Five Fluoroquinolones in a Neutropenic Murine Model
Five Fluoroquinolones in a Neutropenic Murine Model
Study Objective. To compare the antistreptococcal activity of five fluoroquinolone antibiotics, using a neutropenic murine model of pneumococcal pulmonary infection.
Design. Animal experiment.
Setting. University-affiliated research center.
Animals. Neutropenic and control mice weighing 24-29 g.
Intervention. After induction of neutropenia, renal failure, and infection with Streptococcus pneumoniae, the mice received one of five fluoroquinolones twice/day for 72 hours beginning 12 hours after infection. Dosages were selected to approximate 0.1 x AUC0-24 (area under the concentration-time curve from 0-24 hours) and AUC0-24 achieved in humans. Control mice received normal saline. Survival was assessed at regular intervals for up to 10 days. At least 10 mice were included in each cohort (range 10-34).
Measurements and Main Results. Ciprofloxacin, clinafloxacin, grepafloxacin, levofloxacin, and moxifloxacin were studied at subtherapeutic and therapeutic dosages against three quinolone-susceptible isolates of S. pneumoniae that lacked mutations in parC, parE, and gyrA. Pharmacokinetic profile of each agent and dosing regimen was determined. A composite survival curve for all fluoroquinolones and isolates was constructed. Relationships between survival rate at 72 hours and AUC:MIC (minimum inhibitory concentration), peak:MIC, time above the MIC (percentage of dosing interval) for total and free drug concentrations were fit by using a sigmoid maximal effect (Emax) model. Survival was significantly better in the higher dosage group than in the lower dosage group. Time above MIC did not display a correlation with outcome. The AUC:MIC showed a greater correlation with outcome (R = 0.56 total, 0.54 free) than did peak:MIC (R = 0.52 total, 0.51 free). With use of composite data, total AUC:MIC ratios associated with 50%, 90%, and 99% of Emax were 34:1, 56:1, and 95:1, respectively.
Conclusions. In this model, efficacy was achieved with the fluoroquinolone antibiotics at dosages yielding AUC0-24 comparable to those obtained in humans. One pharmacodynamic parameter (i.e., AUC:MIC) may be applied to various fluoroquinolones and isolates of S. pneumoniae. The AUC:MIC was more predictive of outcome than was time above the MIC or peak:MIC.
The introduction of newer fluoroquinolone antimicrobial agents into the marketplace has been met with both enthusiasm and caution. Newer agents in this class have greater gram-positive activity, including activity against Streptococcus pneumoniae, compared with those that have preceded them. With the emergence of multidrug-resistant S. pneumoniae, newer fluoroquinolones are thought by some to be appropriate agents for the management of community-acquired bronchopulmonary infec-tions. However, in light of previous experience with ciprofloxacin failures occurring during the treatment of pneumococcal infections because of the emergence of resistance while on therapy, the question arises, will newer fluoroquinolones with improved pharmaco-dynamic properties result in clinical success without the development of resistance? Many studies describing the pharmacodynamic properties of the fluoro-quinolones against S. pneumoniae used in vitro model systems. In this study, we compared five fluoroquinolones in the treatment of pneumococcal lung infections in neutropenic mice and the pharmacodynamic properties associated with survival.
Study Objective. To compare the antistreptococcal activity of five fluoroquinolone antibiotics, using a neutropenic murine model of pneumococcal pulmonary infection.
Design. Animal experiment.
Setting. University-affiliated research center.
Animals. Neutropenic and control mice weighing 24-29 g.
Intervention. After induction of neutropenia, renal failure, and infection with Streptococcus pneumoniae, the mice received one of five fluoroquinolones twice/day for 72 hours beginning 12 hours after infection. Dosages were selected to approximate 0.1 x AUC0-24 (area under the concentration-time curve from 0-24 hours) and AUC0-24 achieved in humans. Control mice received normal saline. Survival was assessed at regular intervals for up to 10 days. At least 10 mice were included in each cohort (range 10-34).
Measurements and Main Results. Ciprofloxacin, clinafloxacin, grepafloxacin, levofloxacin, and moxifloxacin were studied at subtherapeutic and therapeutic dosages against three quinolone-susceptible isolates of S. pneumoniae that lacked mutations in parC, parE, and gyrA. Pharmacokinetic profile of each agent and dosing regimen was determined. A composite survival curve for all fluoroquinolones and isolates was constructed. Relationships between survival rate at 72 hours and AUC:MIC (minimum inhibitory concentration), peak:MIC, time above the MIC (percentage of dosing interval) for total and free drug concentrations were fit by using a sigmoid maximal effect (Emax) model. Survival was significantly better in the higher dosage group than in the lower dosage group. Time above MIC did not display a correlation with outcome. The AUC:MIC showed a greater correlation with outcome (R = 0.56 total, 0.54 free) than did peak:MIC (R = 0.52 total, 0.51 free). With use of composite data, total AUC:MIC ratios associated with 50%, 90%, and 99% of Emax were 34:1, 56:1, and 95:1, respectively.
Conclusions. In this model, efficacy was achieved with the fluoroquinolone antibiotics at dosages yielding AUC0-24 comparable to those obtained in humans. One pharmacodynamic parameter (i.e., AUC:MIC) may be applied to various fluoroquinolones and isolates of S. pneumoniae. The AUC:MIC was more predictive of outcome than was time above the MIC or peak:MIC.
The introduction of newer fluoroquinolone antimicrobial agents into the marketplace has been met with both enthusiasm and caution. Newer agents in this class have greater gram-positive activity, including activity against Streptococcus pneumoniae, compared with those that have preceded them. With the emergence of multidrug-resistant S. pneumoniae, newer fluoroquinolones are thought by some to be appropriate agents for the management of community-acquired bronchopulmonary infec-tions. However, in light of previous experience with ciprofloxacin failures occurring during the treatment of pneumococcal infections because of the emergence of resistance while on therapy, the question arises, will newer fluoroquinolones with improved pharmaco-dynamic properties result in clinical success without the development of resistance? Many studies describing the pharmacodynamic properties of the fluoro-quinolones against S. pneumoniae used in vitro model systems. In this study, we compared five fluoroquinolones in the treatment of pneumococcal lung infections in neutropenic mice and the pharmacodynamic properties associated with survival.
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