Evaluation of ceftriaxone, vancomycin and rifampicin alone and combined in an experimental model of meningitis caused by highly cephalosporin-resistant Streptococcus pneumoniae ATCC 51916.
OBJECTIVE
The aim of the study was to assess the in vitro and in vivo efficacy of ceftriaxone, vancomycin and rifampicin alone and combined against Streptococcus pneumoniae ATCC 51916 (MIC of ceftriaxone: 32 mg/L).


METHODS
In vitro killing curves were performed with clinically achievable CSF antibiotic concentrations. In the rabbit model of pneumococcal meningitis, we studied the efficacy of and effects on inflammation of treatment with ceftriaxone 100 mg/kg/day, vancomycin 30 mg/kg/day and rifampicin 15 mg/kg/day, alone and combined, over a 26 h period.


RESULTS
Time-kill curves showed that vancomycin was bactericidal, and ceftriaxone and rifampicin produced a bacteriostatic effect. An additive effect was observed when combinations of ceftriaxone plus vancomycin were studied at subinhibitory concentrations. Emergence of resistance to rifampicin was detected both when rifampicin was studied alone and when combined with ceftriaxone or vancomycin. In the rabbit meningitis model, ceftriaxone was bacteriostatic, whereas rifampicin and vancomycin were bactericidal at 24 h. Although not synergistic, the combinations of ceftriaxone plus vancomycin or rifampicin, and vancomycin plus rifampicin, improved the efficacy of any antibiotic tested alone--all combinations were bactericidal from 6 h--and significantly decreased inflammatory parameters in CSF compared with control and ceftriaxone groups.


CONCLUSIONS
Ceftriaxone plus vancomycin, and vancomycin plus rifampicin appeared to be effective in the therapy of experimental pneumococcal meningitis caused by highly cephalosporin-resistant strains such as ATCC 51916. Our results provide an experimental basis for using these combinations as empirical therapy for pneumococcal meningitis, regardless of the degree of cephalosporin resistance of the causative strain.
Ribes
Sandra
S
Laboratory of Experimental Infection, Infectious Diseases Department, IDIBELL-Hospital Universitari de Bellvitge-Universitat de Barcelona, L'Hospitalet, Barcelona, Spain. sribes@ub.edu
Taberner
Ferran
F
Domenech
Alejandro
A
Cabellos
Carmen
C
Tubau
Fe
F
Liñares
Josefina
J
Fernández Viladrich
Pedro
P
Gudiol
Francesc
F
D000818:Animals; D002443:Ceftriaxone / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D018550:Cephalosporin Resistance; D002555:Cerebrospinal Fluid / Q000382:microbiology; D015169:Colony Count, Microbial; D004195:Disease Models, Animal; D004338:Drug Combinations; D004347:Drug Interactions; D024881:Drug Resistance, Bacterial; D005260:Female; D008586:Meningitis, Pneumococcal / Q000188:drug therapy* / Q000382:microbiology; D008826:Microbial Sensitivity Tests; D011817:Rabbits; D012293:Rifampin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D013296:Streptococcus pneumoniae / Q000187:drug effects*; D014640:Vancomycin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
D004338:Drug Combinations; D014640:Vancomycin; D002443:Ceftriaxone; D012293:Rifampin