Journal Article

Ceftriaxone acts synergistically with levofloxacin in experimental meningitis and reduces levofloxacin-induced resistance in penicillin-resistant pneumococci

L. Flatz, M. Cottagnoud, F. Kühn, J. Entenza, A. Stucki and P. Cottagnoud

in Journal of Antimicrobial Chemotherapy

Published on behalf of British Society for Antimicrobial Chemotherapy

Volume 53, issue 2, pages 305-310
Published in print February 2004 | ISSN: 0305-7453
Published online February 2004 | e-ISSN: 1460-2091 | DOI: http://dx.doi.org/10.1093/jac/dkh082
Ceftriaxone acts synergistically with levofloxacin in experimental meningitis and reduces levofloxacin-induced resistance in  penicillin-resistant pneumococci

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Ceftriaxone acted synergistically with levofloxacin in time–killing assays in vitro over 8 h against two penicillin-resistant pneumococcal strains (WB4 and KR4; MIC of penicillin: 4 mg/L). Synergy was confirmed with the chequerboard method, showing FIC indices of 0.25. In the experimental rabbit meningitis model, ceftriaxone (1× 125 mg/kg) was slightly less bactericidal (–0.30 Δlog10 cfu/mL.h) compared with levofloxacin (–0.45 Δlog10 cfu/mL.h) against the penicillin-resistant strain WB4. The combination therapy (levofloxacin and ceftriaxone) was significantly superior (–0.64 Δlog10 cfu/mL.h) to either monotherapy. In cycling experiments in vitro, the addition of ceftriaxone at a sub-MIC concentration (1/16 MIC) reduced levofloxacin-induced resistance in the two strains KR4 and WB4. After 12 cycles with levofloxacin monotherapy, the MIC increased 64-fold in both strains versus a 16-fold increase with the combination (levofloxacin + ceftriaxone 1/16 MIC). In both strains, levofloxacin-induced resistance was confirmed by mutations detected in the genes parC and gyrA, encoding for subunits of topoisomerase IV and gyrase, respectively. The addition of ceftriaxone suppressed mutations in parC but led to a new mutation in parE in both strains.

Keywords: Keywords: Streptococcus pneumoniae, quinolones, β-lactam antibiotics

Journal Article.  3809 words.  Illustrated.

Subjects: Medical Oncology ; Critical Care

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