Evaluation of fosfomycin alone and in combination with ceftriaxone or vancomycin in an experimental model of meningitis caused by two strains of cephalosporin-resistant Streptococcus pneumoniae.
OBJECTIVE
To study the in vitro and in vivo efficacy of fosfomycin, alone and in combination with ceftriaxone or vancomycin, against two strains of Streptococcus pneumoniae: HUB 2349 (fosfomycin and ceftriaxone, MICs 16 and 2 mg/L) and ATCC 51916 (MICs 4 and 32 mg/L).


METHODS
Pharmacokinetics/pharmacodynamics data were collected from the study of eight infected animals after a single intravenous dose of 300 mg/kg of fosfomycin. Time-kill curves were plotted using CSF antibiotic concentrations achievable clinically. In the rabbit model, we studied the efficacy and effects on inflammation of treatment with fosfomycin 1200 mg/kg/day, ceftriaxone 100 mg/kg/day and vancomycin 30 mg/kg/day, over 26 h.


RESULTS
Fosfomycin peak level in serum was 324.48 +/- 102.1 mg/L at 0.5 h; CSF penetration was 49.2%. Time-kill curves showed that fosfomycin was bactericidal against the ATCC 51916 strain and that the addition of fosfomycin to ceftriaxone or vancomycin was synergic against the HUB 2349 strain. Resistance to fosfomycin was detected both when fosfomycin was studied alone and in combination. In the rabbit model, fosfomycin showed bactericidal activity only against the ATCC 51916 strain. Combinations of fosfomycin with ceftriaxone or vancomycin were bactericidal against both strains; they improved efficacy and decreased CSF inflammatory parameters over monotherapies, without showing statistical differences in comparison with the combination of ceftriaxone and vancomycin.


CONCLUSIONS
Fosfomycin in combination with ceftriaxone or vancomycin appeared to be effective for the treatment of experimental cephalosporin-resistant pneumococcal meningitis. These combinations are possible alternatives in cases of allergy or intolerance to first-line drugs or in rare meningitis caused by highly cephalosporin-resistant pneumococci.
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
Viladrich
Pedro Fernández
PF
Gudiol
Francesc
F
D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D002443:Ceftriaxone / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D018550:Cephalosporin Resistance / Q000187:drug effects*; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D005578:Fosfomycin / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D008586:Meningitis, Pneumococcal / Q000097:blood / Q000188:drug therapy*; D008826:Microbial Sensitivity Tests; D011817:Rabbits; D013296:Streptococcus pneumoniae / Q000187:drug effects*; D014640:Vancomycin / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use
D000900:Anti-Bacterial Agents; D005578:Fosfomycin; D014640:Vancomycin; D002443:Ceftriaxone