Gentamicin inactivation by piperacillin or carbenicillin in patients with end-stage renal disease

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.

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

“…In combination with aminoglycosides, piperacillin exhibits synergistic bactericidal activity, which is particularly useful in febrile, neutropenic patients (12). It has been postulated, however, that piperacillin, like other penicillins, inactivates aminoglycoside antibiotics by converting them to microbiologically inert amides (22). In vitro, piperacillin concentrations of .250 pug/ml have been shown to diminish the activity of gentamicin, tobramycin, and amikacin (7).…”

mentioning

confidence: 99%

“…To date, the in vivo significance of this interaction has been examined only between piperacillin and gentamicin. In six patients with end-stage renal disease, piperacillin decreased the mean half-life of gentamicin from 53.9 to 37.7 h (22). In the face of such limited published data, we undertook this clinical evaluation of the action of piperacillin on tobramycin, which appears to be the aminoglycoside most susceptible to inactivation (7).…”

mentioning

confidence: 99%

Effect of piperacillin on tobramycin pharmacokinetics in patients with normal renal function

Lau

Lee

Flascha

et al. 1983

Aminoglycosides are inactivated by extended-spectrum penicillins in vitro and in patients with end-stage renal failure. In this prospective controlled study, we determined the effect of piperacillin on tobramycin pharmacokinetics. In 10 clinically stable male patients with calculated creatinine clearances of greater than or equal to 60 ml/min, serial levels in serum of tobramycin alone and after single 4-g intravenous doses of piperacillin were determined. No statistically significant changes in the concentration of drug in serum, the half-life (t1/2), the elimination rate constant (Ke), the volume of distribution (Vd), or the area under the serum concentration-time curve (AUC0-oo) occurred when tobramycin was used concurrently with piperacillin. Therefore, this antibiotic combination will not result in a clinically significant interaction in patients with normal renal function.

“…However, by assessing the data (5,12,23,28). This can be especially significant in patients with severe renal failure, since accumulation of APPs, as well as AMGs, can occur in serum, resulting in significant inactivation of both agents (5,23).…”

Section: Resultsmentioning

confidence: 99%

“…However, amikacin demonstrates the greatest stability in vitro when combined with various concentrations of beta-lactams (12), as well as resistance to inactivation in vivo (5). In addition, piperacillin has been shown to have an increased rate of nonrenal elimination in renal failure patients (27,28). The superiority of the combination in vitro, as well as the stability of amikacin and the pharmacokinetics of piperacillin, could be clinically significant in the treatment of patients with renal failure with severe gram-negative infections.…”

Section: Resultsmentioning

confidence: 99%

In vitro activity of piperacillin, ticarcillin, and mezlocillin alone and in combination with aminoglycosides against Pseudomonas aeruginosa

Lyon¹,

Smith²,

Saag³

et al. 1986

A total of 103 isolates of Pseudomonas aeruginosa were studied to compare the in vitro effectiveness of three beta-lactam antibiotics (piperacillin, ticarciflin, and meziocillin) when used alone and in combination with four aminoglycosides (tobramycin, gentamicin, amikacin, and netilmicin). All drugs were tested as single agents against a standard inoculum (5 x 105 CFU/ml). The three antipseudomonal penicillins were also tested against the isolates at a higher inoculum concentration (107 CFU/ml). Synergy testing was performed by the two-dimensional checkerboard method and was defined by (i) a fractional bactericidal index of -0.5 and (ii) bacterial killing accomplished at antibiotic concentrations no greater than those achievable in serum. All combinations were assessed for synergy. The degree of synergy was further'analyzed by dividing the isolates into groups based on their susceptibility and resistance to the individual agents in the combination. The overall effectiveness of the various aminoglycoside-antipseudomonal penicillin combinations was assessed regarding their ability to kill the isolates either as single agents or through synergy. Piperacillin was the most active antipseudomonal penicillin, and tobramycin and amikacin were the most active aminoglycosides when used as single agents. When tested against isolates at a higher inoculum concentration, ticarcillin was significantly more active than the other beta-lactams. The highest degree of overall synergy was noted with gentamicin-ticarcillin (78.2% of strains) and amikacin-piperacillin (77% of strains). When assessed for overall effectiveness, all combinations containing amikacin were the most active. The combination of amikacin-piperacillin was the most effective, with activity against 96% of all isolates.The newer semisynthetic penicillins have been shown by previous investigators to demonstrate increased antibacterial activity against a wide range of organisms (3,17,26,29), including strains of members of the family Enterobacteriaceae and Pseudomonas aeruginosa that are multiply resistant to other antimicrobial agents (3, 10). Moreover, these antimicrobial agents have been found to be especially useful when combined with an aminoglycoside (AMG) in the treatmnent of severe infections with gram-negative bacilli (1, 2), perhaps reflecting their in vitro synergistic activity (10,11,13,15,16,19,24).The purpose of this study was to compare the in vitro synergistic activity of the four most commonly used AMGs with that of three of the newer semisynthetic antipseudomonal penicillins (APP) against 103 hospital strains of P. aeruginosa. Only results demonstrating synergy at clinically attainable concentrations in serum of both antimicrobial agents were considered to be synergistic. In addition, we examined each drug combination for overall effectiveness in vitro. Analyses of these results took into consideration synergistic responses as well as single-drug activities.MATERIALS AND METHODS Organisms. Altogether, 103 P. aeruginosa strains were obtained from th...