Clinical Pharmacokinetics of Antibacterial Drugs in the Elderly

The pharmacokinetics of ampicillin-sulbactam in elderly subjects (65 to 85 years; group 3, n = 8), compared with those in middle-aged (41 to 64 years; group 2, n = 8) and younger (20 to 40 years; group 1, n = 8) subjects, were investigated. A single 2-g dose of anpicillin combined with 1 g of sulbactam in 60 ml of intravenous solution was administered to each subject over a 30-min period. Blood and urine samples were taken at baseline and serially over an 8.5-h period foliowing the infusion. Ampicillin and sulbactam concentrations were assayed by high-performance Liquid chromatography on a reversed-phase C-8 column. The mean levels in serum of both ampicilin and sulbactam were significantly higher for samples from group 3: for ampillin from 1 through 8.5 h, and for sulbactam for the same time interval except at 5.5 h (P ' 0.05). The mean urinary excretion of both ampicillin and sulbactam was lowest, and urinary concentrations were highest in group 3. The areas under the serum drug concentration-time curve, the half-lives, and the maimum concentrations in serum were greatest, while the total clearance was lowest, for group 3 for both ampilin and sulbactam. These results are consistent with a prolongation of antimicrobial activity of ampicilli-sulbactam in the elderly compared with that in younger subjects.Demographic trends over the past 50 years reveal that the elderly (over age 65) are a rapidly growing segment of the population (16). Physiologic changes in the elderly compared with younger populations have been noted (9). Age-related diferences in absorption, excretion, metabolism, and distriIlution make it necessary to study new agents in elderly populations. In the elderly, there is an increase in body fat, a decrease in body water, and an age-related decline in renal function. Other factors that may impact on the pharmacokinetics of antimicrobial agents include serum albumin and protein binding. A guideline for the study of drugs in the elderly has recently been released (3).Prior studies of the pharmacokinetics of antibiotics in the elderly have been recently reviewed in two publications (8,11). 4alysis of the data for beta-lactam antibiotics reveals that, id the elderly, the maximum concentrations in serum, (CX,~) Each subject was given a single 60-mi intravenous infusion of ampicillin-sulbactam containing 2 g of ampicillin and 1 g of sulbactam delivered over a 30-min period. Blood samples were collected at the following times: 0 (prior to the start of infusion), 0.25, 0.5 (end of infusion), 1, 1.5, 2, 2.5, 3.5, 5.5, and 8.5 h. Urine samples were collected prior to dosing and at the following time intervals: 0 to 2, 2 to 4, 4 to 6, and 6 to 8.5 h. All specimens were immediately centrifuged, separated, and frozen at -70°C. The specimens were later assayed by high-performance liquid chromatography (HPLC) on a reversed-phase C-8 column. Assays of serum and urine were performed by Pfizer Research Labs, Groton, Conn. Sulbactam and ampicillin were analyzed after dilution with S mM sodium citrate buffer at pH 5....

“…The calculated CLCR was significantly lower for group 3. This is not unexpected, since renal function is known to decrease with age (11,14).…”

Section: Discussionmentioning

confidence: 75%

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confidence: 99%

“…Prior studies of the pharmacokinetics of antibiotics in the elderly have been recently reviewed in two publications (8,11). 4alysis of the data for beta-lactam antibiotics reveals that, id the elderly, the maximum concentrations in serum, (CX,~), area under the concentration-time curve (AUC), and half-life (tQ122) are increased, whereas total clearance (CLT) and renal clearance (CLR) are decreased, compared with what is observed for younger populations.…”

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confidence: 99%

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Pharmacokinetics of ampicillin-sulbactam in healthy elderly and young volunteers

Meyers

Wilkinson

Mendelson

et al. 1991

“…The most common TEAE was nausea, which was more common in women (48%) than in men (24%). Only 1 (8%) of 13 subjects over 75 years of age reported nausea, compared with 4 of 15 (27%) subjects in the young-elderly group and 11 of 18 (61%) The aging process is known to affect the disposition of drugs by altering both body composition and organ function and, thus, may influence the pharmacokinetics of some drugs (9,12,14,15,19); these effects have been reviewed recently with respect to age (16) and sex (24). Overall, the results of this study demonstrate that the pharmacokinetic parameters of tigecycline do not differ significantly between sexes of the same age group or across age groups.…”

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confidence: 99%

Effects of Age and Sex on Single-Dose Pharmacokinetics of Tigecycline in Healthy Subjects

Muralidharan

Fruncillo

Micalizzi

et al. 2005

The pharmacokinetics of tigecycline was evaluated in 46 healthy young and elderly men and women. Except for the volumes of distribution at steady state (approximately 350 liters in women versus 500 liters in men), there were no significant differences in tigecycline pharmacokinetic parameters. Based on pharmacokinetics, no dosage adjustment is warranted based on age or sex.Tigecycline is a novel intravenously administered glycylcycline antibiotic exhibiting an expanded spectrum of in vitro and in vivo activity against gram-positive, gram-negative, atypical, anaerobic, and other difficult-to-treat pathogens (1-8, 10, 13, 18, 20-23, 25, 26). Clinical studies suggest that tigecycline is generally well tolerated and easy to use with a twice-daily dose regimen (17,21). The clinical dosing regimen presently being evaluated is 100 mg followed by 50 mg every 12 h (17).The primary objective of this open-label study was to determine if subject age or sex affects the pharmacokinetic profile of a single 100-mg intravenous dose of tigecycline, and the secondary objective was to compare the levels of observed openlabel safety and tolerability of tigecycline among the age and sex groups.Forty-six healthy men and women from the following three age categories were enrolled: young (18 to 50 years, inclusive), young-elderly (65 to 75 years, inclusive), and elderly (Ͼ75 years). Subjects were in good health on the basis of medical histories, physical examinations, electrocardiograms, and laboratory evaluations. The Institutional Review Board of The Methodist Hospital in Philadelphia, Pennsylvania approved the study, and all subjects gave written informed consent before enrollment. The demographic profile of each age-sex group is presented in Table 1.Tigecycline (100 mg) was administered as a single intravenous dose infused over 60 min. Serial blood samples for the determination of tigecycline concentrations in serum were collected over 120 h after the start of tigecycline infusion, and complete urine output was collected over 48 h after the start of the tigecycline infusion. Tigecycline concentrations in serum and urine were quantified by using validated analytical methods that are similar to those described previously (17).Pharmacokinetic parameters based on serum data for tigecycline were estimated with standard noncompartmental methods (11) using a validated SAS (version 8.02) program. Pharmacokinetic parameters were compared among the age-sex groups by using a two-factor analysis of variance with factors for age, sex, and age-by-sex interaction.Based on the intersubject variability observed in previous studies (17), it was estimated that having at least 20 subjects per sex and at least 17 in the younger cohort compared with the pooled elderly cohorts would provide a statistical power of at least 80% to detect a 30% difference for both the maximum concentrations of the drug in serum and the areas under the concentration-time curve (AUCs) between sexes or age groups.Safety was evaluated from spontaneously reported signs and sympt...

“…Previous clinical studies with other cephalosporins indicate that the elimination half-life (t112) is prolonged in elderly patients (23). Both male and female patients of different age groups are potential recipients of cefepime therapy.…”

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confidence: 99%

Effects of age and gender on pharmacokinetics of cefepime

Barbhaiya

Knupp

Pittman

1992

The effects of age and gender on the pharmacokinetics of cefepime were examined in 48 volunteers following administration of a single 1,000-mg intravenous dose. Male and female subjects were divided into four groups, each consisting of 12 subjects, according to their age and gender. The young subjects were between 20 and 40 years of age and elderly subjects were between 65 and 81 years of age. Serial blood and urine samples were collected from each subject and were analyzed for cefepime by validated high-pressure liquid chromatographic assays with UV detection. Key pharmacokinetic parameters were calculated by noncompartmental methods.There were no gender-related differences in elimination half-life (tl2) and weight-normalized total body clearance (CLT), renal clearance (CLR), and steady-state volume of distribution (Vr,). Statistically significant age-related effects were found for t4/2, CLT, CLR, and V., parameters. In different study groups, Vr,, ranged from 0.21 to 0.24 liter/kg. The values for V., were significant greater for elderly subjects than they were for young subjects. The cefepime t112 was significantly longer in elderly subjects (about 3 h) than that observed in young subjects (about 2.2 h). The mean values for CLr and CLR in the four study groups ranged from 1.11 to 1.56 and 0.99 to 1.44 ml/min/kg, respectively. In elderly subjects, the estimates for CLr and CLR were significantly lower than those observed in young subjects. Linear regression revealed good correlations between clearance values of cefepime and creatinine. The magnitude of age-related changes in the pharmacokinetics of cefepime is not significant enough to recommend dosage adjustment in elderly patients with kidney functions normal for their age.Cefepime (BMY-28142) is a new parenteral "fourth-generation" cephalosporin antibiotic with a spectrum of antimicrobial activity broader than those of other new cephalosporins and nontraditional antibiotics (12, 18). The in vitro activities of cefepime have been reproduced in numerous in vivo infection models (19,28). Compared with cefotaxime, cefepime has been shown to be five-to ninefold more active against Pseudomonas aenrginosa (18). In addition, cefepime has been found to be approximately fourfold more active than ceftazidime against gram-positive organisms (12,18). Cefepime was also more active than ceftazidime, moxalactam, cefoperazone, cefpirome, and cefotaxime when the compounds were tested against 326 species of members of the family Enterobacteriaceae (18). Cefepime has a low affinity for major chromosomally mediated 1-lactamases (24).Values of key pharmacokinetic parameters after the administration of single and repeated intravenous and intramuscular doses to normal volunteers indicate that cefepime is safe and well-tolerated and exhibits linear pharmacokinetics within the 62.5-to 2,000-mg dose range (2, 3, 7).In normal subjects, cefepime is cleared primarily by urinary excretion in the unchanged form (2,3,6,7). Previous clinical studies with other cephalosporins indicate that th...