Pharmacokinetics and Pharmacodynamics of Aerosolized Antibacterial Agents in Chronically Infected Cystic Fibrosis Patients

Abstract

SUMMARY Bacteria adapt to growth in lungs of patients with cystic fibrosis (CF) by selection of heterogeneously resistant variants that are not detected by conventional susceptibility testing but are selected for rapidly during antibacterial treatment. Therefore, total bacterial counts and antibiotic susceptibilities are misleading indicators of infection and are not helpful as guides for therapy decisions or efficacy endpoints. High drug concentrations delivered by aerosol may maximize efficacy, as decreased drug susceptibilities of the pathogens are compensated for by high target site concentrations. However, reductions of the bacterial load in sputum and improvements in lung function were within the same ranges following aerosolized and conventional therapies. Furthermore, the use of conventional pharmacokinetic/pharmacodynamic (PK/PD) surrogates correlating pharmacokinetics in serum with clinical cure and presumed or proven eradication of the pathogen as a basis for PK/PD investigations in CF patients is irrelevant, as minimization of systemic exposure is one of the main objectives of aerosolized therapy; in addition, bacterial pathogens cannot be eradicated, and chronic infection cannot be cured. Consequently, conventional PK/PD surrogates are not applicable to CF patients. It is nonetheless obvious that systemic exposure of patients, with all its sequelae, is minimized and that the burden of oral treatment for CF patients suffering from chronic infections is reduced.

Optimization and Dose Estimation of Aerosol Delivery to Non-Human Primates

“…(1) The most common application is treatment of chronic pulmonary diseases such as asthma and cystic fibrosis. (2,3) In recent years aerosol inhalation has also been considered as an alternative route of vaccine delivery. (4)(5)(6) Vaccination is mostly performed in children, and this presents particular challenges for efficient pulmonary delivery and dose control.…”

Pharmacokinetic and pharmacodynamic implications in inhalable antimicrobial therapy

“…Numbers of confounding factors are responsible for high variability in respiratory tract drug levels of inhalation antimicrobials [44,54,55]. These confounding factors include solubility differences of antimicrobial agents, different formulations used (liquid aerosols versus dry powder inhalations (DPI)), aerosol related fluid/particle dynamics and patient related factors including age, disease status, lung pathophysiology and functions including mucociliary and pulmonary macrophage clearance of inhalation particles etc.…”

“…The binding of aminoglycosides , fluoroquinolones and polymixin-colistin to the DNA gets inhibited in the presence of pus and debris[82][83][84][85]. Furthermore, efficacy of the antimicrobial agent may also get influenced by the biofilm formation and anaerobic condition caused by poor ventilation in the lung[44].The bacterial population in lung infections such as CF and TB is highly heterogeneous and capturing the heterogeneity of bacterial population in the in vitro susceptibility testing may be difficult. Several different strain of bacteria with varying MIC values harbor infection and sputum sampling and susceptibility test using sputum samples may not be able to provide complete heterogeneous profile of bacteria and their respective abundance in the infection.Furthermore, the use of non-specific antimicrobial agents or sub-therapeutic doses may cause the…”

Inhaled Antibiotics for Gram-Negative Respiratory Infections

“…The use of inhaled antibiotics in CF patients is excluded from this work, as this topic was reviewed in depth recently (44). Formulation considerations, including particle characteristics and drug delivery systems, along with microbiological and in vitro concerns, PK/PD parameters, and a review of safety and clinical outcomes are discussed.…”