JAC Advance Access published online on January 16, 2004
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkh082
© 2004 by The British Society for Antimicrobial Chemotherapy
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Original article
1 Department of Internal
Medicine, Spital Bern-Ziegler, Bern;
* Corresponding author. E-mail: pcottagn{at}insel.ch.
Received 13 April 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
Keywords: Streptococcus pneumoniae, quinolones, Ceftriaxone acts synergistically with levofloxacin
in experimental meningitis and reduces levofloxacin-induced resistance
in
penicillin-resistant pneumococci
2 Department of Infectious Diseases, CHUV, Lausanne;
3 Department of Internal Medicine,
Inselspital, Bern, Switzerland
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.
-lactam antibiotics
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