Gentamicin, netilmicin, dibekacin, and amikacin nephrotoxicity and its relationship to tubular reabsorption in rabbits

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The tubular disposition of five aminoglycosides was studied in humans to establish a possible relationship between tubular reabsorption and the nephrotoxicity that has been described in the literature. Thirty-three healthy male volunteers received a continuous intravenous infusion of isotonic saline with inulin, followed 1 h later by inulin plus gentamicin, dibekacin, tobramycin, netilmicin, or amikacin (1 mg/kg per h) or amikacin (4 mg/kg per h) over a period of 2 h. Brain-stem-evoked response audiometry was performed both before and at the end of each infusion. The latency of wave V remained constant whichever antibiotic was considered. The glomerular filtration rate did not vary significantly during the infusion of each drug. The percent fractional excretion was 79 + 6, 81 ± 22, 85 5, and 99 ± 9 for gentamicin, dibekacin, tobramycin, and netilmicin, respectively, and 83 4 and 124 13 for amikacin at concentrations of 1 and 4 mg/kg per h, respectively. Net balance and renal clearance were similar for the five aminoglycosides when administered at a rate of 1 mg/kg per h. With gentamicin only, fractional excretion was correlated with the urinary flow rate. We can conclude that (i) gentamicin, generally considered the most nephrotoxic agent, had the highest degree of net reabsorption; (ii) netilmicin exhibited a net zero tubular balance; (iii) amikacin had different patterns of tubular disposition according to the dose, i.e., reabsorption at 1 mg/kg per h and secretion at 4 mg/kg per h, raising the hypothesis of a saturable process of reabsorption; and (iv) these differences in tubular reabsorption could account at least in part for the known different nephrotoxic potentials of these five aminoglycosides in humans.

“…These results, obtained with humans, are quite similar to those reported previously for rabbits (4). The same decreasing order of tubular reabsorption applied in both cases.…”

Section: Discussionsupporting

confidence: 82%

Renal disposition of gentamicin, dibekacin, tobramycin, netilmicin, and amikacin in humans

Contrepois¹,

Brion²,

Garaud³

et al. 1985

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“…That is why we used netilmicin instead of gentamicin. We have previously demonstrated, in rabbits, the lower nephrotoxicity of netilmicin compared with that of gentamicin in terms of creatinine concentrations in serum and histological lesions at low and high doses (2), and clinical studies corroborated these findings (4,13).…”

Section: Resultssupporting

confidence: 57%

Importance of the aminoglycoside dosing regimen in the penicillin-netilmicin combination for treatment of Enterococcus faecalis-induced experimental endocarditis

Fantin

Carbon

1990

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The penicillin-aminoglycoside combination is recommended for the treatment of systemic enterococcal infections. However, the optimal dosing regimen of the aminoglycoside remains to be elucidated. We evaluated the efficacy of penicillin, alone or in combination with various dosing regimens of netilmicin, for the treatment of experimental left-sided Enterococcusfaecalis endocarditis in rabbits. Animals were injected intramuscularly for 4 days with penicillin alone or in combination with netilmicin in one of the following regimens: netilmicin at a low dose (2 mg/kg of body weight every 8 h), netilmicin at a high dose (4 mg/kg every 8 h), or netilmicin at a single daily high dose (12 mg/kg every 24 h). MICs and MBCs were 3.1 and 6.2 ,ug/ml and 8 and 8 ,ug/ml for penicillin and netilmicin, respectively. A netilmicin concentration of 4 ,ug/ml was the lowest concentration that achieved synergism with penicillin, as shown by the kill-curve method. Mean peak levels of netilmicin in serum were 5.6 (netilmicin at 2 mg/kg), 9.8 (netilmicin at 4 mg/kg), and 20.6 (netilmicin at 12 mg/kg) ,g/ml.Mean penicillin levels in serum were constantly above the MIC. Penicillin plus netilmicin at a high dose given three times daily was more effective (P < 0.05) than any other regimen in reducing bacterial titers in vegetations and was the only treatment that induced a significant bactericidal activity in rabbit serum during the trough. We concluded that divided doses of aminoglycoside are more effective than the same total dose given once daily in combination with penicillin. Our data suggest that prolonged levels of aminoglycoside in serum might be important to exhibit the greatest in vivo efficacy of the combination against E. faecalis. They also indicate that use of a reduced total daily dose of aminoglycoside or an increase in the interval between each dose might reduce the efficacy of therapy in animals with this type of infection.

“…Renal uptake of gentamicin is avid, with over 50-to 100-fold concentrations in renal tubule cells compared with that in plasma (19). However, the extent of drug accumulation in renal tissue does not necessarily relate to the extent of change in renal function (2,7,20,24).…”

Section: Resultsmentioning

confidence: 99%

Role of sodium in the protective effect of ticarcillin on gentamicin nephrotoxicity in rats

Ohnishi

Bryant

Branch

et al. 1989

Coadministration of sodium ticarcillin with an aminoglycoside is known to reduce the nephrotoxicity of the aminoglycoside. However, it is not known whether the penicillin or the obligatory sodium load confers protection. To investigate this, gentamicin has been administered intraperitoneally in doses of 50, 60, or 80 mg/kg per day for 12 days in groups of rats receiving either a normal or a low sodium intake. Alterations in creatinine clearance have been measured. Salt depletion resulted in an enhanced nephrotoxic response with a shift in the dose-response curve to the left. Administration of sodium ticarcillin to rats with a salt-depleted intake at a dose sufficient to replace sodium intake conferred an equal degree of protection to rats with a normal salt intake. We report that the obligatory salt supplement with ticarcillin is sufficient to account for the renal sparing effect of the combination treatment without having to infer a direct chemical interaction of penicillin with the aminoglycoside.Aminoglycosides are rarely used alone in contemporary medicine. They are usually administered as a component of broad antibacterial spectrum cover, often being given in combination with extended-spectrum penicillins such as ticarcillin to provide additional antipseudomonal activity. However, prior admixture of aminoglycosides with penicillins will result in the two drugs forming an inactive complex (11,12,(27)(28)(29). The interaction is also thought to occur in vivo (9), but it has been suggested that this has an influence only on an effective available drug for antimicrobial action when the dose of penicillin is very high or the dosage interval of aminoglycoside is prolonged, as in renal failure (4,9,14). In these situations, the combination results in a shortening of half-life.If complex aminoglycoside-penicillin formation occurs in vivo, it is probable that the interaction would occur in the extracellular fluid space. This would result in less aminoglycoside being available for renal uptake. This might be expected to influence the potential of the aminoglycoside to induce nephrotoxicity (1, 16, 25), particularly as aminoglycosides are concentrated in the renal cortex (24) and the half-life of aminoglycosides in the cortex is longer than in plasma (23,24). Experimental studies in rats with the combination of tobramycin and ticarcillin have confirmed that the change in renal function during chronic but separate administration of these drugs was less than that found by administration of tobramcyin alone (13). This protection occurs despite equal or even higher concentrations of tobramycin in renal tissue in the combination therapy group (13).A similar study has also demonstrated a protective effect by the combination of gentamicin and carbenicillin (5). These observations in animal models would be consistent with the clinical findings of a low incidence of nephrotoxicity when combination therapy was used in immunocompromised patients in the European Organization for Research on Cancer Report (15). Similarly, Wade and...