Co-trimoxazole versus nafcillin in the therapy of experimental meningitis due to Staphylococcus aureus

Abstract

Co-trimoxazole was compared with nafcillin against Staphylococcus aureus in vitro and in the therapy of experimental Staph. aureus meningitis in rabbits. Co-trimoxazole (trimethoprim:sulphamethoxazole in a 1:20 ratio) was synergistic against 22/24 strains of Staph. aureus in vitro. The MBC90 of co-trimoxazole and nafcillin were 0.156-3.12 mg/l and 0.25 mg/l, respectively, concentrations below those achievable in purulent cerebrospinal fluid. The rate of bacterial killing (Staph. aureus) by co-trimoxazole and nafcillin were similar in both broth and pooled CSF in vitro. However, the MBC increased and the rate of bactericidal activity of both agents declined when tested in CSF at a higher inoculum (10(7) cfu/ml). During continuous intravenous infusion therapy of a reproducible, uniformly fatal (if untreated) model of experimental Staph. aureus meningitis, serum concentrations of all agents closely approximated those found in humans receiving standard parenteral regimens. The mean percent penetration into CSF ([CSF]/[serum] X 100) was 2.9, 35.6 and 27.1% for nafcillin, trimethoprim and sulphamethoxazole, respectively. Although both nafcillin and co-trimoxazole therapy reduced CSF Staph. aureus concentrations significantly more rapidly (P less than 0.001) when compared to untreated controls, the bactericidal rate was modest. The CSF was rendered sterile in 0/64 animals treated with either regimen for 8 h. Nafcillin was more rapidly bactericidal in vivo (P less than 0.03) than co-trimoxazole in this model. Caution is advised in the use of co-trimoxazole for infections of the central nervous system caused by Staph. aureus.

Treatment of experimental endocarditis due to methicillin-susceptible or methicillin-resistant Staphylococcus aureus with trimethoprim-sulfamethoxazole and antibiotics that inhibit cell wall synthesis

“…Previous studies showed that the MBC of TMP-SMX for staphylococci did increase when the inoculum was raised from 10 5 to 10 7 CFU per ml (24). In our studies, the kinetics of killing of staphylococci assessed by the time-kill method with high inocula showed a slow and modest decrease in the number of microorganisms, which predicted a suboptimal in vivo effect.…”

“…To the best of our knowledge, only one experimental study has addressed the comparative efficacy of TMP-SMX versus other antimicrobial agents against S. aureus in vivo (24). Using the experimental model of meningitis, Scheld et al showed that TMP-SMX killed S. aureus at a slower rate and more incompletely than nafcillin did (24).…”

“…Using the experimental model of meningitis, Scheld et al showed that TMP-SMX killed S. aureus at a slower rate and more incompletely than nafcillin did (24).…”

Methicillin-Resistant Staphylococcus aureus: An Evolutionary, Epidemiologic, and Therapeutic Odyssey

“…TMP-SMZ was less active than vancomycin in a rabbit model of MRSA endocarditis and less rapidly bactericidal than nafcillin in a rabbit model of MSSA meningitis [78,79]. A randomized trial of treatment of S. aureus infections, 47% of which were due to MRSA, concluded that treatment with TMP-SMZ was inferior to treatment with vancomycin [80].…”

Methicillin-Resistant Staphylococci and Their Treatment in the Intensive Care Unit

“…These data suggest that for MRSA infection, T/S may be equivalent in efficacy to vancomycin and might even be associated with faster clinical improvement. However, other studies have shown a less rapid bactericidal effect for T/S than for beta-lactams or vancomycin, 76 so T/S is not recommended for treatment of serious infections (e.g., endocarditis) where more rapid killing is thought to be necessary, though it may be an option for nonbacteremic skin and soft tissue infections.…”