden, and all the killing profiles were mathematically modeled. The inoculum effect was attributed to a reduction of effective drug concentration available for bacterial killing, which was expressed as a function of the baseline inoculum. Biomasses associated with different inocula were examined using a colorimetric method. Despite identical drug-pathogen combinations, the baseline inoculum had a significant impact on bacterial killing. Our proposed mathematical model was unbiased and reasonable in capturing all 28 killing profiles collectively (r(2) = 0.88). Biomass was found to be significantly more after 24 h with a baseline inoculum of 1 × 10(8) CFU/ml, compared to one where the initial inoculum was 1 × 10(5) CFU/ml (P = 0.002). Our results corroborated previous observations that in vitro killing by piperacillin was significantly reduced against a dense bacterial inoculum. This phenomenon can be reasonably captured by our proposed mathematical model, and it may improve prediction of bacterial response to various drug exposures in future investigations.
Bhagunde
Pratik
P
Department of Chemical and Biomolecular Engineering, University of Houston, 4800 Calhoun Avenue, Houston, TX 77204, USA.
Chang
Kai-Tai
KT
Singh
Renu
R
Singh
Vandana
V
Garey
Kevin W
KW
Nikolaou
Michael
M
Tam
Vincent H
VH
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects / Q000254:growth & development; D008826:Microbial Sensitivity Tests; D008962:Models, Theoretical; D010878:Piperacillin / Q000494:pharmacology; D047090:beta-Lactams / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D047090:beta-Lactams; D010878:Piperacillin
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