Interaction between beta-lactam antibiotics and gentamicin against Streptococcus pneumoniae in vitro and in vivo

In vitro synergy was demonstrated for each of the beta-lactam antibiotics, penicillin, ampicillin, piperacillin and cefuroxime, respectively, in combination with gentamicin, by the time-kill method within 6 h. The combination of the beta-lactam antibiotics with gentamicin as compared to therapy with each drug alone was investigated by the mouse-protection test after intraperitoneal inoculation of the pneumococcus. Antibiotics were administered sc one h after inoculation. Three sub-therapeutic doses calculated on the basis of the 50% effective doses for each antibiotic were given individually or in combination (beta-lactam + gentamicin) by a factorial design, in order to study all possible dose-combinations. Penicillin, piperacillin, or cefuroxime in combination with gentamicin were significantly superior to either drug administered individually. Ampicillin + gentamicin was significantly superior to gentamicin alone but not to ampicillin alone. With combination therapy, survival of mice correlated significantly with increasing gentamicin doses but was independent of the size of the dose of beta-lactam antibiotics.