Objectives: Because the pharmacokinetic/pharmacodynamic (PK/PD) characteristics of colistin against Enterobacteriaceae are not well explored, we studied the activity of colistin against K. pneumoniae in an in vitro PK/PD model simulating different dosing regimens. Methods: Three clinical isolates of K. pneumoniae with MICs of 0.5, 1 and 4mg/L were tested in an in vitro PK/PD model following a dose-fractionation design over a period of 24h. A high and low inoculumof 107 and 104 cfu/mL with and without a heteroresistant subpopulation, respectively, were used. PK/PD indices associated with colistin activity were explored and Monte Carlo analysis was performed in order to determine the PTA for achieving a bactericidal effect (2 log kill). Results: The fAUC/MIC (R2"0.64-0.68) followed by fCmax/MIC (R2=0.55-0.63) best described colistin's 24 h log10 cfu/mL reduction for both low and high inocula. Dosing regimens with fCmax/MIC≥6 were always associated with a bactericidal effect (P=0.0025). However, at clinically achievable concentrations, usually below fCmax/MIC=6, an fAUC/MIC ≤25 was more predictive of a bactericidal effect. Using a dosing regimen of 9 MU/ day, the PTA for this pharmacodynamic target was 100%, 5%-70%and 0%, for isolates with MICs of ≤0.5, 1 and ≥2 mg/L, respectively. Dosing regimens that aim for a trough level of 1 mg/L achieve coverage of strains up to 0.5 mg/L (target trough/MIC=2 mg/L). Conclusions: Characterization of the pharmacodynamics of colistin against Enterobacteriaceae in an in vitro model of infection indicates that a revision of current susceptibility breakpoints is needed. Therapeutic drug monitoring of colistin to achieve pharmacodynamic targets in individual patients is highly recommended.

dx.doi.org/10.1093/jac/dkx522, hdl.handle.net/1765/105659
Journal of Antimicrobial Chemotherapy
This work was funded by the European Commission 7th Framework Programme; grant id fp7/278348 - Preserving old antibiotics for the future : assessment of clinical efficacy by a pharmacokinetic/pharmacodynamic approach to optimize effectiveness and reduce resistance for off-patent antibiotics (AIDA)
Department of Medical Microbiology and Infectious Diseases

Tsala, M, Vourli, S, Georgiou, P.-C. (Panagiota-Christina), Pournaras, S, Tsakris, A, Daikos, G.L, … Meletiadis, J. (2018). Exploring colistin pharmacodynamics against Klebsiella pneumoniae: A need to revise current susceptibility breakpoints. Journal of Antimicrobial Chemotherapy, 73(4), 953–961. doi:10.1093/jac/dkx522