Single-dose pharmacokinetics of piperacillin and tazobactam in infants and children

Abstract

The pharmacokinetics of piperacillin and tazobactam were assessed after single-dose administration to 47 infants and children. Study subjects ranging in age from 2 months to 12 years were randomized to receive one of two different doses of a piperacillin-tazobactam combination (8:1): a low dose (n = 23) of 50 and 6.25 mg of piperacillin and tazobactam per kg of body weight, respectively, or a high dose (n = 24) of 100 and 12.5 mg, respectively. The pharmacokinetic behavior of tazobactam was very similar to that observed for piperacillin, supporting the use of these two agents in a fixed-dose combination. No differences in the pharmacokinetics of piperacillin or tazobactam were observed between the two doses administered. The elimination parameters half-life and total body clearance decreased and increased, respectively, with increasing age, whereas volume parameters (volume of distribution and steady-state volume of distribution) remained relatively constant for both compounds. The primary metabolite of tazobactam, metabolite Ml, was measurable in the plasma of 18 of the 47 study subjects; 17 of these 18 subjects received the high doses. More than 70%o of the administered piperacillin and tazobactam doses were excreted unchanged in the urine over a 6-h collection period. These data combined with the known in vitro susceptibilities of a broad range of pediatric bacterial pathogens indicate that a dose of 100 mg of piperacillin and 12.5 of mg tazobactam per kg of body weight administered as a fixed-dose combination every 6 to 8 h would be appropriate to initiate clinical efficacy studies in infants and children for the treatment of systemic infections arising outside of the central nervous system. The beta-lactam antibiotics are among the most widely prescribed classes of drugs for infants and children. For decades these drugs have been used successfully for the treatment of most bacterial infections arising in childhood, particularly for those infections involving skin and soft tissues, the genitourinary tract, the upper and lower respiratory tracts, and the central nervous system (30,31). Unfortunately, over the last decade, the number of infections caused by penicillinand cephalosporin-resistant bacteria has increased dramatically, reducing the clinical utilities of these safe and previously very effective antibiotics (22,29). By 1975 nearly 85% of all isolates of Staphylococcus aureus were resistant to penicillin (22), and a similar trend has been observed for Haemophilus influenzae and Moraxella catarrhalis, in which nearly 40% of all H. influenzae type B strains and more than 80% of M. catarrhalis isolates are resistant to ampicillin (6, 29). Moreover, variable and changing susceptibility patterns to a wide range of penicillin and cephalosporin antibiotics are observed for other gram-negative pathogens (6,22,29).Bacterial resistance to beta-lactam antibiotics is most often mediated via one of three primary mechanisms; alterations in drug binding to their cellular targets, the penicillin-binding proteins; alt...

Developmental Pharmacokinetics of Piperacillin and Tazobactam Using Plasma and Dried Blood Spots from Infants

“…Piperacillin-tazobactam CL was significantly associated and increased with surrogate covariates of maturation, including body weight, PMA, PNA, and SCR. This finding is consistent with prior investigations of piperacillin-tazobactam PK in infants and was expected given that the kidneys are the primary route of elimination for this drug (7,19,25). In our population, piperacillin-tazobactam CL increased rapidly (on average, by 100%) after the first 2 weeks of life.…”

“…Our slightly lower CL may reflect the lower GA at birth in our study population. Overall, differences in piperacillin-tazobactam CL across ages can be attributed to the maturation of renal function during childhood (19). Similarly, population V estimates in our study were not clinically different (within 15%) from reported V estimates for older children (19).…”

“…In our population, piperacillin-tazobactam CL increased rapidly (on average, by 100%) after the first 2 weeks of life. In spite of this change, the population CL of piperacillin in the present study was ϳ60% lower than that reported for older infants (full term, 2 to 5 months of age; 0.198 liter/kg/h) (19), Ͼ75% lower than that for children (9 months to 12 years of age, 0.338 liter/h/kg) (26), and ϳ60% lower than that for adults (18 to 82 years of age, 0.183 liter/h/kg) (27). In a recent study of piperacillin-tazobactam in infants, including those born prematurely, piperacillin CL estimates were comparable with those in our study (0.092 liter/kg/h versus 0.080 liter/k/h for an infant with 8 days' PNA) (7).…”

“…This range of MICs is consistent with MICs found in causative agents of infections in premature infants and includes the susceptibility breakpoints for the Enterobacteriaceae (16 mg/liter) and for Pseudomonas aeruginosa (32 mg/ liter) (16)(17)(18). We used unbound (30% protein-binding [19]) piperacillin concentrations at 50% and 75% of the dosing interval as the surrogate PD target. We included the more stringent surrogate PD endpoint (75% of the dosing interval) due to the immunocompromised state of premature infants and the need to achieve effective drug concentrations for a longer period of time to achieve bacterial killing (20).…”

Population Pharmacokinetic Analysis of Nonlinear Behavior of Piperacillin during Intermittent or Continuous Infusion in Patients with Cystic Fibrosis

“…Piperacillin concentrations in serum were analyzed by high-performance liquid chromatography by a modification of the method of Reed et al (14). For piperacillin, briefly, 0.2 ml of a methanol solution containing 50 mg of methicillin/liter as an internal standard was added to an equal volume of serum sample, and the mixture was centrifuged.…”