Simulated human serum profiles of one daily dose of ceftriaxone plus netilmicin in treatment of experimental streptococcal endocarditis.
We performed experiments in rats aimed at determining whether a combination of ceftriaxone (CRO) and netilmicin (NET), by using once-daily administration in rats, which simulated profiles of drug in human serum, was more effective than either agent alone in the treatment of endocarditis caused by viridans group streptococci. A programmable infusion pump system enabled the production of profiles of CRO in serum that simulate those found in humans after the intravenous administration of 2 g. The subcutaneous administration of 18 mg of NET per kg of body weight produced levels in the sera of rats comparable to those after the intravenous administration of a dose of 5 mg of NET per kg in humans. Rats with catheter-induced aortic vegetations were infected intravenously with two test strains, a CRO-susceptible Streptococcus sanguis strain (MICs of CRO and NET, 0.064 and 8 mg/liter, respectively) and a relatively CRO-resistant Streptococcus mitis strain (MICs of CRO and NET, 2 and 8 mg/liter, respectively). Against both strains, the combination of CRO and NET was synergistic in vitro as determined by time-kill curves. Treatment of rats was started 48 h postinfection and lasted for 3 days. CRO alone was effective against the susceptible strain (P < 0.001 compared with control animals) but was not effective against the resistant organism. A significantly enhanced antibacterial activity of the CRO-NET combination in reducing the valvular bacterial counts was observed with both test strains (P < 0.001). The synergistic effect was obtained with a single daily injection of NET which provided detectable levels in serum for only 8 h, suggesting that in vivo synergism in the treatment of infections caused by viridans group streptococci can be obtained without 24 h of aminoglycoside coverage. These experimental data might provide a rationale for clinical trials of a once-a-day dosing regimen in the treatment of streptococcal but nonenterococcal endocarditis.
Blatter
M
M
Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Fluckiger
U
U
Entenza
J
J
Glauser
M P
MP
Francioli
P
P
D000818:Animals; D002443:Ceftriaxone / Q000008:administration & dosage / Q000097:blood* / Q000627:therapeutic use*; D004697:Endocarditis, Bacterial / Q000097:blood* / Q000188:drug therapy* / Q000382:microbiology; D005260:Female; D006801:Humans; D007260:Infusion Pumps; D008826:Microbial Sensitivity Tests; D009428:Netilmicin / Q000008:administration & dosage / Q000097:blood* / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D015610:Serum Bactericidal Test; D013290:Streptococcal Infections / Q000097:blood* / Q000188:drug therapy* / Q000382:microbiology; D013291:Streptococcus / Q000187:drug effects; D013298:Streptococcus sanguis / Q000187:drug effects
D009428:Netilmicin; D002443:Ceftriaxone