High dose treatment with antibiotics in cystic fibrosis — A reappraisal with special reference to the pharmacokinetics of betalactams and new fluoroquinolones in adult CF-patients

Abstract

In this review we analyzed the pharmacokinetic basis for high dose treatment with antibiotics of patients with cystic fibrosis. Both our results and those from other well designed pharmacokinetic studies do not support the view that low blood levels of antibacterials are a common feature of CF. We were unable to detect a decrease in absorption, nor could we find evidence for enhanced elimination of antibacterials in CF. Both these factors have been considered responsible for reducing the plasma (and tissue) levels of antibiotics. Most recent studies on kidney function are in agreement with these findings, since neither inulin nor creatinine clearance differ between CF-patients and healthy volunteers. In contrast to previous discussion, the volume of distribution (Vdss) was not elevated for any compound. The rational of weight correction of volume terms like Vdss or total clearance has never been clearly demonstrated and should therefore not be used without prior proof of relevance. Since the variability of pharmacokinetic parameters of antibiotics in CF-patients may be considerable, we suggest that a dose increase of 20-30% may be justified, but cannot agree with two to fourfold increases in dosage as previously proposed and applied in many CF-centers. Until more findings become available for non-adult CF-patients, these conclusions are only valid for adult CF-patients.

Pharmacokinetics of Aztreonam in Healthy Subjects and Patients with Cystic Fibrosis and Evaluation of Dose-Exposure Relationships Using Monte Carlo Simulation

“…However, the relationship between antibiotic concentrations in pulmonary secretions and clinical effect has not been well studied or documented. Sputum concentrations of ␤-lactam antibiotics in CF remain disappointingly low despite high intermittent dosages (36). Despite the general idea that with intermittent dosing the high peak concentrations reached in plasma would facilitate penetration of the antibiotic in sputum, the diffusing antibiotic typically shows a relatively flat concentration-time profile that does not follow the concentration profile in plasma (4).…”

“…In a small pediatric CF study aztreonam clearance was found to be higher than in unaffected adults, with no apparent PK differences compared to two children without CF (30,31). Over the years there has been controversy over whether patients with CF truly exhibit different PK characteristics as a result of their disease or whether the observed differences in part are an artifact and the result of normalizing parameters to total body weight or surface area in a patient group with known altered body composition (36,37). Most of the earlier published PK studies in CF patients lack adequate control groups that match for age, gender, height, and weight.…”

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

“…Although pronounced differences in clearance and volume of distribution between CF patients and healthy volunteers were reported by some authors (60,73), other data show smaller differences (24,45,64). We are not aware of any PK study of piperacillin in CF patients which included a healthy volunteer control group.…”

Population Pharmacokinetic Comparison and Pharmacodynamic Breakpoints of Ceftazidime in Cystic Fibrosis Patients and Healthy Volunteers

“…Our third objective was to predict the PK-PD MIC breakpoints for various ceftazidime dosage regimens in CF patients. We applied the latest parametric and nonparametric population PK methodology and evaluated linear and allometric body size models comparing the PK in CF patients and healthy volunteers in order to greatly extend a descriptive noncompartmental analysis of our study reported previously (65)(66)(67).…”