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.

The unique pharmacokinetic properties as well as the body fluid and tissue penetration of quinolones are discussed.Quinolones are well absorbed from the gastrointestinal tract and are eliminated with considerable d{fJerences in their terminal half-lives. The major elimination pathways of quinolones are renal excretion and hepatic metabolism. Renally. these drugs undergo the potential excretion mechanisms (glomerular filtration. tubular secretion. reabsorption). In the liver. they are metabolised primarily by oxidation as well as by conjugative pathways. However. the metabolic pattern and extent of metabolism d{f!er significantly between individual agents.Alterations in the pharmacokinetic disposition of these agents in liver and renal failure as well as in elderly patients are observed as predicted from their excretion pattern. In addition. quinolones can interact with a number of other compounds at hepatic (e.g. with xanthine derivatives). renal (with probenecid) and gastrointestinal (with antacids) sites.The volume of distribution of quinolones is considerably higher than body volume. which suggests intracellular penetration. Studies on tissue penetration show that concentrations exceeding plasma levels are obtained in most tissues. The highest tissue/plasma concentration ratios are achieved in lung and kidney. whereas concentrations in fat are considerably lower than in plasma.Body fluid penetration is introduced as a new approach to evaluate distribution kinetics of quinolones. With the exception of those in nasal secretions and ejaculate. body flUid levels of these drugs rarely reach plasma levels. The body fluid penetration model allows for d{f!erentiation among individual agents. There is no apparent relationship between d{f!erences in body fluid penetration of quinolones and d{f!erences in volume of distribution. For the clinical use of these drugs it is important that the concentrations achieved in body fluids and tissues are sufficient to kill most pathogens. A discussion on the relationship between plasma and tissue levels and the MICs of quinolones is. however. beyond the scope of this article.

Despite the promising activity of ceftazidime against Pseudomonas aeruginosa and Burkholderia cepacia, there has not yet been a study that directly compared the pharmacokinetics (PK) of ceftazidime in cystic fibrosis (CF) patients and healthy volunteers by population PK methodology. We assessed the population PK and PK/pharmacodynamic (PD) breakpoints of ceftazidime in CF patients and healthy volunteers.