Pharmacodynamics of Fluoroquinolones against Streptococcus pneumoniae in Patients with Community-Acquired Respiratory Tract Infections

Fluoroquinolone antibiotic agents have demonstrated efﬁcacy in the treatment of respiratory tract infections. This analysis was designed to examine the relationship between drug exposure, as measured by the free-drug area under the concentration-time curve at 24 h (AUC 24 )/MIC ratio, and clinical and microbiological responses in patients with community-acquired respiratory tract infections involving Streptococcus pneumoniae . The study population included 58 adult patients (34 males, 24 females) who were enrolled in either of two phase III, randomized, multicenter, double-blind studies of levoﬂoxacin versus gatiﬂoxacin for the treatment of commu-nity-acquired pneumonia or acute exacerbation of chronic bronchitis. Clearance equations from previously published population pharmacokinetic models were used in conjunction with dose and adjusted for protein binding to estimate individual patient free-drug AUC 24 s. In vitro susceptibility was determined in a central laboratory by broth microdilution in accordance with NCCLS guidelines. Pharmacodynamic analyses were performed on data from all evaluable patients with documented S. pneumoniae infection using univariate and multivariable logistic regression; pharmacodynamic breakpoints were estimated using Classiﬁcation and Regression Tree analysis. A statistically signiﬁcant ( P (cid:1) 0.013) relationship between microbiological response and the free-drug AUC 24 /MIC ratio was detected. At a free-drug AUC 24 /MIC ratio of <33.7, the probability of a microbiological response was 64%, and at a free-drug AUC 24 /MIC ratio of >33.7, it was 100% ( P < 0.01). These ﬁndings provide a minimum target free-drug AUC 24 /MIC ratio for the treatment of infections involving S. pneumoniae with ﬂuoroquinolone antibiotics and provide a paradigm for the selection of ﬂuoroquinolones to be brought forward from drug discovery into clinical development and dose selection for clinical trials. target free-drug AUC /MIC ratios are used in conjunction with stochastic modeling techniques, these ﬁndings may be used to support susceptibility breakpoints for ﬂuoroquinolone antibiotics 24 /MIC. For the clinical evaluation, patients were classiﬁed as cured or the treatment was classiﬁed a failure as previously de-scribed. For the microbiological evaluation, eradication and presumed eradica- tion of the organism were considered successful outcomes; the persistence and presumed persistence of the organism were considered unsuccessful outcomes. Classiﬁcation and Regression Tree (CART) analysis (as implemented in S-Plus 2000 professional release 2) was used to select a breakpoint(s) which partitioned patients’ responses on the basis of free-drug AUC 24 /MIC ratios. Model bias and precision. Model bias and precision were evaluated using drug concentration data from the subset of patients from whom actual drug concentration data were obtained. The plasma-sampling schedules included two steady- state time points (peak and trough) and were measured using high-performance liquid chromatographic assay (9). A plot of free-drug AUC 24 s estimated using these concentrations in plasma in conjunction with demographic data versus free-drug AUC 24 s estimated using demographic data alone was made to validate the regression equation used in these analyses. The slope, y intercept, r value, median bias, and level of precision for AUC prediction were calculated.