Inactivation of Gentamicin by Penicillins in Patients with Renal Failure

The interaction potential between cefepime and amikacin was investigated in a steady-state pharmacokinetic study in 16 healthy male subjects. Eight subjects (group A) received a first course of 2,000 mg of cefepime; this was followed by a second course of 2,000 mg of cefepime with 300 mg of amikacin and a third course of 2,000 mg of cefepime. Eight other subjects (group B) received a first course of 300 mg of amikacin, a second course of 300 mg of amikacin with 2,000 mg of cefepime, and a third course of 300 mg of amikacin. Each course consisted of four consecutive doses administered every 8 h as 30-min intravenous infusions. Serial plasma and urine samples, which were collected after administration of the fourth dose of each course, were assayed for cefepime and/or amikacin by validated high-performance liquid chromatographic assays. Trough levels of cefepime and amikacin indicated that these antibiotics attained a steady state prior to administration of the fourth dose of each course. Key pharmacokinetic parameters for each antibiotic were determined by noncompartmental methods. The peak concentrations of cefepime and amikacin in plasma when the drugs were given alone were about 160 and 27 ,g/ml, respectively. Levels of each antibiotic in plasma declined, with an apparent half-life of approximately 2.2 h. Urinary recovery of cefepime and amikacin accounted for more than 85% of the administered dose of each antibiotic. Mean renal clearances for cefepime and amikacin ranged from 79 to 95 ml/min and suggested that glomerular filtration is the primary excretion mechanism. The results of the statistical analyses indicated that the pharmacokinetic parameters of cefepime following the concurrent administration of amikacin and following the discontinuation of the amikacin therapy were not significantly altered. Similarly, the pharmacokinetic parameters of amikacin following the concurrent administration of cefepime and following the discontinuation of the cefepime therapy were not significantly altered. Cefepime and amikacin can be coadministered to patients with normal renal function by using the standard recommended dosing regimens.Cefepime (BMY-28142) is a new parenteral cephalosporin with significant potential advantages over other new cephalosporins and nontraditional ,3-lactam antibiotics with respect to its antimicrobial spectrum of activity (12,15). In addition, cefepime appears to have a low affinity for chromosomally derived P-lactamases (23). Clinical experience indicates that cefepime is safe and well tolerated when single or multiple (every 8 or 12 h) doses of 250 to 2,000 mg are given by the intravenous (4, 5) or intramuscular (9) routes of administration. The pharmacokinetics of this cephalosporin are linear (4, 5, 9). Over 80% of the administered dose of cefepime is recovered in urine in an unchanged form (4, 5, 7-9).In the most severely infected patients, empiric therapy consists of the administration of antibacterial therapy before pathogen identification. The standard approach has been to use an ant...

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Lack of pharmacokinetic interaction between cefepime and amikacin in humans

Barbhaiya

Knupp

Pfeffer

et al. 1992

“…However, in patients with significant renal failure, subtherapeutic aminoglycoside concentrations and a decreased aminoglycoside elimination half-life during combination therapy with broad-spectrum P-lactam penicillins have been reported (1,18,19). The inactivation of aminoglycosides in patients receiving chronic dialysis therapy has been reported for gentamicin in combination with carbenicillin (1,4,5,19), ticarcillin (4,24), and piperacillin (26). Inactivation of tobramycin given in combination with ticarcillin (18) and carbenicillin (29) has also been described.…”

Section: Materuils and Methodsmentioning

confidence: 99%

Effect of concomitant administration of piperacillin on the dispositions of isepamicin and gentamicin in patients with end-stage renal disease

Halstenson

Wong

Herman

et al. 1992

Piperacillin inactivation of the aminoglycosides isepamicin and gentamicin in 12 chronic hemodialysis patients was assessed. Six subjects each received isepamicin (7.5 mg/kg of body weight) or gentamicin (2 mg/kg) alone and in combination with piperacillin (4 g every 12 h for four doses). Isepamicin and gentamicin concentrations in plasma and urine were monitored over 48 h after each dose and analyzed by highperformance liquid chromatography and fluorescence polarization immunoassay, respectively. The pharmacokinetics of isepamicin were not significantly altered during combination treatment with piperacillin. piperacillin (3.56 0.38 ml/min) increased significantly compared with that of gentamicin (2.03 0.50 ml/min) given alone. The results of this study suggest that no additional dosage adjustment of isepamicin during concomitant therapy with piperacillin in hemodialysis patients is necessary. However, this does not preclude the need for appropriately ex vivo-handled specimens for monitoring isepamicin concentrations in plasma to ensure therapeutic efficacy and prevent toxicity. Furthermore, additional dosage adjustments may be necessary when gentamicin is used concomitantly with piperacillin, on the basis of the significant in vivo inactivation that takes place in end-stage renal disease patients.

“…In such patients, extensive destruction of both gentamicin and tobramycin in the presence of carbenicillin or ticarcillin has been demonstrated (4,5,7,8,10,19). The reduction in aminoglycoside serum disappearance half-life can be as much as 75%.…”

mentioning

confidence: 99%

Inactivation of amikacin and gentamicin by carbenicillin in patients with end-stage renal failure

Blair¹,

Duggan²,

Schroeder³

1982

Aminoglycosides are inactivated by carbenicillin in vitro and in patients with end-stage renal failure. In vitro, amikacin is inactivated to a lesser extent than is gentamicin. In five patients on chronic hemodialysis, serum levels of amikacin alone and after repeated intravenous carbenicillin infusions were determined. Analogous gentamicin studies were conducted with five different patients. Neither amikacin serum levels nor serum clearances were affected by carbenicillin. The mean gentamicin serum half-life was significantly lower in the presence of carbenicillin: 18.4 ± 8.2 compared with 61.6 ± 30.7 h. Serum clearance increased significantly. The inactivation of gentamicin by carbenicillin was both time related (>12 h of exposure) and concentration dependent (molar carbenicillin/gentamicin ratios -39:1). Amikacin would be preferable to gentamicin in patients with endstage renal failure.