Pharmacodynamic profiling of continuously infused piperacillin/tazobactam against Pseudomonas aeruginosa using Monte Carlo analysis.

Standard doses of piperacillin/tazobactam (9-13.5 g over 24 h) administered by continuous infusion (CI) routinely provide serum concentrations in excess of the susceptibility breakpoint (< or =16/4 micro g/ml) for most Enterobacteriaceae. Since the breakpoint of this agent for Pseudomonas aeruginosa is considerably higher (< or=64/4 micro g/ml), the likelihood of obtaining adequate drug exposures with these doses against this bacterium is currently unknown. Monte Carlo simulation was utilized to determine the probability of obtaining adequate piperacillin concentrations above its MICs for P. aeruginosa in patients receiving CI. MICs of 557 P. aeruginosa isolates were determined by E-test and a distribution was constructed for the 496 susceptible isolates. Using a previously validated population pharmacokinetic equation, steady-state serum concentrations were estimated for 210 patients who received piperacillin/tazobactam via CI. A Monte Carlo simulation was performed to predict the probability of obtaining concentrations at the MIC, 2 x MIC, 4 x MIC, 5 x MIC, and 6 x MIC for patients infected with susceptible P. aeruginosa isolates. MICs ranged from 0.09 to 64 micro g/ml with modal and median values of 3 and 4 micro g/ml, respectively. Steady-state concentrations of 51.14 +/- 17.52 micro g/ml were estimated in our patient population. The simulation resulted in a median level of exposure 12.62 times the MIC. The level of certainty of obtaining concentrations at the MIC, 2 x MIC, 4 x MIC, 5 x MIC, and 6 x MIC for piperacillin administered by CI was 97, 93, 85, 81, and 77%, respectively. Despite concern for the place of CI piperacillin/tazobactam in the management of P. aeruginosa infections due to the higher established breakpoint, these data suggest a high probability of achieving adequate drug exposure against susceptible isolates with this dosing regimen.

Pharmacokinetics of antibiotic prophylaxis in major orthopedic surgery and blood-saving techniques.

The pharmacokinetics of cefuroxime, cefotiam, cefamandole, and ampicillin/sulbactam were randomly measured in 40 patients undergoing major orthopedic surgery associated with high blood and volume turnover and intraoperative blood salvage. Serum and bone concentrations and the pharmacokinetics occurring in the context of these procedures were measured. No changes in elimination half-life relative to a normal population occurred with cefuroxime, cefotiam, and ampicillin. Serum and tissue concentrations were slightly lower with cefamandole and sulbactam, but reapplication of the initial dose was required with all antibiotics 4 hours after the first application.

Assessment of the enzymuria resulting from gentamicin alone and combinations of gentamicin with various beta-lactam antibiotics.

OBJECTIVE: To determine the propensity of beta-lactam antimicrobials to ameliorate or potentiate aminoglycoside-induced renal enzymuria. DESIGN: Two open, randomized, double-blind, parallel-group studies were conducted in young, healthy, male volunteer subjects. Using a common protocol, 24-hour urine collections were analyzed for the renal tubular enzymes alanine aminopeptidase (AAP) and N-acetyl-beta-D-glucosaminidase (NAG), as well as for creatinine. Antimicrobial combinations studied included gentamicin plus placebo and gentamicin plus ticarcillin/clavulanate (protocol 1); and gentamicin plus placebo, gentamicin plus piperacillin, and gentamicin plus ceftazidime (protocol 2). The antimicrobial regimens were administered for 7 days. Eight subjects completed each treatment group. RESULTS: There were no significant differences between treatment groups with regard to urine creatinine excretion or serum gentamicin concentrations in either protocol. Enzymuria (AAP [p = 0.039] and NAG [p = 0.337]) was decreased in the gentamicin plus ticarcillin/clavulanate treatment compared with that in the gentamicin plus placebo treatment. Increased enzymuria, as indicated by increased urine concentrations of AAP and NAG, was observed in the gentamicin plus ceftazidime treatment (p < 0.05) compared with the other two treatments. CONCLUSIONS: Based on relative enzymuria, ticarcillin/clavulanate may be renal protective. Piperacillin neither potentiated nor ameliorated aminoglycoside-induced enzymuria. Since acute elevations in AAP and NAG reflect insults to the kidney, these studies suggest that ceftazidime may enhance aminoglycoside-induced renal injury. Piperacillin had no effect on enzymuria and would appear not to enhance or protect against aminoglycoside-induced renal injury.

Ampicillin/sulbactam in lower respiratory tract infections: a review.

The pathophysiology and microbiology of lower respiratory tract infections are outlined and diagnostic and therapeutic problems considered. The use of sulbactam/ampicillin in the treatment of these infections is evaluated. The two drugs have similar pharmacokinetic characteristics; predictable and dose-dependent peak serum concentrations of both agents are achieved after parenteral administration. More than 90% of strains of Staphylococcus aureus, Haemophilus influenzae, Moraxella catarrhalis, Klebsiella sp, Escherichia coli, and Acinetobacter sp were inhibited by ampicillin/sulbactam concentrations of 16/8 micrograms/ml. Serum concentrations of ampicillin and sulbactam were 18 to 28 micrograms/ml and 13 micrograms/ml, respectively, after intramuscular administration of 1 gm/0.5 gm of ampicillin/sulbactam and 58 micrograms/ml and 30 micrograms/ml, respectively, after intravenous administration of the same dose. Good distribution of ampicillin/sulbactam into lung tissue, sputum, and bronchial fluid has been demonstrated. In over 2,250 patients treated with ampicillin/sulbactam, the rate of discontinuance of treatment because of side effects was less than 1%. Satisfactory clinical and bacteriologic outcome has been reported in over 80% of patients treated with ampicillin/sulbactam. The cost of ampicillin/sulbactam treatment is generally lower than that of other comparable antibiotic regimens.