Pharmacokinetic Optimisation of Antibacterial Treatment in Patients with Cystic Fibrosis

Abstract

Antibacterials play a central role in the medical management of patients with cystic fibrosis (CF). Administration of adequate dosages of antibacterials results in pronounced beneficial effects on the morbidity and mortality of this patient group. The dosage of the antibacterial that is needed for optimal treatment depends on the individual patient's pharmacokinetics and the pharmacokinetic-pharmacodynamic effect on the micro-organism of relevance in the host. In general, the disposition of antibacterial drugs in patients with CF is not as 'atypical' as once thought. Recent research with adequately matched controls demonstrated that, for a few beta-lactam antibacterials only, a CF-specific increase of the total body clearance seems to exist and that the large volumes of distribution observed are the result of malnutrition and the relative lack of adipose tissue. Pharmacokinetic-pharmacodynamic relationships in patients with CF are less well studied. Apart from the pharmacokinetics, there is a need for optimisation of antibacterial therapy. For the aminoglycosides, pharmacokinetic optimisation based on measured serum drug concentrations is common practice. The Sawchuk-Zaske method based on peak and trough drug concentrations is widely used. A more sophisticated approach is the 'goal-oriented model-based Bayesian adaptive control' method, where integration of mathematically determined optimally (D-optimally) sampled serum drug concentrations and a population model results in the most likely set of individual pharmacokinetic parameter values suitable for further pharmacokinetic optimisation of the therapy. A future development is the integration of changing serum drug concentrations and killing rates of the target micro-organism to a pharmacokinetic-pharmacodynamic surrogate relationship to optimise drug therapy. The latter approach may be extremely useful in deciding on the frequency of aminoglycoside administration as well as the optimal use of the beta-lactam antibacterials and fluoroquinolones.

Antibiotic therapy against Pseudomonas aeruginosa in cystic fibrosis: a European consensus

“…Intravenous aminoglycoside doses have to be adjusted according to the serum levels of the patient because of toxicity and efficacy of the drugs and therefore may change from patient to patient. Doses can be adjusted based on a mathematical model [64], which, however, is not available in many centres. A practical approach is to determine serum trough and peak levels of aminoglycosides.…”

“…Administration of ciprofloxacin orally has resulted in sputum concentrations ranging from 46±90% of those obtained in serum [64,71]. flouroquinolones are given either intravenously or orally.…”

“…A further obstacle for antibiotics to reach the P. aeruginosa outer cell membrane in CF plugs is the mucoid exopolysaccgaride (alginate) matrix [79]. In vitro models have been developed to evaluate the penetration of ceftazidime into plugs [64]. Taken together, bactericidal concentrations of antibiotics in CF plugs are difficult to reach and it has to be assumed that often only subinhibitory concentrations can be obtained.…”

“…Nevertheless, optimal doses of various intravenously administered antibiotics in CF are debated. The initial doses of aminoglycosides may be calculated based on the body surface area [76] or body weight [64,90,93]. A theoretical calculation of the dosing of ceftazidime demonstrates that the previously recommended doses of <200 mg .…”

“…kg -1 . day -1 and more have been recommended [22,64,99,100]. An adjustment in dose interval based on the serum tobramycin level has a significant effect on pulmonary function [93].…”