Simulation of amoxicillin pharmacokinetics in humans for the prevention of streptococcal endocarditis in rats

Abstract

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 animal results to human situations. To overcome this limitation, we have mimicked in rats the amoxicillin kinetics in humans following a 3-g oral dose (as often used for prophylaxis of endocarditis) by delivering the drug through a computerized pump. Rats with catheter-induced vegetations were challenged with either of two strains of antibiotic-tolerant viridans group streptococci. Antibiotics were given either through the pump (to simulate the whole kinetic profile during prophylaxis in humans) 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 290% of untreated controls. In contrast, simulation of kinetics in humans significantly protected animals challenged with 10 to 100 times the inoculum of either of the test organisms infecting .90% of untreated controls. Thus, simulation of the profiles of amoxicillin prophylaxis in human serum was more efficacious than mere imitation of the transient peak level in rats. This confirms previous studies suggesting that the duration for which the serum amoxicillin level remained detectable (not only the magnitude of the peak) was an important parameter in successful prophylaxis of endocarditis. The results also suggest that single-dose prophylaxis with 3 g of amoxicillin in humans might be more effective than predicted by conventional animal models in which only peak levels of antibiotic in human serum were simulated.The optimal antibiotic regimen for the prophylaxis of infective endocarditis in patients at risk undergoing dental procedures is not known. Many authorities recommend a single oral dose of 3 g of amoxicillin 1 h before the procedure (9, 15), whereas the American Heart Association advocates a repeated dose of 1.5 g 6 h later (3). These recommendations are in part based on experimental data obtained from animals. In experimental models, single-dose regimens were efficacious in preventing endocarditis, but only in animals challenged with inoculum sizes corresponding to the infectious dose producing endocarditis in 90% of control animals (ID90). The single dose of antibiotic failed in animals challenged with inoculum sizes larger than the ID90 (6, 12).Moreover, interpretation of the dosing regimen tested with animal models is difficult (11), since elimination half-lives of antibiotics differ between animals and humans (5,18,19). Amoxicillin, for example, has a half-life of 20 min in rats, in comparison with 50 to 60 min in humans. Thus, it is conceivable that a single-dose regimen in humans, resulting in sustained levels in blood, might provide more effective protection than a single dose in rats.To mimic more closely in rats the amoxicillin pharmacokinetic...

Induction of Experimental Endocarditis by Continuous Low-Grade Bacteremia Mimicking Spontaneous Bacteremia in Humans

“…In parallel, an intravenous (i.v.) line was inserted via the jugular vein into the superior vena cava and connected to a programmable infusion pump (Pump 44; Harvard Apparatus, Inc., South Natick, MA) in order to deliver the inocula (10).…”

Use of a Human-Like Low-Grade Bacteremia Model of Experimental Endocarditis To Study the Role of Staphylococcus aureus Adhesins and Platelet Aggregation in Early Endocarditis

“…Catheter-induced aortic vegetations were produced in female Wistar rats, and an intravenous (i.v.) line, connected to a programmable infusion pump (Pump 44; Harvard Apparatus), was inserted into the jugular vein to deliver the inocula, as described previously (28,29).…”

Single-Dose Oral Amoxicillin or Linezolid for Prophylaxis of Experimental Endocarditis Due to Vancomycin-Susceptible and Vancomycin-Resistant Enterococcus faecalis

“…Twenty-four hours after catheterization, groups of 10 rats were given antibiotic prophylaxis with amoxicillin, linezolid, or vancomycin. Antibiotics were delivered at changing flow rates, using the delivery pump described above, in order to mimic in the animals the human serum kinetics produced by a single oral dose of 2 to 3 g of amoxicillin (24,27,42), a single or multiple consecutive oral doses (every 12 h) of 600 mg of linezolid (9), or a single i.v. dose of 1 g of vancomycin (6).…”

“…In addition, a permanent intravenous (i.v.) line was placed in the superior vena cava to infuse the antibiotics (24). The distal portion of the catheter was connected to a programmable delivery pump (pump 44; Harvard Apparatus, South Natick, MA) as described previously (24).…”