The optimal aminoglycoside and its dosage for the treatment of severe Enterococcus faecalis infection. An experimental study in the rabbit endocarditis model

Abstract

Aminoglycosides are recommended for the treatment of Enterococcus faecalis infections, especially in severe and bacteremic infection. However, the optimal aminoglycoside or the optimal dosage remains uncertain. This study aimed to compare the activity of four aminoglycosides against E. faecalis (gentamicin, netilmicin, tobramycin, and amikacin) and two dosages of gentamicin. One clinical strain of E. faecalis was used to induce aortic endocarditis in the study rabbits. Each aminoglycoside was infused daily over 3 days with a computer-regulated flow simulating human pharmacokinetics of 15 mg/kg/day for amikacin, 6 mg/kg/day for netilmicin, and 3 mg/kg/day for gentamicin and tobramycin. Additionally, two dosages of gentamicin (simulating 3 or 6 mg/kg/day) were compared over 1 or 3 days of treatment. The in vivo efficacy was assessed according to the bacterial count in vegetations, in comparison with a control group. Of the four aminoglycosides tested, only gentamicin and netilmicin showed significant antibacterial efficacy after 3 days of treatment. After only 1 day of treatment, the high dosage of gentamicin (6 mg/kg/day) was more effective than the standard dosage (3 mg/kg/day). Among the tested aminoglycosides, gentamicin showed the best efficacy, with the best results after 24 h of treatment for the highest dosage.

Enterococcal Endocarditis Revisited

“…Animal models have not shown a superiority of high versus low doses of gentamicin in combination with penicillin [85], and clinical data reveal an increased nephrotoxicity for larger doses [86]. However, a recent study showed superiority of high doses of gentamicin (6 mg/kg/ day) over the standard one in the in vivo model of EFIE [87]. International guidelines recommend gentamicin at a dose of 3 mg/kg/day in three equally divided doses (t.i.d.)…”

Treatment of Enterococcus faecalis Infective Endocarditis: A Continuing Challenge

“…We would therefore need two routes (one of which would be for the continuous or intermittent administration of ampicillin by means of a perfusion pump) or a well-trained family member capable of performing (two or three times a day) these manipulations, in addition to the logistics inherent to the monitoring of levels. However, these recommendations are based on experimental studies [ 181 , 182 , 183 , 184 ], sometimes contradictory [ 185 , 186 ] possibly due to differences related to the different pharmacokinetics of the experimental model and humans. On the other hand, there are abundant studies that show the efficacy of single-dose administration of aminoglycosides, with excellent activity due to their prolonged post-antibiotic effect and much less renal toxicity [ 187 ].…”

Treatment of <em>Enterococcus faecalis</em> Infective Endocarditis: A Continuing Challenge

“…We would therefore need two routes (one of which would be for the continuous or intermittent administration of ampicillin by means of a perfusion pump) or a well-trained family member capable of performing (two or three times a day) these manipulations, in addition to the logistics inherent to the monitoring of levels. However, these recommendations are based on experimental studies [177][178][179][180] , sometimes contradictory 181,182 possibly due to differences related to the different pharmacokinetics of the experimental model and humans. On the other hand, there are abundant studies that show the efficacy of singledose administration of aminoglycosides, with excellent activity due to their prolonged post-antibiotic effect and much less renal toxicity 183 .…”