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

“…Chemical inactivation of 1-lactam and aminoglycoside antibiotics occurs in vitro (18). Phamacokinetic interactions between these two classes of antibiotics have been reported in patients with normal and impaired renal functions (3,10,11,14,19,25). Since cefepime, as a 3-lactam, could be used in such a combination therapy, it was deemed * Corresponding author.…”

mentioning

confidence: 99%

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%

“…Reports also indicate that some aminoglycosides are more susceptible to inactivation by these P-lactam antibiotics. Gentamicin and tobramycin have been shown to be inactivated to a greater extent than amikacin or netilmicin (1,9,11). Similarly, some P-lactam antibiotics have a greater propensity to inactivate aminoglycosides.…”

mentioning

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.

“…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.…”

mentioning

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...