SIMULATION OF AMOXICILLIN PHARMACOKINETICS IN HUMANS FOR THE PREVENTION OF STREPTOCOCCAL ENDOCARDITIS IN RATS

The pharmacokinetic determinants of successful antibiotic prophylaxis of endocarditis are not precisely known. Differences in half-lives of antibiotics between animals and humans preclude extrapolation of anima l results to human situations. To overcome this limitation, we have mi micked in rats the amoxicillin kinetics in humans following a 3-g oral dose (as often used for prophylaxis of endocarditis) by delivering th e drug through a computerized pump. Rats with catheter-induced vegetat ions were challenged with either of two strains of antibiotic-tolerant viridans group streptococci. Antibiotics were given either through th e pump (to simulate the whole kinetic profile during prophylaxis in hu mans) or as an intravenous bolus which imitated only the peak level of amoxicillin (18 mg/liter) in human serum. Prophylaxis by intravenous bolus was inoculum dependent and afforded a limited protection only in rats challenged with the minimum inoculum size infecting greater than or equal to 90% of untreated controls. In contrast, simulation of kin etics in humans significantly protected animals challenged with 10 to 100 times the inoculum of either of the test organisms infecting great er than or equal to 90% of untreated controls. Thus, simulation of the profiles of amoxicillin prophylaxis in human serum was more efficacio us than mere imitation of the transient peak level in rats. This confi rms previous studies suggesting that the duration for which the serum amoxicillin level remained detectable (not only the magnitude of the p eak) was an important parameter in successful prophylaxis of endocardi tis. The results also suggest that single-dose prophylaxis with 3 g of amoxicillin in humans might be more effective than predicted by conve ntional animal models in which only peak levels of antibiotic in human serum were simulated.