Worldwide Antimicrobial Susceptibility Patterns and Pharmacodynamic Comparisons of Gatifloxacin and Levofloxacin against Streptococcus pneumoniae : Report from the Antimicrobial Resistance Rate Epidemiology Study Team

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Abstract
The use of fluoroquinolones for the treatment of community-acquired respiratory tract infection is increasing. Since for Streptococcus pneumoniae a ratio of the 24-h area under the concentration-time curve (AUC 24 ) for the agent to the MIC (AUC 24 /MIC) greater than 30 for the fraction of unbound drug ( f u ) is the major pharmacokinetic-pharmacodynamic (PK-PD) parameter correlating with bacterial eradication by fluoroquinolones in nonclinical models of infection and in infected patients, the Antimicrobial Resistance Rate Epidemiology Study Team systematically compared the in vitro susceptibility patterns and estimated the probability of attainment of the PK-PD target ratios for gatifloxacin and levofloxacin against pneumococci worldwide. Monte Carlo simulation was used to estimate the probability that gatifloxacin or levofloxacin would achieve an f u AUC 24 /MIC ratio of 30 or greater. A total of 10,978 S. pneumoniae isolates collected from 1997 to 2000, each indexed by site of infection and geographic region (North America, Latin America, Europe, and Asia-Pacific), were used to estimate the probability mass functions of the microbiological activities for each region considered in the analysis. f u AUC 24 probability distribution functions were estimated by using data that were part of each product's submission accepted by the Food and Drug Administration. A 10,000-patient simulation was performed for each drug-organism-region combination. The percentages of strains susceptible to each drug by region were as follows: for gatifloxacin, North America, 99.6%; Latin America, 99.8%; Europe, 99.9%; and Asia-Pacific, 99.2%; for levofloxacin, North America, 99.6%; Latin America, 99.8%; Europe, 99.8%; and Asia-Pacific, 99.1%. The MIC at which 50% of isolates are inhibited (MIC 50 ) and the MIC 90 of each drug by region were as follows: for gatifloxacin, North America, 0.25 and 0.5 mg/liter, respectively; Latin America, 0.25 and 0.5 mg/liter, respectively; Europe, 0.25 and 0.5 mg/liter, respectively; and Asia-Pacific, 0.25 and 0.5 mg/liter, respectively; for levofloxacin, North America, 1 and 2 mg/liter, respectively; Latin America, 1 and 2 mg/liter, respectively; Europe, 1 and 1 mg/liter, respectively; and Asia-Pacific, 1 and 1 mg/liter, respectively. The probabilities of attaining an f u AUC 24 /MIC ratio greater than 30 for each drug by region were as follows: for gatifloxacin, North America, 97.6%; Latin America, 98.3%; Europe, 99.1%; and Asia-Pacific, 98.8%; for levofloxacin, North America, 78.9%; Latin America, 84.1%; Europe, 87.1%; and Asia-Pacific, 86.5%. These results for a very large collection of recent clinical strains demonstrate that, globally, gatifloxacin is two- to fourfold more active than levofloxacin against S. pneumoniae and that gatifloxacin has an overall 14.3% higher probability of achieving clinically important PK-PD target ratios than levofloxacin.

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