Pharmacodynamics of Gatifloxacin against Streptococcus pneumoniae in an In Vitro Pharmacokinetic Model: Impact of Area under the Curve/MIC Ratios on Eradication

Previous studies have demonstrated that fluoroquinolone area under the curve (AUC)/MIC ratios of 30 to 50 are sufficient to eradicate pneumococci from in vitro pharmacokinetic models (IVPMs). However, more systematic studies of the impact of AUC/MIC ratios on the antipneumococcal activities of fluoroquinolones are needed. In the present study, a two-compartment IVPM was used to evaluate the impact of AUC/MIC ratios on the pharmacodynamics of gatifloxacin against four strains of Streptococcus pneumoniae. Gatifloxacin MICs were 0.4 to 1 g/ml, whereas levofloxacin MICs were 1.8 to 3.2 g/ml. Since both peak concentration/MIC (peak/MIC) and AUC/MIC ratios affect fluoroquinolone pharmacodynamics, logarithmic-phase cultures (5 10 7 CFU/ml) were exposed to gatifloxacin at constant peak/MIC ratios of 2:1 to 3:1 at 0 and 24 h, elimination half-lives were varied to provide a range of AUC/MIC ratios, and changes in viable counts were measured over 30 h. As a comparison, levofloxacin was evaluated at similar peak/MIC ratios and at AUC/MIC ratios of 30 to 38. For each strain, killing rates through 4 to 8 h were similar since peak/MIC ratios were kept constant. However, continued killing and eradication were observed only when gatifloxacin AUC/MIC ratios were 27 to 48. Levofloxacin also provided eradication. In contrast, substantial regrowth was observed in most experiments when gatifloxacin AUC/MIC ratios were 9 to 24. These data provide further support that fluoroquinolone AUC/MIC ratios of approximately 30 or higher can be sufficient for eradication of pneumococci from IVPMs. Furthermore, the overall impact of the AUC/MIC ratio was not influenced by the strain evaluated or its susceptibility to gatifloxacin. Further studies with other fluoroquinolones and pneumococci that exhibit wider ranges of susceptibilities are warranted. In addition, similar studies with higher peak/MIC ratios are needed to better define the impact of AUC/MIC ratios and peak/MIC ratios on the antipneumococcal pharmacodynamics of fluoroquinolones. Clinical data and data from in vitro pharmacodynamic studies have suggested that the ratio of the area under the concentration curve (AUC) divided by the MIC (the AUC/MIC ratio) is an important pharmacodynamic parameter that influences the outcome of fluoroquinolone therapy. Although initial clinical observations with ciprofloxacin in the treatment of serious infections caused by gram-negative bacteria suggested that AUC/MIC ratios of 125 or greater were needed to optimize the clinical response (8), data from studies with in vitro pharmacokinetic models (IVPMs) have suggested that AUC/MIC ratios in the range of 30 to 50 are sufficient to achieve eradication of Streptococcus pneumoniae with various fluoroquinolones (9–11). On the basis of these published observations, it has been suggested that the minimum AUC/MIC ratio required to achieve eradication from IVPMs and to potentially provide clinical efficacy with fluoroquinolones is approximately 30. However, these initial studies were narrow in their focus and were not designed to systematically evaluate the impacts of AUC/MIC ratios on the pharmacodynamics of fluoroquinolones. In order to truly understand the relationship between the AUC/MIC ratios of fluoroquinolones and pharmacodynamic interactions with S. pneumoniae, a systematic evaluation of the pharmacodynamics of fluoroquinolones against pneumococci over a range of AUC/MIC ratios is required. In the present study, a two-compartment IVPM was used to expose clinical isolates of S. pneumoniae to gatifloxacin over a range of AUC/MIC ratios from approximately 10 to 50 and to evaluate the impacts of the AUC/MIC ratios on the eradication of pneumococci from the model. As a control, the pharmacodynamics of levofloxacin at AUC/MIC ratios of approximately 30 were also studied. Since fluoroquinolones are concentration-dependent bactericidal agents and, thus, peak concentration/MIC (peak/MIC) ratios influence their pharmacodynamics, peak/MIC ratios were kept constant in these studies and AUC/MIC ratios were varied by altering the elimination half-lives.