Evaluation of survival and pharmacodynamic relationships for five fluoroquinolones in a neutropenic murine model of pneumococcal lung infection.
OBJECTIVE
To compare the antistreptococcal activity of five fluoroquinolone antibiotics, using a neutropenic murine model of pneumococcal pulmonary infection.


METHODS
Animal experiment.


METHODS
University-affiliated research center.


METHODS
Neutropenic and control mice weighing 24-29 g.


METHODS
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).


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 (R2 = 0.56 total, 0.54 free) than did peak:MIC (R2 = 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.
Ernst
Erika J
EJ
Colleges of Pharmacy, University of Iowa, Iowa City 52242-1112, USA. erika-ernst@uiowa.edu
Klepser
Michael E
ME
Petzold
C Rosemarie
CR
Doern
Gary V
GV
D000818:Animals; D000890:Anti-Infective Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods / Q000706:statistics & numerical data; D024841:Fluoroquinolones; D051379:Mice; D008826:Microbial Sensitivity Tests / Q000706:statistics & numerical data; D009503:Neutropenia / Q000097:blood* / Q000139:chemically induced / Q000188:drug therapy; D011018:Pneumonia, Pneumococcal / Q000097:blood* / Q000188:drug therapy; D051437:Renal Insufficiency / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy; D016019:Survival Analysis
D000890:Anti-Infective Agents; D024841:Fluoroquinolones