Polymyxins for the treatment of lower respiratory tract infections; lessons learned from the integration of clinical pharmacokinetic studies and clinical outcomes

Int J Antimicrob Agents. 2021 Mar 27:106328. doi: 10.1016/j.ijantimicag.2021.106328. Online ahead of print.

ABSTRACT

The global rise in nosocomial pneumonia caused by multidrug-resistant (MDR) Gram-negative pathogens and increasingly limited antibiotic treatment options are growing threats to modern medicine. As a result, older antibiotics like polymyxins are being used as drugs of last resort for MDR nosocomial pneumonia. Polymyxins are bactericidal against most aerobic Gram-negative bacilli, but the sub-therapeutic concentrations achieved at infection sites following high-dose intravenous administration make treatment challenging. Therefore, there is a need to consider alternate forms of polymyxin delivery to achieve the necessary concentrations at sites of infection. Several studies have evaluated the effectiveness of aerosolized polymyxins in patients with nosocomial pneumonia caused by MDR Gram-negative pathogens like Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae. Here we evaluate the pharmacokinetic data supporting the use of inhaled polymyxin in nosocomial pneumonia and provide insight into the limitations and challenges future studies should address. We have also reviewed the literature published between 2006 and 2020 on the use of aerosolized polymyxins for the treatment of nosocomial pneumonia including ventilator-associated pneumonia in patients without cystic fibrosis to evaluate their safety and efficacy as monotherapy or as adjuncts to intravenous antimicrobials. This review highlights the need for well-designed, multicenter studies with standardized methodologies to further evaluate the effectiveness of inhaled polymyxins and provide reliable PK/PD data to redefine appropriate dosing strategies.

PMID:33785362 | DOI:10.1016/j.ijantimicag.2021.106328