Literature have shown that Gram-negative bacteria release endotoxins which alter drug membrane transporters and could potentially influence antimicrobials distribution to the infection site depending on the infecting bacteria. Previously, a population pharmacokinetic (popPK) model describing ciprofloxacin (CIP) concentrations in healthy, and Pseudomonas aeruginosa pneumonic rats showed that the chronic stage of the infection significantly reduced the drug lung penetration. In this study, CIP lung penetration in Klebsiella pneumoniae chronically (14 d) infected rats following CIP 20 mg/kg i.v. bolus dosing was investigated and the popPK model developed previously was used to evaluate CIP lung exposure. Drug plasma exposure was similar for both bacteria and higher than observed in healthy animals. Probability of target attainment analysis using plasma data following current dosing regimen (20 mg q8h equivalent to 400 mg q8h in humans) showed that CIP PK/PD index (ƒAUC0-24/MIC ≥90) is achieved for the most prevalent MIC's of both bacteria. However, CIP free lung concentrations were reduced in infected animals by 46.8 % (P. aeruginosa) and 68.4 % (K. pneumoniae) in comparison to healthy animals. The higher lung clearance observed (0.306 L/h/kg) in K. pneumoniae infected animals lead to a lower free CIP lung exposure in comparison to the P. aeruginosa group (0.105 L/h/kg). In summary, although plasma PK/PD index is achieved by the current regimen, chronic pneumonia by biofilm-forming bacteria decreases lung exposure to CIP and this decrease is dependent on the infecting bacteria. The clinical relevance of this finding needs to be determined.
Keywords: Ciprofloxacin; Klebsiella pneumoniae, lung infection; Microdialysis; Population pharmacokinetic model; Pseudomonas aeruginosa.
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