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- Title
Exploring colistin pharmacodynamics against Klebsiella pneumoniae: a need to revise current susceptibility breakpoints.
- Authors
Tsala, Marilena; Vourli, Sophia; Georgiou, Panagiota-Christina; Pournaras, Spyros; Tsakris, Athanasios; Daikos, George L; Mouton, Johan W; Meletiadis, Joseph
- Abstract
<bold>Objectives: </bold>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.<bold>Methods: </bold>Three clinical isolates of K. pneumoniae with MICs of 0.5, 1 and 4 mg/L were tested in an in vitro PK/PD model following a dose-fractionation design over a period of 24 h. A high and low inoculum of 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).<bold>Results: </bold>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).<bold>Conclusions: </bold>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.
- Subjects
KLEBSIELLA; MICROBIAL sensitivity tests; SYSTEM analysis; COLISTIN; IN vitro studies; PHARMACODYNAMICS
- Publication
Journal of Deaf Studies & Deaf Education, 2018, Vol 23, Issue 2, p953
- ISSN
1081-4159
- Publication type
journal article
- DOI
10.1093/jac/dkx522