The pharmacokinetics of antibiotics in cystic fibrosis

ABSTRACT

Introduction

Dosing of antibiotics in people with cystic fibrosis (CF) is challenging, due to altered pharmacokinetics, difficulty of lung tissue penetration, and increasing presence of antimicrobial resistance.

Areas covered

The purpose of this work is to critically review original data as well as previous reviews and guidelines on pharmacokinetics of systemic and inhaled antibiotics in CF, with the aim to propose strategies for optimization of antibacterial therapy in both children and adults with CF.

Expert opinion

For systemic antibiotics, absorption is comparable in CF patients and non-CF controls. The volume of distribution (Vd) of most antibiotics is similar between people with CF with normal body composition and healthy individuals. However, there are a few exceptions, like cefotiam and tobramycin. Many antibiotic class-dependent changes in drug metabolism and excretion are reported, with an increased total body clearance for ß-lactam antibiotics, aminoglycosides, fluoroquinolones, and trimethoprim. We, therefore, recommend following class-specific guidelines for CF, mostly resulting in higher dosages per kg bodyweight in CF compared to non-CF controls. Higher local antibiotic concentrations in the airways can be obtained by inhalation therapy, with which eradication of bacteria may be achieved while minimizing systemic exposure and risk of toxicity.

KEYWORDS:

• Antibiotics
• cystic fibrosis
• drug disposition
• pharmacodynamics
• pharmacokinetics

Article highlights

• Dosing of antibiotics in people with cystic fibrosis is challenging, due to altered pharmacokinetics (PK), difficulty of lung tissue penetration, and increasing presence of antimicrobial resistance.

• PK of antibiotics plays a pivotal role in maximizing clinical effect, while minimizing toxicity. Due to the altered PK in the CF population, optimizing antibiotic treatment using therapeutic drug monitoring (TDM) is of clinical relevance. So, knowledge about the pharmacodynamic part of the TDM, including the Minimum Inhibitory Concentrations (MIC) and the physicochemical properties of the antibiotics is important.

• In the past, for nearly all antibiotics an increased volume of distribution (V_d) was found in cystic fibrosis patients. Newer studies show that after accounting for body size and composition, V_d is rather similar between people with cystic fibrosis and healthy individuals for most antibiotics. However, there are a few exceptions, like an increased V_d for cefotiam and a higher V_d/kg for tobramycin in pediatric CF patients.

• For penicillins and most cephalosporins, a decreased plasma protein binding was described in cystic fibrosis patients, resulting in increased clearance rates. This requires higher dosing of these antibiotics or a switch to continuous infusion to optimize pharmacodynamics. Increased clearance rates were also found for aminoglycosides and trimethoprim, requiring higher dosing in patients with cystic fibrosis.

• A combination of antibiotics of different classes can be given at the same time to prevent the emergence of resistance and to achieve synergy, especially in the treatment of Pseudomonas aeruginosa.

• Higher local antibiotic concentrations in the airways can be obtained by inhalation therapy, with which eradication of bacteria may be achieved while minimizing systemic exposure and risk of toxicity.

• Optimizing pharmacokinetics by drug delivery to the lungs is complex and depends on several factors: the delivery device in combination with the physico-chemical properties of the drug itself, particle-related factors, and patients related factors.

• Studies have shown that central airway deposition of inhaled antibiotics is higher with increased bronchial obstruction and mucus plugging, and that peripheral, diseased parts of the lungs receive less inhaled antibiotics than healthy areas. Therefore, it might be necessary to treat patients with more advanced disease with higher doses to achieve sufficient drug concentrations in the entire lung, in particular in diseased parts of the lung.

This box summarizes key points contained in the article.

Declaration of interest

P Hagedoorn and H Frijlink have patents WO2004/110538 and WO2015/187025 with royalties paid to the University of Groningen. GH Koppelman reports grants from the Lung Foundation of the Netherlands, TEVA the Netherlands, VERTEX, GlaxoSmithKline, Ubbo Emmius Foundation, TETRI foundation, outside of the submitted work. He has participated in advisory boards for GlaxoSmithKline and for PURE-IMS, outside of the submitted work. DJ Touw reports grants from ZONmw, Astellas, Chiesi, Tekke Huizinga Foundation and SKML, all outside the submitted work. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.