Therapeutic evaluation of piperacillin for acute pulmonary exacerbations in cystic fibrosis

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...

Section: Resultssupporting

confidence: 75%

“…The overall amounts of drug excreted declined over the next 4 h. The cumulative amount of drug excreted over the 6-h sampling period and pooled as composite data is also shown in Fig. 4 (26,28,30). Nevertheless, the drug's susceptibility (Tables 2 and 3; Fig.…”

Section: Resultsmentioning

confidence: 99%

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

Reed

Goldfarb

Yamashita

et al. 1994

“…The calculated pharmacokinetic parameter values after intermittent infusion are different from earlier observations in young patients with CF. Reed et al (15) and Bertino et al (Pediatr. Res.…”

Section: Discussionmentioning

confidence: 99%

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

Vinks

Hollander²,

Overbeek

et al. 2003

The purpose of this study was to describe the nonlinear pharmacokinetics of piperacillin observed during intermittent infusion and continuous infusion by using a nonparametric population modeling approach. Data were 120 serum piperacillin concentration measurements from eight adult cystic fibrosis (CF) patients. Individual pharmacokinetic parameter estimates during intermittent infusion or continuous infusion were calculated by noncompartmental analysis and with a maximum iterative two-stage Bayesian estimator. To simultaneously describe concentration-time data during intermittent infusion and continuous infusion, nonlinear models were parameterized as two-compartment Michaelis-Menten models. Models were fit to the data with the nonparametric expectation maximization algorithm. The calculations were executed on a remote supercomputer. Nonlinear models were evaluated by log-likelihood estimates, residual plots, and Piperacillin-tazobactam is a parenterally administered combination of a ␤-lactam antibiotic with a ␤-lactamase inhibitor (4). This drug combination is frequently used in the treatment of pulmonary exacerbations in patients with cystic fibrosis (CF) because of its good bactericidal activity against Pseudomonas aeruginosa and gram-positive microorganisms (20). Piperacillin, like other ␤-lactam antibiotics, exhibits time-dependent killing, and the parameter for the bactericidal effect is the time during which the concentration of the drug exceeds the MIC (5). As shown for ceftazidime (23), continuous infusion of piperacillin-tazobactam may result in superior efficacy with equal or lower total daily doses. Administration by continuous infusion also has distinct advantages in CF home treatment programs (24). A recent report on continuous intravenous administration of vancomycin also emphasized this point (27).Data on the pharmacokinetics of piperacillin in patients with CF are scarce (12; J. S. Bertino, M. D. Reed, C. Meyers, and J. L. Blumer, Pediatr. Res. 16:1210A, abstr. 254, 1982), while data for the combination are lacking. Piperacillin-tazobactam is commonly administered by intermittent infusion. In non-CF patient populations and with this mode of administration, the pharmacokinetics of the ␤-lactamase inhibitor-antibiotic combination appeared to be linear (1), although nonlinear analysis was not addressed. Some authors, however, have argued for nonlinear behavior, and studies have documented evidence for decreasing clearance with increasing concentrations (2,3,19). Piperacillin is, for the most part, excreted through the kidneys by active tubular secretion and by glomerular filtration. A typical characteristic of the active secretion process is a limitation in the capacity of this process. This behavior can be described in terms of Michaelis-Menten (MM) kinetics, where the rate of active transport increases toward a maximum value (V max ) with increasing plasma drug concentrations (11). The concentration at which the rate is 50% of its maximum is the K m . At concentrations well below the K m , the r...

“…Dosages of up to 900 mg/kg daily divided into six doses (equivalent to 63 g for a 70-kg patient) were administered to CF patients aged 12 years or less (59). A distinct serum sickness-like adverse reaction was observed for 32% of these patients, and its incidence appeared to be correlated with the piperacillin dose.…”

Section: Discussionmentioning

confidence: 99%

Systematic Comparison of the Population Pharmacokinetics and Pharmacodynamics of Piperacillin in Cystic Fibrosis Patients and Healthy Volunteers

Bulitta

Duffull

Kinzig‐Schippers

et al. 2007

109

102

Respiratory tract infections cause 90% of premature mortality in patients with cystic fibrosis (CF). Treatment of Pseudomonas aeruginosa infection is often very problematic. Piperacillin-tazobactam has good activity against P. aeruginosa, but its pharmacokinetics (PK) in CF patients has not been compared to the PK in healthy volunteers in a controlled clinical study. Therefore, we compared the population PK and pharmacodynamics (PD) of piperacillin between CF patients and healthy volunteers. We studied 8 adult (median age, 20 years) CF patients (average total body weight [WT], 43.1 ؎ 7.8 kg) and 26 healthy volunteers (WT, 71.1 ؎ 11.8 kg) who each received 4 g piperacillin as a 5-min intravenous infusion. We determined piperacillin levels by high-performance liquid chromatography, and we used NONMEM for population PK and Monte Carlo simulation. We used a target time of nonprotein-bound concentration above the MIC of 50%, which represents near-maximal bacterial killing. Unscaled total clearance was 25% lower, and the volume of distribution was 31% lower in CF patients. Allometric scaling by lean body mass reduced the unexplained (random) betweensubject variability in clearance by 26% compared to the variability of linear scaling by WT. A standard dosage regimen of 3 g/70 kg body WT every 4 h as a 30-min infusion (daily dose, 18 g) achieved a robust (>90%) probability-of-target attainment (PTA) for MICs of <12 mg/liter in CF patients and <16 mg/liter in healthy volunteers. Alternative modes of administration allowed a marked dose reduction to 9 g daily. Prolonged (4-h) infusions of 3 g/70 kg WT every 8 h and continuous infusion (daily dose, 9 g), achieved a robust PTA for MICs of <16 mg/liter in both groups. Piperacillin achieved PTA expectation values of 64% and 89% against P. aeruginosa infection in CF patients, based on susceptibility data from two German CF clinics.