Pharmacokinetics of piperacillin in subjects with various degrees of renal function.

The pharmacokinetics of piperacillin were examined after single intravenous doses to three groups of male patients with creatinine clearances of greater than or equal to 60 (group I), greater than or equal to 20 but less than 60 (group II), and less than 20 (group III) ml/min per 1.73 m2. Each of 32 patients received either 1 or 4 g of piperacillin as a bolus injection. Three patients received both doses. After a rapid 0.5- to 1-h distribution phase, antibiotic levels in serum declined monoexponentially. After the 1-g dose, mean peak piperacillin levels in serum were 60, 103, and 67 micrograms/ml and the beta phase elimination half-lives were 1.0, 1.6, and 3.9 h in groups I, II, and III, respectively. After the 4-g dose, the respective mean peak piperacillin levels in serum were 329, 232, and 262 micrograms/ml and beta phase half-lives were 1.4, 2.3, and 2.6 h in the three groups. There was no clear evidence of significant dose-dependent effects on any pharmacokinetic parameters in any of the groups. Piperacillin levels in urine were far higher than those in serum, generally exceeding the minimal inhibitory concentrations for susceptible organisms during the 24 h after both the 1- and the 4-g dose. Piperacillin dosage modification is required only in patients with severe renal impairment.

Pharmacokinetics of cefuroxime in normal and impaired renal function: comparison of high-pressure liquid chromatography and microbiological assays.

The pharmacokinetics of cefuroxime were studied after a single dose of 750 mg was given intravenously to each of 21 male volunteers grouped according to their creatinine clearances; these clearances were 60 to 120, 20 to 59, and less than 20 ml/min per 1.73 m,2 respectively, for groups 1 (12 subjects), 2 (4 subjects), and 3 (5 subjects). Cefuroxime obeyed two-compartment model kinetics in all three groups. Initial serum levels of cefuroxime were approximately 130 microgram/ml in group 1 and 2 and 80 microgram/ml in group 3. the levels then declined rapidly for 0.5 to 1 h after injection. After that time, cefuroxime levels declined more slowly, and the elimination rate became monoexponential. The mean serum half-lives for cefuroxime in groups 2, 2, and 3 were 1.7, 2.4, and 17.6 h, respectively. Mean cefuroxime levels in serum were greater than 8 microgram/ml for 3 h in group 1, for 6 h in group 2, and for 30 h in group 3. Cumulative 24-h urinary excretion accounted for essentially 100% of the dose in group 1 and 2, and for 40% in group 3. Urine levels exceeded the minimal inhibitory concentration for susceptible organisms for more than 12 h in all groups. Cefuroxime distribution characteristics were independent of renal function. In patients with creatinine clearances less than 20 ml/min per 1.73 m2, doses of cefuroxime needs to be reduced. A microbiological disk diffusion assay and a high-pressure liquid chromatography assay for cefuroxime yielded statistically identical results, except for serum levels in uremic patients (group 3).

Postantibiotic suppression of bacterial growth.

Persistent suppression of bacterial growth following exposure of both gram-positive and gram-negative bacteria to numerous antimicrobial agents was studied. The persistent, or postantibiotic, effect was quantitated by periodic counts of colony-forming units after removal of the drug by washing, dilution, or inactivation with penicillinase. Although a postantibiotic effect was observed with all drugs studied, there were marked differences among drugs in their postantibiotic effects on certain organisms. With gram-positive organisms, concentrations of beta-lactam antibiotics near the minimal inhibitory concentration produced persistent effects lasting 1-3 hr. With gram-negative organisms much higher concentrations were required to elicit a postantibiotic effect. Inhibitors of protein and RNA synthesis produced the longest persistent suppression of growth, which was of comparable duration in gram-positive and gram-negative bacteria. Only a short persistent effect of gentamicin was observed with Staphylococcus aureus and Escherichia coli, but a postantibiotic effect lasting 1.6-2.6 hr was observed with Pseudomonas aeruginosa. The duration of the postantibiotic effect was related linearly to concentration of drug and duration of exposure up to a point of maximal response. Persistent effects following exposure to antibiotics were also demonstrated in 90% human serum.

Mezlocillin pharmacokinetics after single intravenous doses to patients with varying degrees of renal function.

The pharmacokinetics of mezlocillin were examined after single 2- and 4-g intravenous injections to three groups of male patients with creatinine clearances of I >/= 60, II = 21 to 59, and III

Cefotaxime pharmacokinetics following a single intravenous dose to patients with varying renal function.

The pharmacokinetics of cefotaxime (HR 756) were investigated in two groups of patients (Groups I and II) with creatinine clearances of greater than or equal to 60 and < 60 ml/min per 1.73 m2 respectively. Each of the 24 patients included in the study received 0.5 g or 1.0 g cefotaxime intravenously as a bolus injection. The decline of serum concentrations was biphasic in all patients, and the data were fitted to the pharmacokinetic two-compartment model. The mean distribution and elimination half-lives of cefotaxime in individuals in Group I were 0.2 and 1.2 hours respectively. In the uremic individuals, the pharmacokinetic parametes did not differ markedly from those in normal subjects, except when renal function was markedly reduced. In severe renal impairment, the elimination half-life increased to 8.3 hours. Cumulative 24-hour urinary excretion accounted for a mean of 59% of the dose in normal individuals, and from 0.3 to 36% of the dose in uremic individuals. Incomplete recovery of intact drug in urine of normal individuals reflects excretion by an extrarenal pathway, possibly as desacetyl cefotaxime. Urine levels were greater than the minimum inhibitory concentrations for susceptible organisms for at least eight hours after dosing in all individuals who produced urine. Because of the relatively small effect of renal impairment on the pharmacokinetics of cefotaxime, dose reduction is necessary only in cases of severe renal impairment.