CLINICAL PHARMACOKINETICS OF PIPERACILLIN-TAZOBACTAM COMBINATION IN PATIENTS WITH MAJOR BURNS AND SIGNS OF INFECTION

The pathophysiology associated with major burns is complex and subject to a state of flux. The combination of beta-lactamase inhibitors with powerful penicillins is an interesting and an attractive potential so lution to the emergence of bacterial resistance. The kinetics in serum and urine and the clinical safety of a fixed combination of 4 g of pi peracillin (PPR) and 0.5 g of tazobactam (TZB) were studied in 10 pati ents (22 to 50 years old and weighing 45 to 105 kg) with major burns w ho were infected with Pseudomonas aeruginosa and various enterobacteri a. All of them received additional antimicrobial drugs. Treatment invo lved one dose every 6 h. The mean body surface area affected by third- degree burns was 30.0% +/- 4.0%. The study took place in accordance wi th current ethical guidelines. Two series of blood samples were drawn after the first (day 1) and ninth (day 3 at steady state) doses; urine was collected during the same periods. Levels of PPR and TZB in serum and urine were measured by high pressure liquid chromatography. A non compartmental method was used for kinetic and graphic analysis of conc entration-time pairs. The safety of the treatment was excellent. There was no systemic accumulation of the beta-lactam combination. Residual concentrations measured on days 1 and 3 [mean (standard error of the mean)] were above the MIC for the organism responsible for infection; i.e., C(min)day 1 = 26.3 (8.5) and C(min)day 3 = 21.0 (9.1) for PPR an d C(min)day 1 = 1.9 (0.6) and C(min)day 3 = 1.4 (0.3) for TZB. There w as no statistically significant difference between pharmacokinetic par ameters determined for day 1 and day 3. Evidence was found in burn pat ients, in contrast to healthy subjects, of a marked increase in appare nt volumes of distribution, in such a way that the apparent eliminatio n half-lives of the combination were notably prolonged, i.e., 1.8 (0.3 ) versus 1.5 (0.3) h for PPR in patients and healthy subjects, respect ively, and 1.7 (0.3) versus 1.4 (0.3) h for TZB. These findings indica te the possibility of nonrenal translesional diffusion of PPR-TZB in b urn patients. The polarity of the association would further support th is hypothesis. It has been shown here that the recommended dosage regi men for administration of PPR-TZB must be high in major-burn patients, i.e., 4 g/0.5 g every 6 h. The data obtained provide valuable informa tion, which is suitable for immediate application in everyday clinical practice.