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Antimicrobial Agents and Chemotherapy, August 2003, p. 2487-2491, Vol. 47, No. 8
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.8.2487-2491.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Cefotaxime Acts Synergistically with Levofloxacin in Experimental Meningitis Due to Penicillin-Resistant Pneumococci and Prevents Selection of Levofloxacin-Resistant Mutants In Vitro

F. Kühn,1 M. Cottagnoud,1 F. Acosta,1 L. Flatz,1 J. Entenza,2 and P. Cottagnoud3*

Department of Internal Medicine, Spital Bern-Ziegler,1 Department of Internal Medicine, Inselspital, Bern,3 Department of Infectious Diseases, CHUV, Lausanne, Switzerland2

Received 26 November 2002/ Returned for modification 4 March 2003/ Accepted 12 May 2003

Cefotaxime, given in two doses (each 100 mg/kg of body weight), produced a good bactericidal activity (-0.47 {Delta}log10 CFU/ml · h) which was comparable to that of levofloxacin (-0.49 {Delta}log10 CFU/ml · h) against a penicillin-resistant pneumococcal strain WB4 in experimental meningitis. Cefotaxime combined with levofloxacin acted synergistically (-1.04 {Delta}log10 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.

* Corresponding author. Mailing address: Department of Internal Medicine, Inselspital, Freiburgstrasse, 3010 Bern, Switzerland. Phone: 41-31-632-34-72. Fax: 41-31-632-38-47. E-mail: pcottagn{at}insel.ch.

Antimicrobial Agents and Chemotherapy, August 2003, p. 2487-2491, Vol. 47, No. 8
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.8.2487-2491.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Cottagnoud, P., Johnson, M., Cottagnoud, M., Piddock, L. (2005). Preincubation of Pneumococci with {beta}-Lactams Alone or Combined with Levofloxacin Prevents Quinolone-Induced Resistance without Increasing Intracellular Levels of Levofloxacin. Antimicrob. Agents Chemother. 49: 3517-3519 [Abstract] [Full Text]  
  • Cottagnoud, P., Pfister, M., Acosta, F., Cottagnoud, M., Flatz, L., Kuhn, F., Muller, H.-P., Stucki, A. (2004). Daptomycin Is Highly Efficacious against Penicillin-Resistant and Penicillin- and Quinolone-Resistant Pneumococci in Experimental Meningitis. Antimicrob. Agents Chemother. 48: 3928-3933 [Abstract] [Full Text]  


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