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 combin ation of ceftriaxone (CRO) and netilmicin (NET), by using once-daily a dministration in rats, which simulated profiles of drug in human serum , was more effective than either agent alone in the treatment of endoc arditis caused by viridans group streptococci. A programmable infusion pump system enabled the production of profiles of CRO in serum that s imulate those found in humans after the intravenous administration of 2 g. The subcutaneous administration of 18 mg of NET per kg of body we ight 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 intraveno usly with two test strains, a CRO-susceptible Streptococcus sanguis st rain (MICs of CRO and NET, 0.064 and 8 mg/liter, respectively) and a r elatively CRO-resistant Streptococcus mitis strain (MICs of CRO and NE T, 2 and 8 mg/liter, respectively). Against both strains, the combinat ion of CRO and NET was synergistic in vitro as determined by time-kill curves. Treatment of rats was started 48 h postinfection and lasted f or 3 days. CRO alone was effective against the susceptible strain (P < 0.001 compared with control animals) but was not effective against th e resistant organism. A significantly enhanced antibacterial activity of the CRO-NET combination in reducing the valvular bacterial counts w as observed with both test strains (P < 0.001). The synergistic effect was obtained with a single daily injection of NET which provided dete ctable 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 experim ental data might provide a rationale for clinical trials of a once-a-d ay dosing regimen in the treatment of streptococcal but nonenterococca l endocarditis.