Cefotaxime acts synergistically with levofloxacin in experimental meningitis due to penicillin-resistant pneumococci and prevents selection of levofloxacin-resistant mutants in vitro.
Cefotaxime, given in two doses (each 100 mg/kg of body weight), produced a good bactericidal activity (-0.47 Deltalog(10) CFU/ml. h) which was comparable to that of levofloxacin (-0.49 Deltalog(10) CFU/ml. h) against a penicillin-resistant pneumococcal strain WB4 in experimental meningitis. Cefotaxime combined with levofloxacin acted synergistically (-1.04 Deltalog(10) CFU/ml. h). Synergy between cefotaxime and levofloxacin was also demonstrated in vitro in time killing assays and with the checkerboard method for two penicillin-resistant strains (WB4 and KR4). Using in vitro cycling experiments, the addition of cefotaxime in sub-MIC concentrations (one-eighth of the MIC) drastically reduced levofloxacin-induced resistance in the same two strains (64-fold increase of the MIC of levofloxacin after 12 cycles versus 2-fold increase of the MIC of levofloxacin combined with cefotaxime). Mutations detected in the genes encoding topoisomerase IV (parC and parE) and gyrase (gyrA and gyrB) confirmed the levofloxacin-induced resistance in both strains. Addition of cefotaxime in low doses was able to suppress levofloxacin-induced resistance.
Kühn
F
F
Department of Internal Medicine, Spital Bern-Ziegler, Inselspital, Bern, Switzerland.
Cottagnoud
M
M
Acosta
F
F
Flatz
L
L
Entenza
J
J
Cottagnoud
P
P
D000818:Animals; D000890:Anti-Infective Agents / Q000134:cerebrospinal fluid / Q000494:pharmacology / Q000627:therapeutic use*; D002439:Cefotaxime / Q000134:cerebrospinal fluid / Q000494:pharmacology / Q000627:therapeutic use*; D002511:Cephalosporins / Q000134:cerebrospinal fluid / Q000494:pharmacology / Q000627:therapeutic use*; D004269:DNA, Bacterial / Q000235:genetics; D024881:Drug Resistance, Bacterial; D004357:Drug Synergism; D064704:Levofloxacin; D008586:Meningitis, Pneumococcal / Q000188:drug therapy* / Q000382:microbiology; D008826:Microbial Sensitivity Tests; D009154:Mutation / Q000235:genetics; D015242:Ofloxacin / Q000134:cerebrospinal fluid / Q000494:pharmacology / Q000627:therapeutic use*; D010403:Penicillin Resistance; D011817:Rabbits; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000235:genetics*
D000890:Anti-Infective Agents; D002511:Cephalosporins; D004269:DNA, Bacterial; D064704:Levofloxacin; D015242:Ofloxacin; D002439:Cefotaxime