Pharmacokinetics of cefoperazone and tobramycin alone and in combination

Abstract

Certain beta-lactams have been shown to increase the clearance of tobramycin. We evaluated the pharmacokinetics of cefoperazone and tobramycin, alone and in combination, in healthy volunteers. No significant alteration in pharmacokinetic behavior was noted for cefoperazone or tobramycin alone or in combination.The treatment of serious pseudomonal infections often requires the use of beta-lactanms in combination with aminoglycosides (3). Although this combination is well established in therapy (8), it is known that the antipseudomonal is well established in therapy, it is known that the antipseudomonal penicillins can interact with aminoglycosides both in vitro and in vivo to form a microbiologically inactive compound. This effect appears to be time, concentration, and temperature related (9) and is particularly relevant in those patients with decreased glomerular filtration rates (4). Cephalosporins appear to interact minimally with aminoglycosides in this manner. However, moxalactam has been observed to interact in vivo with tobramycin when given in combination (1). Unlike the previous interactions with beta-lactams and aminoglycosides, no in vitro interaction was noted. Tobramycin clearance increased when it was administered along with moxalactam to normal volunteers and to patients with renal failure. Conversely, moxalactam clearance decreased when tobramycin was given at the same time to volunteers with normal renal function.In this study, we investigated the pharmacokinetic behavior of cefoperazone and tobramycin alone and in combination. Cefoperazone and tobramycin were studied because of their known potent antipseudomonal activity (7) and their likelihood of being used in combination in serious pseudomonal infection. MATERIALS AND METHODSVolunteers. Eight healthy test subjects (four males and four females) with no known allergies to penicillin or other beta-lactam agents participated in the study. Informed written consent was obtained from all volunteers. The study was approved by the Committee on Human Research of the University of California. None of the females was known to be pregnant, and none of the volunteers took other antimicrobial agents, probenecid, aspirin, or other inhibitors of active tubular secretion during the 2 weeks preceding the study. No caffeine or alcohol was taken on the study days. The mean age of the subjects was 25 years (range, 23 to 28 years), and the mean weight was 66 kg (range, 49 to 88 kg). * Corresponding author. Dosage. After an overnight fast, the subjects were dosed randomly with 30 mg of cefoperazone per kg, 1.5 mg of tobramycin per kg, or a combination of cefoperazone and tobramycin. After a 1-week washout period, the subjects were crossed over to the second regimen. A subsequent 1-week washout period was followed by the third antibiotic regimen. The antibiotics were administered separately in 50 ml of a 5% glucose solution over 25 min via a peripheral vein access by using a constant-rate Harvard infusion pump. After infusion of the antibiotic(s), the intravenous lin...

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