Simulation of Human Gentamicin Pharmacokinetics in an Experimental Enterococcus faecalis Endocarditis Model

Abstract

Significant differences between animal and human pharmacokinetics may be responsible for the conflicting results of experimental studies. This study determined the impact of human pharmacokinetic simulation (HPS) on gentamicin activity in an Enterococcus faecalis endocarditis model. The decrease in bacterial counts was greater with HPS than with a dose-equivalent regimen without HPS.Enterococcal organisms are a frequent cause of nosocomial infections (2,3,23,25,32,35). While a synergistic combination involving a cell wall-active agent with an aminoglycoside is customarily recommended (6,25), recent reports suggest a genuine activity of the latter alone (17,30). Interspecies variations in metabolism and pharmacokinetic properties have been observed for the same drug (15,20,29). Thus, experimental models with animal native kinetics may not ensure reliable assessment for human therapeutics (11), and the choice of treatment schedule can have a dramatic influence, especially in the field of antibacterial agents (33). Notably, the elimination rate is usually faster in small animals than in humans (8,13,21,31). This may explain the poor results obtained in experimental models. To circumvent this drawback, the dosage in the animal is often increased according to the clearance ratio, resulting in a similar area under the concentration-time curve (AUC), but at the expense of a considerable rise in the peak.The purpose of the present study was to compare this latter dosage adjustment with a true simulation of the human pharmacokinetics (HPS), as previously described (1,14,22,36), and to determine the impact of HPS on the antibacterial effect of gentamicin in an experimental model of enterococcal endocarditis.(This work was presented in part at the 15th Annual Congress of the European Society of Intensive Care Medicine, Barcelona, Spain, 29 September to 2 October 2002.)In vitro studies. MICs and MBCs of gentamicin (ScheringPlough Laboratories, Paris, France) were determined by the microdilution technique in Mueller-Hinton broth (MHB) and in MHB with serum (MHBS) for the two clinical strains of Enterococcus faecalis studied, HM 1061 and JH2-2 (16, 17). For both strains, MICs and MBCs were identical, equal to 8 and 4 mg/liter in MHB and MHBS, respectively (24).In vivo studies. In vivo studies were carried out with New Zealand White female rabbits (CEGAV, St. Mars-d'Egrenne, France) approved by the animal study committee. Experimental endocarditis was induced as previously described (9, 26) with an inoculum of 10 8 CFU of either E. faecalis HM 1061 or E. faecalis JH2-2. For each strain, animals were randomly assigned to nine groups, including an untreated control group and eight therapeutic groups, according to a crossed design with doses of 16.6 or 33.2 mg/kg of body weight/day producing either native or human-like pharmacokinetics for 3 or 5 days. The doses administered corresponded to those required to reproduce an AUC in the rabbit similar to that obtained in humans with dosages of 3 or 6 mg/kg/day, respectively. Gentamici...

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

“…However, using single-bolus injections completely overlooked the fact that most drugs have a much shorter half-life in rodents than in humans. Thus, it underestimated the importance of the more prolonged presence of antibiotics in the sera of humans (2,19,25,26). The critical importance of this aspect was demonstrated in further studies (5,7,8,11,23,24,40,46).…”

Injectable gentamicin-loaded thermo-responsive hyaluronic acid derivative prevents infection in a rabbit model

“…This may indicate a slightly lower burst release of gentamicin upon application of the thermoresponsive HApN Gen than for the Collagen Gen. This is, however, difficult to verify as the half-life of gentamicin in the blood circulation of the rabbit is very short and accurate assessment of the pharmacokinetics with such few time-points is therefore a challenge [41,42]. Nevertheless, the peak plasma gentamicin levels measured in both groups are much lower than the commonly observed maximum concentration (C max ) of gentamicin in the human serum (18 lg/ml) upon intravenous administration of a conventional dose of 6 mg gentamicin/ kg body weight [43], indicating systemic toxicity is not a concern after application of either ALB.…”

Enterococcal Endocarditis Revisited

“…dosing [92]. Despite this controversy, multiple doses are still recommended by guidelines, although such opposing results concerning the dosage of aminoglycosides in experimental IE might be due to significant differences between animal and human pharmacokinetics [93]. Moreover, a Danish group, in one of the most relevant contributions to EFIE treatment, recently demonstrated that q.d.…”