Efficacy of Teicoplanin-Gentamicin Given Once a Day on the Basis of Pharmacokinetics in Humans for Treatment of Enterococcal Experimental Endocarditis

Abstract

With the aim of investigating home therapy for enterococcal endocarditis, we compared the efficacy of teicoplanin combined with gentamicin given once a day or in three daily doses (t.i.d.) with the standard treatment, ampicillin plus gentamicin administered t.i.d., for treating experimental enterococcal endocarditis. The antibiotics were administered by using "human-like pharmacokinetics" (H-L), i.e, pharmacokinetics like those in humans, that simulated the profiles of these drugs in human serum. Animals with catheter-induced endocarditis were infected intravenously with 10 8 CFU of Enterococcus faecalis EF91 (MICs and MBCs of ampicillin, gentamicin, and teicoplanin, 0.5 and 32, 16 and 32, and 0.5 and 1 g/ml, respectively) and were treated for 3 days with ampicillin H-L at 2 g every 4 h plus gentamicin H-L at 1 mg/kg every 8 h, or teicoplanin H-L at 10 mg/kg every 24 h, alone or combined with gentamicin, administered at dose of H-L at 1 mg/kg every 8 h or H-L at 4.5 mg/kg every 24 h. The results of therapy for experimental endocarditis due to EF91 showed that teicoplanin alone was as effective as ampicillin alone in reducing the bacterial load (P > 0.05). The combination of ampicillin or teicoplanin with gentamicin was more effective than the administration of both drugs alone in reducing the log 10 CFU/gram of aortic vegetation (P < 0.01 and P < 0.05, respectively). Teicoplanin plus gentamicin H-L at 4.5 mg/kg, both administered every 24 h, showed an efficacy equal to the "gold standard," ampicillin plus gentamicin H-L at 1 mg/kg t.i.d. (P > 0.05). Increasing the interval of administration of gentamicin to a single daily dose combined with teicoplanin resulted in a reduction of bacteria in the vegetations equivalent to that achieved with the recommended regimen of ampicillin plus thrice-daily gentamicin in the treatment of experimental endocarditis due to E. faecalis. Teicoplanin plus gentamicin, both administered once a day, may be useful home therapy for selected cases of enterococcal endocarditis.

Efficacy of Ceftriaxone and Gentamicin Given Once a Day by Using Human-Like Pharmacokinetics in Treatment of Experimental Staphylococcal Endocarditis

“…In experimental and clinical studies investigating treatments for streptococcal endocarditis, the efficacy of ceftriaxone plus aminoglycosides, both administered once a day, was similar to that of penicillin plus aminoglycosides 2, 8, 9; (H. F. Chambers, S. Kennedy, M. 203,1990). Additionally, the efficacy of teicoplanin plus gentamicin both administered once a day was similar to that of the standard therapy of ampicillin plus gentamicin in a rabbit model of enterococcal endocarditis (20).…”

“…The pharmacokinetic studies which led to the H-L pharmacokinetics of ceftriaxone and gentamicin in rabbits, including the explanation of the mathematical model used on the basis of an open two-compartment model, have been described previously (12,20). The pharmacokinetic data from the human-adapted model of 2 g of ceftriaxone and gentamicin at 1 or 4.5 mg/kg given i.v.…”

“…The profile in serum and the pharmacokinetic parameters of ceftriaxone or gentamicin in rabbits administered by use of this model were similar to those of i.v. ceftriaxone or gentamicin in humans (12,20).…”

“…Pharmacodynamic data obtained from animal models (17,18,37) have shown concentration-dependent killing by the aminoglycosides, which supports the idea that administration of these drugs once a day might be more effective. Along this line, gentamicin given once a day has been shown to be effective against experimental endocarditis due to viridans group streptococci (2,11,28) and experimental endocarditis due to Enterococcus faecalis (13,20) and in in vitro simulations of enterococcal endocarditis (14,32). To date, the efficacy of gentamicin administered once a day against MSSA has not been evaluated.…”

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

“…Our results are in complete agreement with these findings. Other studies in which this aminoglycoside was evaluated in the treatment of experimental endocarditis with HPS are not informative about its intrinsic activity in monotherapy, because it was associated with ampicillin (11,18), teicoplanin (18), or penicillin (19).…”