Effect of linezolid on the 50% lethal dose and 50% protective dose in treatment of infections by Gram-negative pathogens in naive and immunosuppressed mice and on the efficacy of ciprofloxacin in an acute murine model of septicemia.
Murine 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 with Klebsiella pneumoniae 53A1109, K. pneumoniae GC6658, and Pseudomonas aeruginosa UC12120 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 (LD(50)s) and 50% protective doses (PD(50)s). A clinically relevant, high-dose regimen of linezolid had no significant effect on LD(50) in these models. This lack of effect was independent of immune status. A combination of oral ciprofloxacin with linezolid yielded lower PD(50)s 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.
Pfizer Worldwide Research and Development, Groton, Connecticut, USA.
Andrea
A
Marra
Lucinda
L
Lamb
Ivette
I
Medina
David
D
George
Glenn
G
Gibson
Joel
J
Hardink
Jady
J
Rugg
Jeffrey
J
Van Deusen
John P
JP
O'Donnell
D000081:Acetamides / Q000008:administration & dosage*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D002939:Ciprofloxacin / Q000008:administration & dosage*; D004333:Drug Administration Routes; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D016867:Immunocompromised Host; D007710:Klebsiella Infections / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology / Q000401:mortality; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000254:growth & development; D007928:Lethal Dose 50; D000069349:Linezolid; D051379:Mice; D023421:Models, Animal; D023303:Oxazolidinones / Q000008:administration & dosage*; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology / Q000401:mortality; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000254:growth & development; D018805:Sepsis / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology / Q000401:mortality; D015996:Survival Rate; D016896:Treatment Outcome
D000081:Acetamides; D000900:Anti-Bacterial Agents; D023303:Oxazolidinones; D002939:Ciprofloxacin; D000069349:Linezolid