Τίτλος:
Pharmacokinetic and pharmacodynamic properties of polymyxin B in Escherichia coli and Klebsiella pneumoniae murine infection models
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
BACKGROUND: Although polymyxin B has been in use since the late 1950s, there have been limited studies done to unravel its pharmacokinetics (PK) and pharmacodynamics (PD) index. METHODS: We determined, in neutropenic infected mice, the PK, plasma protein binding and PK/PD index best correlating with efficacy for Escherichia coli and Klebsiella pneumoniae strains. RESULTS: The pharmacokinetic profile showed non-linear PK; dose was significantly correlated with absorption rate and clearance. The inhibitory sigmoid dose-effect model for the fCmax/MIC index of E. coli fitted best, but was only modestly higher than the R2 of %fT>MIC and fAUC/MIC (R2 0.91-0.93). For K. pneumoniae the fAUC/MIC index had the best fit, which was slightly higher than the R2 of %fT>MIC and fCmax/MIC (R2 0.85-0.91). Static targets of polymyxin B fAUC/MIC were 27.5-102.6 (median 63.5) and 5.9-60.5 (median 11.6) in E. coli and in K. pneumoniae isolates, respectively. A 1 log kill effect was only reached in two E. coli isolates and one K. pneumoniae. The PTA with the standard dosing was low for isolates with MIC >0.25 mg/L. CONCLUSIONS: This study confirms that fAUC/MIC can describe the exposure-response relationship for polymyxin B. The 1 log kill effect was achieved in the minority of the isolates whereas polymyxin B PK/PD targets cannot be attained for the majority of clinical isolates with the standard dosing regimen, indicating that polymyxin B may be not effective against serious infections as monotherapy. © The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Συγγραφείς:
van der Meijden, A.
Aranzana-Climent, V.
van der Spek, H.
de Winter, B.C.M.
Couet, W.
Meletiadis, J.
Muller, A.E.
van den Berg, S.
Περιοδικό:
The Journal of antimicrobial chemotherapy
Λέξεις-κλειδιά:
antiinfective agent; plasma protein; polymyxin B, animal; Escherichia coli; Klebsiella pneumoniae; microbial sensitivity test; mouse, Animals; Anti-Bacterial Agents; Blood Proteins; Escherichia coli; Klebsiella pneumoniae; Mice; Microbial Sensitivity Tests; Polymyxin B
