Clinical Pharmacokinetics of Aminoglycoside Antibiotics

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: Resultssupporting

confidence: 89%

“…Like most other cephalosporins and aminoglycosides, cefepime and amikacin are minimally metabolized in humans (8,21) and are primarily excreted in urine in unchanged forms. The CLR values of cefepime and amikacin indicate that these antibiotics are primarily excreted by glomerular filtration.…”

Section: Resultsmentioning

confidence: 99%

Lack of pharmacokinetic interaction between cefepime and amikacin in humans

Barbhaiya

Knupp

Pfeffer

et al. 1992

“…Urinary excretion of unchanged drug accounted for almost 100% of the dose on days 1, 7, and 10, which suggests that no biotransformation of isepamicin occurs in humans, as was previously reported (13). The recovery of isepamicin in urine over a 24-h period is greater than that observed for gentamicin (70 to 80%) (12), sisomicin (70%) (3), netilmicin (70 to 90%) (2), and tobramycin (88%) (16). Since aminoglycosides are not metabolized and are excreted by renal clearance, decreased recovery in urine may be due to increased tissue distribution, which renders it unavailable for excretion in urine.…”

Section: Vol 39 1995 Pharmacokinetics Of Isepamicin 2775supporting

confidence: 66%

Pharmacokinetics of intravenously administered isepamicin in men

Lin¹,

Radwanski²,

Korduba³

et al. 1995

The pharmacokinetics of isepamicin, a broad-spectrum aminoglycoside antibiotic, were studied in men after intravenous administration. Three groups of six volunteers received isepamicin for 10 consecutive days by 0.5-h intravenous infusions at respective dosages of 7.5 mg/kg of body weight once daily, 7.5 mg/kg twice daily, and 15 mg/kg once daily. Levels of isepamicin in plasma and urine were determined by a specific high-performance liquid chromatography method. For all three groups, steady-state concentrations of the drug in plasma were attained with the first dose. The area under the concentration-time curve for plasma and urinary drug excretion were dose proportional. A half-life ranging from 2.0 to 2.5 h was independent of the dosage regimen. Isepamicin excreted in urine over 24 h accounted for about 100% of the dose. The results show that the pharmacokinetics of isepamicin are linear with these dosage regimens. The drug does not accumulate upon multiple dosing, undergoes no detectable biotransformation, and is cleared solely by urinary excretion.Isepamicin is a new aminoglycoside that has been shown to be active against bacteria that have developed resistance to other aminoglycosides (1,6,7,14). The development of resistance to this class of antibiotics has been attributed to the presence of aminoglycoside-inactivating enzymes (10,12,19). Isepamicin has been shown to be superior to other available aminoglycosides against resistant bacteria (4,14,15). It is more active than amikacin against clinical isolates of Escherichia coli and against Citrobacter, Klebsiella, Enterobacter, and Serratia spp. which do not possess aminoglycoside-inactivating enzymes. Its activity is comparable to that of amikacin against Proteus spp. and Pseudomonas aeruginosa, which lack the aminoglycoside-inactivating enzymes (5, 9). The objective of this study was to evaluate the pharmacokinetics of isepamicin in men following intravenous daily doses of 7.5 and 15 mg/kg of body weight. MATERIALS AND METHODSCompound. Isepamicin for injection was supplied by the Schering-Plough Corporation as a sterile solution in 2-cm 3 ampoules containing 100 mg of isepamicin per ml. Normal saline was supplied by the clinical investigator.Drug administration. Twenty-seven healthy male volunteers with a mean age of 30 years (range, 19 to 39 years) and a mean weight of 167 lb (ca. 75.8 kg) (range, 125 [ca. 56.7 kg] to 215 lb [ca. 97.5 kg]) were enrolled and completed the study. All volunteers were determined to be in good general health by physical examination, electrocardiograms, and a battery of laboratory tests (hematology, blood chemistries, and urine analysis). Prior to study participation, each volunteer signed a written informed consent form.In each group, six volunteers were assigned to receive isepamicin and three were assigned to received placebos (normal saline). All doses were administered as 0.5-h intravenous infusions daily for 10 consecutive days. The dosages were 7.5 mg/kg once daily (group I), 7.5 mg/kg twice daily (group II), and 15 mg...

“…Therefore, the presence of pleural effusions in a patient may necessitate the use of relatively large aminoglycoside doses to achieve (20). However, the increased volume of distribution associated with advancing age for our patients with pleural effusions is in direct contrast to findings for the pediatric population (16). On the basis of body composition changes, one might expect that volume of distribution would decrease with increasing age because of a reduction in total body water (10).…”

contrasting

confidence: 57%

Variation in the pharmacokinetics of gentamicin and tobramycin in patients with pleural effusions and hypoalbuminemia

Etzel

Nafziger

Bertino

1992

The pharmacokinetic parameters of gentamicin and tobramycin were evaluated and compared for 260 patients with pleural effusions and 1,049 patients without pleural effusions by chest radiograph. Pharmacokinetic data were collected prospectively and analyzed by using our aminoglycoside data base. Univariate analysis revealed that the patients with pleural effusions demonstrated significantly lower serum albumin concentrations, greater aminoglycoside volumes of distribution, longer elimination half-lives, and lower peak and higher trough concentrations in serum than the patients without pleural effusions. Patients with pleural effusions were significantly older and had lower total body weight. Stepwise multiple linear regression analysis revealed that lower total body weight and serum albumin concentration, presence of pleural effusion, and greater age were associated with significantly greater volumes of distribution. Calculated creatinine clearance, age, total body weight, and shock were associated with reduced aminoglycoside clearance in these patients.Despite the increased availability of extended-spectrum beta-lactam and fluorinated quinolone antimicrobial agents, the aminoglycosides remain an important group of antibiotics in the treatment of severe gram-negative infections (6). Individualization of aminoglycoside dosing by determining serum drug concentrations has been employed as a means of maximizing efficacy while minimizing drug toxicity (2, 13, 15). Over the past few years, however, several disease states and clinical conditions have been demonstrated to alter aminoglycoside pharmacokinetics from normally accepted parameters (4,7,14,(19)(20)(21)(22). Several authors have demonstrated that these highly polar compounds are capable of penetrating the pleural cavity and can be detected in pleural fluid (8, 9). It is possible that patients with pleural effusions possess altered pharmacokinetic parameters for aminoglycosides. The purpose of our investigation was to assess and describe the pharmacokinetics of these agents for two discrete adult populations: patients with pleural effusions demonstrable by chest radiograph and patients without pleural effusions by chest radiograph. In addition, since hypoalbuminemia has been shown to affect aminoglycoside pharmacokinetics (20), the serum albumin concentrations for these patients were examined to determine whether this nutritional deficiency was an important cofactor or whether pharmacokinetic alterations exist for patients with hypoalbuminemia.This investigation utilized data which were collected prospectively by the Clinical Pharmacy Service of The Mary Imogene Bassett Hospital from January 1983 through August 1991. Patients eligible for the study included all adult patients (ages 18 years or older) who received either gentamicin or tobramycin and who had no pathophysiology (aside from impaired renal function) known to alter aminoglycoside pharmacokinetics (4,11,19,21,22 Within 72 h of the initiation of treatment with the antibiotic, aminoglycoside pharmacokine...