Cefotaxime acts synergistically with levofloxacin in experimental meningitis due to penicillin-resistant pneumococci and prevents selection of levofloxacin-resistant mutants in vitro

Antimicrob Agents Chemother. 2003 Aug;47(8):2487-91. doi: 10.1128/aac.47.8.2487-2491.2003.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Infective Agents / cerebrospinal fluid
  • Anti-Infective Agents / pharmacology
  • Anti-Infective Agents / therapeutic use*
  • Cefotaxime / cerebrospinal fluid
  • Cefotaxime / pharmacology
  • Cefotaxime / therapeutic use*
  • Cephalosporins / cerebrospinal fluid
  • Cephalosporins / pharmacology
  • Cephalosporins / therapeutic use*
  • DNA, Bacterial / genetics
  • Drug Resistance, Bacterial
  • Drug Synergism
  • Levofloxacin*
  • Meningitis, Pneumococcal / drug therapy*
  • Meningitis, Pneumococcal / microbiology
  • Microbial Sensitivity Tests
  • Mutation / genetics
  • Ofloxacin / cerebrospinal fluid
  • Ofloxacin / pharmacology
  • Ofloxacin / therapeutic use*
  • Penicillin Resistance
  • Rabbits
  • Reverse Transcriptase Polymerase Chain Reaction
  • Streptococcus pneumoniae / drug effects*
  • Streptococcus pneumoniae / genetics*

Substances

  • Anti-Infective Agents
  • Cephalosporins
  • DNA, Bacterial
  • Levofloxacin
  • Ofloxacin
  • Cefotaxime