Pharmacokinetics of a parenteral formulation comprised of 5 parts of amoxicillin and 1 part of clavulanic acid were determined in 12 pediatric patients, 2 to 14 years of age. A single dose amounting to 25 mg of amoxicillin and 5 mg of clavulanic acid per kg of body weight was infused intravenously over 2 min. Mean plasma concentrations 5 min after-dosing were 89.4 ,ug of amoxicillin per ml and 19.5 pg of clavulanic acid per ml. Terminal phase plasma half-lives were 1.2 and 0.8 h, respectively. The data acquired in this study indicate that amoxicillin and clavulanic acid are pharmacokinetically compatible. Moreover, taken with assessment of microbiological activities by others, the present data suggest that intravenous administration of 25 mg of amoxicillin plus 5 mg of clavulanic acid per kg every 6 h is a reasonable starting regimen for assessing the activity of the combined drug formulation in noninvasive childhood diseases caused by Haemophilus influenzae, Staphylococcus aureus, Streptococci spp., Neisseria spp., Branhamella catarrhalis, and other susceptible organisms.Clavulanic acid, a ,B-lactam derivative, has comparatively low antibacterial activity but irreversibly inhibits a broad spectrum of P-lactamase enzymes (11). The combination of clavulanic acid with ,B-lactamase-susceptible antimicrobial agents effects a marked enhancement of the activity of these compounds against many beta-lactamase-producing bacteria (6,8,13,14). In vitro studies, experiments in animal models, and preliminary clinical experience indicate that combinations of clavulanic acid with amoxicillin have a high order of antimicrobial activity (2-4, 6-8, 12-14, 16, 17).The purpose of the present study was to evaluate the pharmacokinetics of an intravenous (i.v.)

The disposition of coadm,inistered tic,ircillin (3 g/1.73 m2) and clavulanic acid (100 mg/1.73 m2) was examined after a 30-min infusion in 24 noninfected subjects with various degrees of renal function. Noncompartmental pharmacokinetic parameters for the individual compounds were determined from plasma concentrations and urinary excretion rates. All clearances (total, renal, and nonrenal) and urinary recoveries of unchanged drug were found to be linearly related to creatinine clearance (CLcR). The steady-state volume of distribution (9.9 and 12.9 liters for ticarcillin and clavulanic acid) approximated the extracellular fluid space and was not related to CLCR. The half-lives increased with redqced renal function and ranged from 56 to 392 min for ticarcillin and 26 to 266 min for clavulanic acid. The clearances of both drugs decreased proportionately with reduction in renal function, facilitating dosing adjustments based on CLCR. Calculations of expected steady-state maximum and minimu,, concentrations in pla,sma using constant doses and an extended dosing interval related to CLCR further rationalized use of the 30:1 drug combination ratio for all patients.Ticarcillin is a wide-spectrum penicillin which can be hydrolyzed by a number of beta-lactamases. Clavulanic acid is a potent inhibitor of these enzymes, and a synergistic effect is exhibited when the two agents are coadministered (5,18,20). A ticarcillin:clavulanic acid combination of 30:1 is used clinically, partly on the basis of pharmacokinetic matching in subjects with normal renal function (1).Previous studies evaluated the pharmacokinetics of ticarcillin and clavulanic acid when administered separately (3,4) or in combination (1, 2, 6) in subjects with normal renal function, but the disposition of the combination has not been assessed in relation to renal impairment. The purpose of this study was to evaluate the pharmacokinetics of ticarcillinclavulanic acid in subjects with various degrees of renal impairment to evolve dosage guidelines and to determine whether the dosing ratio of 30:1 remains suitable in the presence of severe renal dysfunction.MATERIALS AND METHODS Subjects. A total of 24 adult subjects, aged 18 to 61 years, who gave informed written consent for the study were divided into four groups based on renal function (creatinine clearances [CLCRI, 10 to 30, 30 to 60, 60 to 80, and >100 ml min-'). By chance, there were no subjects available with CLCR between 80 and 100 ml min-'. Individuals with a history of hypersensitivity to penicillins-or cephalosporins, females with known or suspected pregnancy, and individuals on hemodialysis or peritoneal dialysis, with an infection, or with major cardiovascular or hepatobiliary dysfunction were excluded frpm the study. CLCR for each subject was determined over 24 h within 7 days before the study. Complete blood counts and blood chemistries were also performed within 7 days before the start of the study and 10 days after the study. Th1 subjects were also monitored for possible adverse effects througho...

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