Author:
Marra Andrea,Lamb Lucinda,Medina Ivette,George David,Gibson Glenn,Hardink Joel,Rugg Jady,Van Deusen Jeffrey,O'Donnell John P.
Abstract
ABSTRACTMurine models of infection were used to study the effect of linezolid on the virulence of Gram-negative bacteria and to assess potential pharmacodynamic interactions with ciprofloxacin in the treatment of these infections, prompted by observations from a recent clinical trial. Naive and immunosuppressed mice were challenged withKlebsiella pneumoniae53A1109,K. pneumoniaeGC6658, andPseudomonas aeruginosaUC12120 in acute sepsis and pulmonary infection models, using different serial dilutions of these pathogens (groups of 8 animals each). Linezolid (100 mg/kg/dose) was administered orally at 0.5 and 4.0 h postchallenge in the sepsis model and at 4 h postchallenge followed by 2 days of twice-daily treatment in the pulmonary model. Further, ciprofloxacin alone and in combination with oral linezolid was investigated in the sepsis model. Survival was assessed for 4 and 10 days postchallenge in the systemic and respiratory models, respectively. The data were fitted to a nonlinear regression analysis to determine 50% lethal doses (LD50s) and 50% protective doses (PD50s). A clinically relevant, high-dose regimen of linezolid had no significant effect on LD50in these models. This lack of effect was independent of immune status. A combination of oral ciprofloxacin with linezolid yielded lower PD50s than oral ciprofloxacin alone (ciprofloxacin in combination, 8.4 to 32.7 mg/kg; oral ciprofloxacin, 39.4 to 88.3 mg/kg). Linezolid did not improve the efficacy of subcutaneous ciprofloxacin (ciprofloxacin in combination, 2.0 to 2.4 mg/kg; subcutaneous ciprofloxacin, 2.0 to 2.8 mg/kg). In conclusion, linezolid does not seem to potentiate infections caused by Gram-negative pathogens or to interact antagonistically with ciprofloxacin.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Reference23 articles.
1. Bayer Healthcare. 2008. Cipro® (ciprofloxacin hydrochloride) tablets, Cipro® (ciprofloxacin) oral suspension. Revised October 2008. http://www.univgraph.com/bayer/inserts/ciprotab.pdf.
2. Oxazolidinone antibacterial agents;Brickner;Curr. Pharm. Des.,1996
3. Performance standards for antimicrobial susceptibility testing; twentieth informational supplement;CLSI,2010
4. Oxazolidinone antibiotics;Diekema;Lancet,2001
5. LEADER Program results for 2009: an activity and spectrum analysis of linezolid using 6,414 clinical isolates from 56 medical centers in the United States;Farrell;Antimicrob. Agents Chemother.,2011
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