Controversies and Evolving Concepts in Hospital-Acquired Pneumonia

Jean Chastre, MD

Charles-Edouard Luyt, MD, PhD

Despite some advances in antimicrobial therapy, successful treatment of patients with hospital-acquired pneumonia (HAP) remains a difficult and complex undertaking. Persistently high mortalities for pneumonia in the intensive care unit (ICU) argue, however, for a continued reassessment of our current modalities of therapy and definition of better protocols. More active as well as less toxic antibacterial agents are still needed, especially for problematic pathogens that are now emerging in many countries worldwide, such as multidrug-resistant (MDR) nonfermenting gram-negative bacilli and extended spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae (including carbapenemase-producing gram-negative bacilli), as well as a better use of already available antimicrobial agents. This issue of Seminars in Respiratory and Critical Care Medicine includes contributions from world-renowned experts in the field of HAP who have provided state-of-the-art information on important aspects of the clinical management of this dreadful disease.

In the first article, Nair and Niederman provide a detailed review of the many limitations and pitfalls inherent to any streamlined definition of the ventilator-associated event (VAE) for the surveillance of complications in mechanically ventilated patients, including ventilator-associated pneumonia (VAP). Outcome measures, such as VAE surveillance, can effectively circumvent the diagnostic limitations of VAP, but do not measure only infection, and do little to improve the quality of care since the validity and preventability of these events are still uncertain.

The next three articles deal with important topics that have plagued clinicians in the ICU for many years: Should we immediately start antibiotics in every patient with a clinical suspicion of HAP/VAP? What is the role of emerging diagnostic technologies? Should we treat ventilator-associated tracheobronchitis (VAT) with antibiotics? Although clearly deteriorating patients should undisputedly receive immediate new antimicrobial therapy covering the potentially responsible pathogens, Hassinger and Sawyer rightly point out that, in many cases, therapy could be directed at a confirmed infection following a positive culture result, avoiding medication-associated morbidity, including emerging-resistant microorganisms and Clostridium difficile infection. As indicated by Kollef and Burnham, new biomolecular techniques give us the possibility of rapidly detecting the causative pathogen and thus offer the potential for providing timely administration of appropriate antimicrobial therapy, as well as minimizing the use of broad-spectrum antibiotics when they are not justified. Antibiotic treatment for VAT, an intermediate infectious process limited to the upper airways that could precede VAP is still a matter for debate. When precisely defined by using quantitative culture results of endotracheal aspirates to quantify the bacterial load present in the airways, as proposed by Martin-Loeches, Coakley and Nseir, VAT is frequently associated with prolonged mechanical ventilation and subsequent VAP, probably justifying antimicrobial therapy in that circumstance.

Seven articles in this issue provide up-to-date and very useful information regarding how to improve the treatment of pneumonia caused by very difficult-to-treat bacteria in the ICU setting. With increasing rates of antimicrobial resistance and the marked physiological changes that can occur in ICU patients, which in turn affect antibiotic concentrations and therefore dosing requirements, the attainment of an optimal antibiotic therapeutic drug exposure becomes much more difficult. As indicated by Sulaiman et al, antibiotic therapeutic drug monitoring combined with knowledge of the isolate's minimum inhibitory concentration (MIC) would be required to ensure optimal therapy is provided. In the second article of this series, Timsit et al review the epidemiology and treatment of HAP caused by ESBL-producing Enterobacteriaceae, which have spread worldwide and are now involved in approximately 22 to 35% of VAP cases, as reported in large multicenter databases. Unfortunately, our armamentarium against these bacteria, although improving, is still limited, driving the extensive use of carbapenems. Infections caused by carbapenem-resistant Enterobacteriaceae (CRE) are an emergent problem due to the lack of therapeutic options available, leading to significant increases in morbidity and mortality. Bassetti et al, in a very thoughtful and up-to-date article, are proposing a possible strategy for the empiric and targeted treatment of HAP and VAP in which the involvement of CRE is suspected or confirmed, focusing on the role of both old and new available antimicrobial agents. The following two articles by Lynch et al are devoted to the management of MDR nonfermenters, including Pseudomonas aeruginosa and Acinetobacter baumannii. Over the past decades, antimicrobial resistance among these microorganisms has escalated globally, via dissemination of several international MDR “epidemic” clones. Many physicians advocate the use of combination therapy with agents that act by different mechanisms, but randomized therapeutic trials are sparse, and disparate results have been noted in both retrospective and prospective observational studies, as extensively reviewed in these two outstanding articles. Whether strategies targeting virulence factors expressed by Staphylococcus aureus or P. aeruginosa might be a valuable addition to conventional antimicrobial therapy is still an open question. However, as indicated by François et al, such a strategy could eliminate or reduce the risk of developing pneumonia before or during mechanical ventilation and improve patient outcomes through mechanisms that differ from those of antibiotics, with the major advantage of exerting less selective pressure for the development of antibiotic resistance. In the following article, Palmer and Rello summarize current evidence describing the use of inhaled antibiotics for the treatment of bacterial ventilator-associated infections. Although preliminary data obtained in observational studies and small randomized controlled trials suggest that aerosolized delivery of antimicrobials may effectively treat resistant pathogens with high MICs when delivered with appropriate devices, recent guidelines remain cautious about their use.

The two last articles of this issue present a very detailed and comprehensive discussion of two potentially useful, but controversial, prophylactic measures for HAP/VAP, namely, oropharyngeal decontamination with chlorhexidine and maintaining patients in a semirecumbent position for avoiding aspiration of gastric bacteria into the airways. For many years, practice guidelines have recommended routine oral care with chlorhexidine in all patients on mechanical ventilation. However, as discussed by Klompas in a very well argued article, such a preventive measure remains questionable, especially because it was never demonstrated that the use of chlorhexidine was associated with a significant reduction in the duration of mechanical ventilation or any other clinically relevant endpoint, including ICU length of stay or antibiotic exposure. Instead, there was a possible signal that oral chlorhexidine may increase mortality rates, maybe because of its toxicity for the lung. Extensive efforts have also been devoted in reducing, through body positioning, the risks for oropharyngeal colonization and aspiration of pathogens, with all guidelines recommending keeping ventilated patients in the semirecumbent position especially in the case of enteral nutrition. However, new data are available challenging the underlying rationale of the semirecumbent position, as thoroughly discussed by Li Bassi et al. Interestingly, these authors are now proposing to abandon this positioning for the lateral-Trendelenburg position to promote better outward clearance of respiratory secretions and circumvent any gravity-driven aspiration of fluids from the artificial airways into the lungs. Although attractive, clinical application of these new concepts may be challenging, and additional data are obviously needed before such positioning could be implemented.

We sincerely thank each of the authors who have contributed to this issue of Seminars in Respiratory and Critical Care Medicine dedicated to controversies and evolving concepts in HAP/VAP. We believe that the current state-of-the-art reviews presented here by an internationally recognized group of experts in the field will serve as a valuable resource for clinicians providing care for patients with severe bacterial pneumonia in the ICU.