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Colistin is increasingly being utilized against Gram-negative pathogens, includingPseudomonas aeruginosa , resistant to all other antibiotics. Since limited data exist regarding killing by colistin at different initial inocula (CFUo), we evaluated killing ofPseudomonas aeruginosa by colistin at several CFUo and developed a mechanism-based mathematical model accommodating a range of CFUo.In vitro time-kill experiments were performed using ≥8 concentrations up to 64 × the MIC of colistin againstP. aeruginosa PAO1 and two clinicalP. aeruginosa isolates at CFUo of 106 , 108 , and 109 CFU/ml. Serial samples up to 24 h were simultaneously modeled in the NONMEM VI (results shown) and S-ADAPT software programs. The mathematical model was prospectively “validated” by additional time-kill studies assessing the effect of Ca2+ and Mg2+ on killing of PAO1 by colistin. Against PAO1, killing of the susceptible population was 23-fold slower at the 109 CFUo and 6-fold slower at the 108 CFUo than at the 106 CFUo. The model comprised three populations with different second-order killing rate constants (5.72, 0.369, and 0.00210 liters/h/mg). Bacteria were assumed to release signal molecules stimulating a phenotypic change that inhibits killing. The proposed mechanism-based model had a good predictive performance, could describe killing by colistin for all three studied strains and for two literature studies, and performed well in a prospective validation with various concentrations of Ca2+ and Mg2+ . The extent and rate of killing ofP. aeruginosa by colistin were markedly decreased at high CFUo compared to those at low CFUo. This was well described by a mechanism-based mathematical model, which should be further validated using dynamicin vitro models.

antimicrobial agents and chemotherapy

Attenuation of Colistin Bactericidal Activity by High Inoculum of <i>Pseudomonas aeruginosa</i> Characterized by a New Mechanism-Based Population Pharmacodynamic Model

Attenuation of Colistin Bactericidal Activity by High Inoculum of Pseudomonas aeruginosa Characterized by a New Mechanism-Based Population Pharmacodynamic Model