Temocillin efficacy in experimental Klebsiella pneumoniae meningitis after infusion into rabbit plasma to simulate antibiotic concentrations in human serum

Abstract

An infusion system was developed to simulate in the plasma of rabbits the concentrations of temocillin in human serum measured after administration of a 2-g intravenous bolus dose. The efficacy of therapy with this infusion against experimental Klebsiella pneumoniae meningitis was compared with that of a conventional bolus dose to the animals. The marked difference between the elimination half-life (t4/2) of temocillin in rabbit plasma and human serum (0.3 and 5 h, respectively) was reflected in concentrations in cerebrospinal fluid (CSF). The mean peak concentration after infusion occurred 3.5 h later than after bolus dosing, and levels were more prolonged (tl/2 in CSF was 6.3 h compared with 0.83 h following the bolus dose). After infusion, the mean viable count in CSF decreased by 4 log1o CFU/ml, whereas the bolus dose was ineffective because of the rapid fall to subinhibitory concentrations. These results suggest that the infusion system used is valuable for experimental studies with antibacterial agents whose elimination kinetics differ markedly between animals and humans.The study of the distribution and antibacterial activity of new antibiotics in experimental animal models is important in providing a basis for investigative studies in humans, but the pharmacokinetics of ,-lactam antibiotics may differ greatly between humans and animals (6, 9, 11, 18). This is exemplified by temocillin, a 6-oa-methoxy penicillin which has high and prolonged concentrations in human serum and has an elimination half-life (t1/2) of about 5 h (5, 7, 16) but which, like many other P-lactam antibiotics, is rapidly eliminated from the blood of most laboratory animals, with t1/2 values of between 10 and 30 min (3).In addition to its distinctive pharmacokinetics in humans and its metabolic stability in the body, temocillin shows good activity against gram-negative bacteria and is stable to many bacterial P-lactamases (16 (1,2,8).To compensate for the interspecies differences in pharmacokinetics and to evaluate the influence of the prolonged half-life of temocillin on therapy, a technique was designed that involved the intravenous infusion of a continuously diluted solution to modify the elimination kinetics of temocillin in rabbits. In the studies described here, the penetration and efficacy of temocillin were examined in rabbits with experimental K. pneumoniae meningitis after infusion to simulate in rabbit plasma the concentration-versus-time curve observed for temocillin in human serum following an intravenous bolus dose of 2 g. The results were compared * Corresponding author.with those obtained after normal bolus administration of temocillin to rabbits. MATERIALS AND METHODSTest organism. K. pneumoniae ESH, a clinical isolate from a urinary tract infection, was used to induce meningitis in the rabbits. This strain was ampicillin resistant, producing the chromosomally mediated, Richmond and Sykes Class IV, broad-spectrum P-lactamase typical of K. pneumoniae. The MICs and MBCs of temocillin against K. pneumoniae ESH were determ...

Simulation of human serum pharmacokinetics of ticarcillin-clavulanic acid and ceftazidime in rabbits, and efficacy against experimental Klebsiella pneumoniae meningitis

“…The simulation of human elimination-phase kinetics in rabbit plasma has been described previously (23). In brief, phosphate-buffered saline (0.1 M, pH 7.4) was infused at a constant rate by pump A into a fixed-volume reservoir (VieS) containing an antibiotic solution (Fig.…”

“…To compensate for the more rapid elimination of ticarcillin (elimination half-life, 0.4 to 0.6 h), clavulanic acid (0.3 to 0.6 h), and ceftazidime (0.75 to 0.88 h) from serum in the rabbit (16,21,23; unpublished data) than from serum in humans (half-life, 1.1 ± 0.5, 1.0 + 0.06, and 1.8 ± 0.21, respectively) (7,9), the antibiotics were administered to infected rabbits by using a procedure designed to simulate in rabbit plasma the concentration-versus-time curves observed in human serum after therapeutic doses. The efficacy of ticarcillinclavulanic acid was compared with results for ticarcillin alone and with those for ceftazidime, a broad-spectrum cephalosporin considered useful for the treatment of gramnegative-bacilliary meningitis (2,12).…”

Animal models in the evaluation of antimicrobial agents

“…However, considering recent proposals that the pharmacokinetics of free antibiotic in serum (antibiotic not bound to serum proteins) afford a more realistic indicator of efficacy in humans (13,14), such scaling protocols must be viewed with caution, owing to the sometimes dramatic differences in the serum protein binding of antibiotics between animals and humans (49). Repeated fractional dosing (10,15,16,22,27,35,44) or continuous infusion (29,41) to obtain serum drug concentrations or pharmacokinetics that mimic those in humans have been used to override the faster elimination of antibiotics in animals; however, the advantages of these approaches are limited insofar as they presuppose a knowledge of the pharmacokinetic profiles in humans. They are still useful for the evaluation of compounds with unknown pharmacokinetics when the drugs are administered in a regimen similar to the regimen used for the administration of standard compounds.…”

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

“…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.…”

“…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.…”