title: Ceftriaxone acts synergistically with levofloxacin in experimental meningitis and reduces levofloxacin-induced resistance in penicillin-resistant pneumococci.
abstract: 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 Deltalog(10) cfu/mL(.)h) compared with levofloxacin (-0.45 Deltalog(10) cfu/mL(.)h) against the penicillin-resistant strain WB4. The combination therapy (levofloxacin and ceftriaxone) was significantly superior (-0.64 Deltalog(10) 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.
authors.affiliation: Department of Internal Medicine, Spital Bern-Ziegler, Bern, Switzerland. pcottagn@insel.ch
authors.forename: L
authors.initials: L
authors.lastname: Flatz
authors.forename: M
authors.initials: M
authors.lastname: Cottagnoud
authors.forename: F
authors.initials: F
authors.lastname: Kühn
authors.forename: J
authors.initials: J
authors.lastname: Entenza
authors.forename: A
authors.initials: A
authors.lastname: Stucki
authors.forename: P
authors.initials: P
authors.lastname: Cottagnoud
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000134:cerebrospinal fluid / Q000494:pharmacology*; D002443:Ceftriaxone / Q000134:cerebrospinal fluid / Q000494:pharmacology*; D002511:Cephalosporins / Q000134:cerebrospinal fluid / Q000494:pharmacology*; D027101:DNA Topoisomerase IV / Q000235:genetics; D004269:DNA, Bacterial / Q000235:genetics; D024881:Drug Resistance, Bacterial; D004357:Drug Synergism; D064704:Levofloxacin; D008586:Meningitis, Pneumococcal / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000382:microbiology; D008826:Microbial Sensitivity Tests; D015242:Ofloxacin / Q000134:cerebrospinal fluid / Q000494:pharmacology*; D010403:Penicillin Resistance; D011817:Rabbits; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013296:Streptococcus pneumoniae / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D004269:DNA, Bacterial; D064704:Levofloxacin; D002443:Ceftriaxone; D015242:Ofloxacin; D027101:DNA Topoisomerase IV