Antibiotic Pharmacokinetics in Cystic Fibrosis

Abstract

Antibiotics are administered to cystic fibrosis patients for chronic endobronchial infection complicated by frequent exacerbations. Agents active against Staphylococcus aureus, Pseudomonas aeruginosa or both are administered. Serum antibiotic concentrations were measured in cystic fibrosis patients in an effort to optimise antibiotic dose and frequency. This led to the observation that cystic fibrosis subjects had (in general) a larger Vd and increased total body clearance of beta-lactams and aminoglycosides than non-cystic fibrosis subjects. The larger Vd is mainly due to the increased amount of lean body mass per kg bodyweight, although increased tissue binding may also account for part of this. The increased total body clearance of beta-lactams appears to be due to increased renal elimination, particularly tubular secretion. Decreased tubular reabsorption and increased non-renal clearance contribute to the increased total body clearance of metabolised beta-lactams and aminoglycosides. However, the lack of concomitant controls in many studies make these generalisations tentative. The result of the apparent cystic fibrosis-specific differences is lower peak serum antibiotic concentrations, a smaller AUC, and a shorter elimination half-life than non-cystic fibrosis subjects. Since sputum (and bronchial mucosal) concentration is dependent on the peak serum concentration (and AUC), cystic fibrosis subjects require larger doses of most antibiotics more frequently. Newer quinolones may be an exception. Studies comparing the efficacy and safety of larger and more frequent antibiotic doses to conventional therapy are not available. Although it appears logical to mimic serum antibiotic concentrations found in non-cystic fibrosis subjects, the lack of information on the ideal sputum concentration versus time curve should temper our enthusiasm for cystic fibrosis-specific dosage regimens.

Occurrence and Risk of Cochleotoxicity in Cystic Fibrosis Patients Receiving Repeated High-Dose Aminoglycoside Therapy

“…In CF patients, equivalent milligram/kilogram/day dosing regimes of gentamicin and tobramycin are employed to yield a comparable range of concentrations in plasma (14). These agents also have similar molecular weights (gentamicin, 477; tobramycin, 468).…”

“…A typical course for a CF patient would be 10 mg/kg/day for 14 days (11,34,42). This regime and the resultant higher peak levels attained in plasma (10 to 12 g/ml) are necessary (i) to offset the effects of the shorter half-life and higher volume of distribution (V d ) often seen in CF patients and (ii) to achieve increased penetration of the pulmonary compartment in order to reach an adequate bactericidal concentration in the sputum (14,41).…”

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

“…The volume of distribution per kg body weight is often increased and the elimination half-life decreased [90]. The higher body clearance due to increased renal and nonrenal elimination [76,88] demands that higher antibiotic doses are administered more frequently [87,93]. However, differences between CF patients and non-CF individuals in this context do not seem to be as large as used to be thought and may have been exaggerated by the lack of properly matched controls for clinical studies [69].…”

Optimal Tobramycin Dosage in Patients with Cystic Fibrosis - Evidence for Predictability Based on Previous Drug Monitoring

“…ceftazidim, piperacillin). Because of the different pharmacodynamics of antibiotics in patients with cystic fibrosis as compared to healthy subjects (increased distribution volume per kg body weight and decreased serum half-life) high doses of antibiotics have to be administered for successful therapy [1]. Especially in the case of aminoglycosides, serum levels need to be monitored during therapy to guarantee correct dosage.…”