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

Abstract

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 community-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 ‫؍‬ 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 may 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. Further, when target free-drug AUC 24 /MIC ratios are used in conjunction with stochastic modeling techniques, these findings may be used to support susceptibility breakpoints for fluoroquinolone antibiotics and S. pneumoniae.The relationship that exists between drug exposure and the MIC for an infectious organism has been shown to be predictive of microbiological eradication (3,4,5,14). Existing data suggest that, for fluoroquinolones, an area under the concentration-time curve at 24 h (AUC 24 )/MIC ratio of 100 to 125 correlates with optimal clinical and microbiological outcomes in seriously ill patients infected with gram-negative enteric pathogens and Pseudomonas aeruginosa (7,8). However, over the past several years there has been considerable controversy as to whether or not this pharmacodynamic target applies to all patient populations and all organisms.Data from in vitro and animal models of infection have recently emerged and suggest that, for Streptococcus pneumoniae, the optimal free-drug AUC 24 /MIC ratio is much lower than 100 to 125. For instance, an in vitro model of pneumococcal infec...

Susceptibility of Streptococcus pneumoniae to Fluoroquinolones in Canada

“…Thus, it is also important to understand whether differences in how antibiotics are used can increase or decrease selective pressure. The introduction of ciprofloxacin was associated with the rapid emergence of ciprofloxacin resistance in pneumococci in Canada and around the world (2,6,19,27), and the volume of fluoroquinolone use has been shown to be strongly associated with resistance. When newer fluoroquinolones more active against pneumococci than ciprofloxacin were introduced in the late 1990s, it was hypothesized that their use would reduce selective pressure for resistance in pneumococci.…”

“…The parameter that best predicts the efficacy of the fluoroquinolones in eradicating pneumococci is the ratio of the area under the concentration-time curve (AUC) to the MIC. In vitro and in vivo studies and clinical trials have determined that maintenance of an unbound AUC/ MIC ratio of 30 to 40 maximizes the bactericidal efficacy of fluoroquinolones against S. pneumoniae and minimizes the selection of resistant isolates during therapy (2). Ciprofloxacin at doses used for therapy never achieves this target, levofloxacin at a dose of 500 mg once a day will just achieve it, and moxifloxacin and gatifloxacin used at recommended daily doses will achieve AUC/MIC ratios well above it (19,27,28).…”

Pharmacokinetics of Intravenous Levofloxacin Administered at 750 Milligrams in Obese Adults

“…The most accurate predictor of fluoroquinolone success appears to be AUC/MIC (although the target AUC/MIC ratio likely depends on the causative pathogen). For infections caused by Streptococcus pneumoniae, an AUC/MIC ratio Ͼ 30 has been associated with clinical and microbiologic response (2). The ratio needed to prevent first-step mutations in these bacteria may be higher (20).…”

Ventilator-Associated Pneumonia: Diagnosis, Treatment, and Prevention

“…2). Coupling an understanding of the mechanisms of how bacteria are eradicated and PK/PD parameters results in reduced mortality and morbidity (3,4,18,84,120,151,152,177,217).…”