High-Dose Nebulized Colistin Methanesulfonate and the Role in Hospital-Acquired Pneumonia Caused by Gram-Negative Bacteria with Difficult-to-Treat Resistance: A Review

Abstract

Hospital-acquired pneumonia, including ventilator-associated pneumonia (VAP) due to difficult-to-treat-resistant (DTR) Gram-negative bacteria, contributes significantly to morbidity and mortality in ICUs. In the era of COVID-19, the incidences of secondary nosocomial pneumonia and the demand for invasive mechanical ventilation have increased dramatically with extremely high attributable mortality. Treatment options for DTR pathogens are limited. Therefore, an increased interest in high-dose nebulized colistin methanesulfonate (CMS), defined as a nebulized dose above 6 million IU (MIU), has come into sight. Herein, the authors present the available modern knowledge regarding high-dose nebulized CMS and current information on pharmacokinetics, clinical studies, and toxicity issues. A brief report on types of nebulizers is also analyzed. High-dose nebulized CMS was administrated as an adjunctive and substitutive strategy. High-dose nebulized CMS up to 15 MIU was attributed with a clinical outcome of 63%. High-dose nebulized CMS administration offers advantages in terms of efficacy against DTR Gram-negative bacteria, a favorable safety profile, and improved pharmacokinetics in the treatment of VAP. However, due to the heterogeneity of studies and small sample population, the apparent benefit in clinical outcomes must be proven in large-scale trials to lead to the optimal use of high-dose nebulized CMS.

Treatment Strategies of Colistin Resistance Acinetobacter baumannii Infections

“…With the exception of urinary tract infections, polymyxin-B is preferable to colistin where available due to better pharmacokinetic properties and lower risk of nephrotoxicity. Despite conflicting recommendations by guidelines [56,77], nebulized colistin may be a useful option when administered properly (correct nebulization technique and at high doses) [78][79][80], but larger well-designed studies are necessary to confirm potential benefits. Notably, nebulized colistin may achieve concentrations well above MICs [78], suggesting potential benefit even against colistin-resistant isolates.…”

Ten Issues to Update in Nosocomial or Hospital-Acquired Pneumonia: An Expert Review

“…The dose of nebulized antibiotics should be titrated according to the level of drug resistance of causative pathogens, but always at much higher doses than those recommended for IV administration [89]. The expected benefits from nebulized antibiotics are a shorter time to clinical cure, a decrease in antibiotic-induced renal toxicity, a shorter duration of IV antibiotic administration, and a reduction in mechanical ventilation duration in patients with VAP [90][91][92].…”

Co-Administration of High-Dose Nebulized Colistin for Acinetobacter baumannii Bacteremic Ventilator-Associated Pneumonia: Impact on Outcomes

“…Nebulized colistin, in particular, has been the subject of investigation in VAP from MDR pathogens in a few studies, with conflicting results on its effect on patient outcome. This inconsistency in results has been attributed to the differences in study population, dose of nebulized colistin, co-administration of IV colistin or other intravenous antibiotics and the use of different types of nebulizers [26,27]. In the most recently published meta-analysis, nebulized colistin showed a higher eradication rate but failed to show a statistically significant mortality rate improvement [26].…”

“…Nevertheless, there was significant heterogeneity among studies, and there is a need for further trials. This necessity for new trials is highlighted first of all by the fact that currently much higher doses (12-15 million units of colistin per day) than those studied in these earlier studies are used, and the effect of these higher doses on patient outcome is understudied [27].…”