Abstract and Introduction
Purpose of review Despite multiple protocols for the prevention of ventilator-associated pneumonia (VAP), respiratory infections have not been eliminated in the ICU. The profound disruption in both airway integrity and mucociliary clearance caused by the endotracheal tube makes it unlikely there will ever be a zero rate of respiratory infection in critically ill ventilated patients or a 100% cure rate when infection is present. In fact, options for treatment are diminishing as bacteria resistant to most, or in some hospitals all, systemic antibiotics increase in prevalence from our liberal use of systemic antibiotics. Inhaled therapy with proper delivery will result in the high concentrations of antibiotics needed in the treatment of increasingly resistant organisms.
Recent findings Data from many recent investigations have focused on inhaled antibiotics as: adjunctive therapy to systemic antibiotic for VAP, monotherapy for VAP, and as monotherapy for ventilator-associated tracheobronchitis. The clinical outcomes of these studies will be reviewed as well as their effect on multidrug-resistant organisms.
Summary The present review will focus on the rationale for inhaled therapy, the current studies examining the delivery and clinical efficacy of inhaled antibiotics, and the potential role for this mode of delivery actually decreasing antibiotic resistance in the respiratory tract.
Ventilator-associated pneumonia (VAP) remains the ICU infection associated with the highest morbidity and mortality.[1–3] The actual incidence of ventilator-associated tracheobronchitis (VAT) and VAP remains controversial, because of the poor sensitivity and specificity of the current diagnostic techniques and the overlap between proximal airway infection and deep lung infection.[4,5–7] There is, however, no doubt that ventilator-associated infections remain a significant problem despite a multitude of protocols designed to prevent them.[8–10] They are responsible for up to 50% of the antibiotics used in the ICU. Furthermore, in many ICUs, Acinetobacter baumanii, Pseudomonas aeruginosa, and carbapenemase Enterbacteriaciae spp. are increasing in prevalence, and in some hospitals, these pathogens are now resistant to all antibiotics including colistin.[11–17,18]
ICU physicians in many regions of the world with endemic multidrug resistant (MDR) or extensively drug-resistant (XDR) Gram-negatives are responding to the lack of effective systemic antibiotics by adding inhaled antibiotics empirically to their treatment regimens.[19–29] Empiric therapy remains the only choice as 45 years after the initial instillation of antibiotics into an endotracheal tube or a tracheostomy tube, we have no commercially available US Food and Drug Administration (FDA)-approved inhaled drugs in the market for ventilated patients (listed below).
Aerosolized antibiotics used in mechanically ventilated patients for respiratory infection (off-label use and US FDA-approved):
Amikacin proprietary preparation (phase 3 enrolling patients; Bayer Healthcare delivered with proprietary pulmonary drug delivery system)
Amikacin/fosfomycin proprietary preparation (phase 1 completed; delivered with Pari investigational eFlow inline nebulizer)
Colistin methanesulfonate [prodrug of colistin (polymyxin E)]
Tobramycin proprietary preparation (US FDA approved for spontaneous breathing cystic fibrosis patients known to be colonized with P. aeruginosa)
Because of costs, urgency of treatment, and lack of alternatives, many physicians are using the nebulizers their hospitals have on the shelf which vary considerably from country to country, and their function when placed in a ventilator circuit is not well defined. In fact, the majority of the published research on inhaled therapy in the ICU neither describes the method of aerosolization nor the known deposition site or the concentration achieved in the lung or secretions, which implies these investigations have not met the criteria for acceptable antimicrobial therapy. The dose is described, but is empiric. To outwit the current pathogens, we have to pay far more attention to the details. Dhand has written a detailed review of the types of devices and factors that influence delivery and efficacy. This review will focus on the current clinical trials.
Curr Opin Pulm Med. 2015;21(3):239-249. © 2015 Lippincott Williams & Wilkins