LAUSR

“The War on Drugs” in the 1970s had an unintended effect on the illegal cannabis industry, increasing domestic production such that cannabis has become among the most profitable cash crops in the United States [1]. Legal barriers to cannabis use are also steadily crumbling: 30 states have legalized medical marijuana and nine states permit recreational use [2]. Yet despite its economic impact and increasing mainstream use, the safety and merits of cannabis consumption have not been rigorously studied. Is cannabis an effective antiepileptic or does it cause seizures? How is it possible that cannabis is touted as an anti-emetic, yet cannabinoid hyperemesis syndrome is reported in the medical literature? The answers to these questions likely relate to dose, mode of delivery, and patient selection—the very same questions at the root of whether inhaled antibiotics are an effective therapy for ventilator-associated pneumonia (VAP). VAP, defined as pneumonia developing 48 h after intubation, is associated with increased intensive care unit (ICU) stay and duration of mechanical ventilation and may independently impact mortality [3, 4]. The burden of VAP on the healthcare system is not trivial, with survey data suggesting that VAP represents close to 10% of all hospital-acquired infections [5]. The problem of VAP is more complex in light of the growing scourge of multidrug resistant (MDR) organisms. Coupled with a paucity of new antibiotics, clinicians and researchers have turned their attention to improving the delivery of tried-and-true medications, including the use of extended intravenous effusions and aerosolized antibiotics. Inhaled antimicrobials have been used since the 1940s to treat various respiratory infections. Yet, only three aerosolized antibiotics (aztreonam, tobramycin, and colistin) have received either FDA or European Medicines approval and only for the treatment of infections in patients with cystic fibrosis [6]. The role of inhaled antibiotics for VAP has been studied in numerous independent small randomized trials enrolling—in sum—approximately 400 patients and described in various observational studies totaling nearly 700 patients. These studies encompass heterogeneous populations, infected with different MDR organisms, treated with various antibiotics administered as either a solo or adjunctive therapy, delivered via a variety of technologies (e.g., jet nebulizer, ultrasonic nebulizer, vibrating mesh nebulizer), and used different outcome endpoints [7, 8]. Thus, interpreting these results is a challenging task. Alternatively, it is remarkable that most randomized or observational studies of inhaled antibiotics for VAP have shown some potential benefit (either mortality, clinical recovery, or microbiologic clearance) and low risk for harms such as systemic antibiotic toxicity or development of new antimicrobial resistance. In fact, the high peak concentration and the low systemic exposure of inhaled antibiotics may lead to less selective pressure and lower development to bacterial resistance than intravenous antibiotics. In light of the challenges to interpret the current evidence on the efficacy of inhaled antibiotics, Xu et al. [9] performed both a standard and a network meta-analysis (NMA) involving randomized and observational studies to * Correspondence: [email protected] Division of Infectious Diseases, Department of Medicine, University of Nebraska Medical Center, 985400 Nebraska Medical Center, Omaha, NE 68135, USA Full list of author information is available at the end of the article