In vitro characterization of fluoroquinolone concentration/MIC antimicrobial activity and resistance while simulating clinical pharmacokinetics of levofloxacin, ofloxacin, or ciprofloxacin against Streptococcus pneumoniae

Abstract

The relationship between antibacterial effect, resistance, and concentration/MIC parameters with S. pneumoniae was studied. Thirty duplicate bacterial concentration-time-kill curve (TKC) experiments were performed with an in vitro model. TKC with levofloxacin (LVX), Ofloxacin (OFX), and ciprofloxacin (CIP) were studied against six S. pneumoniae isolates. Experiments simulated variable peak serum concentrations, but clinically relevant half-lives and dosing intervals. TKC were performed in Mueller-Hinton Broth supplemented with horse blood (SMHB) at 10 7 CFU/ml. Susceptibility was assessed on colonies recovered post TKC. Multiple regression tested association of pharmacodynamic variables with antimicrobial effect, and logistic regression with resistance post TKC. Only drug ( r 2 = 0.27; p < 0.0001) and AUC/MIC 24 ( r 2 = 0.15; p < 0.001) were significant variables predictive of antibacterial effect. LVX AUC/MIC 24 of ≤20 CFU/ml · Hr were significantly related to a loss of antimicrobial effect, and CIP was significantly more likely to select for resistant pneumococci than OFX, or LVX ( p = 0.03). Selection of fluoroquinolone resistance only occurred at C max/MIC < 5.0 ( p = 0.03). No independent association between pharmacokinetic or microbiological variables and resistance could be identified. The relationship between AUC/MIC 24 and antibacterial effect may be organism and fluoroquinolone specific. Clinically relevant CIP dosages that result in low C max/MIC against S. pneumoniae may foster fluoroquinolone resistance.