JAC Advance Access originally published online on January 16, 2004
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Journal of Antimicrobial Chemotherapy (2004) 53, 305-310
© 2004 The British Society for Antimicrobial Chemotherapy
Ceftriaxone acts synergistically with levofloxacin in experimental meningitis and reduces levofloxacin-induced resistance in penicillin-resistant pneumococci
1 Department of Internal Medicine, Spital Bern-Ziegler, Bern; 2 Department of Infectious Diseases, CHUV, Lausanne; 3 Department of Internal Medicine, Inselspital, Bern, Switzerland
Received 13 April 2003; returned 27 October 2003, revised 15 November 2003; accepted 17 November 2003
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 (1x 125 mg/kg) was slightly less bactericidal (–0.30 
log10 cfu/mL.h) compared with levofloxacin (–0.45 log10 cfu/mL.h) against the penicillin-resistant strain WB4. The combination therapy (levofloxacin and ceftriaxone) was significantly superior (–0.64 log10 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: Streptococcus pneumoniae, quinolones, ß-lactam antibiotics
* Corresponding author. Tel: +41-31-632-34-72; Fax: +41-31-632-38-47; E-mail: pcottagn{at}insel.ch
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