Ventilator-associated pneumonia: Lessons learned from clinical trials
Article Outline
This issue of the Journal of Critical Care consists of aspects of the rich database generated from the Canadian Critical Care Trials Group (CCCTG) study on diagnosis and treatment of ventilator-associated pneumonia (VAP) [1]. This well-characterized population allows subgroup analyses which inform various aspects of the management of VAP.
Americans cannot help but admire the ability of investigators in Canada [1], France [2], [3], and other European Union countries to undertake large multicenter trials of basic aspects of the clinical care of pneumonia. The CCCTG study conducted by Heyland et al [1] is one of the most ambitious. In one large study, these investigators attempted to answer 2 of the most controversial questions in VAP management [4]: the potential benefit of an invasive quantitative culture diagnostic strategy and the need for combination antibiotic therapy. Avoidance of inappropriate initial empirical antibiotic therapy was a major emphasis in study design [1].
The articles in this issue provide important insights into patients suspected of developing VAP. One important result from the CCCTG study is the equivalence between single and combined therapy for VAP, at least when using broad-spectrum therapy and when Pseudomonas or other potentially multidrug-resistant (MDR) microorganisms are not a consideration. The CCCTG study thus confirms other studies in related areas [5], whereas the issue remains debated when Pseudomonas is involved [6], [7].
Unfortunately, the study design (influenced by its sponsoring), attempting to concurrently study both issues, and the resulting drugs selected for initial therapy for all patients enrolled (meropenem or meropenem + ciprofloxacin) severely compromises the results of the diagnostic study. To minimize the risk of inappropriate initial empirical antibiotic therapy, patients at risk for MDR pathogens, specifically methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa, were excluded from the trial. More than half of patients with suspected VAP were thereby excluded. Those excluded represent patients in which diagnosis and treatment decisions are the most difficult, severely limiting the ability to generalize the primary results of the study. Surprisingly, despite these precautions, and although, by design, all patients initially received broad-spectrum therapy with meropenem (with or without ciprofloxacin), the 10% incidence of inappropriate initial therapy was actually higher than in the French multicenter trial [2], which included many more patients at risk for MDR pathogens.
A major issue with the interpretation of results of both the pivotal article [1] and the secondary articles included in this issue is the reference standard used to decide whether pneumonia was present or absent. The diagnostic approach taken by the authors was a truly “clinical” one, that is, essentially based on the clinical probability of pneumonia and evolution under therapy, whereas culture results were secondary criteria or even ignored. This clinical approach is recognized to lead to overtreating patients who might not actually need therapy for pneumonia [4]. This approach explains both the relatively high proportion of patients adjudicated (by the investigators) as having pneumonia despite negative or below-threshold culture results and the altogether high (85%) proportion of patients with pneumonia in the study, a surprising finding comparative to prior studies in this area [8].
The same issues color every one of the primary data articles in this issue of the journal. The risk factors for Pseudomonas VAP only reflect the risk in those patients who were not already colonized or infected with this pathogen when VAP was suspected [9]. The value of the Gram stain [10] and prior cultures [11] is also potentially affected by exclusion of patients who may have been colonized.
This problem even led to paradoxical conclusions. Sanders et al [11] conclude that prior cultures have poor agreement with subsequent cultures at the time of VAP diagnosis. However, the study was predicated on excluding patients with prior cultures, which included methicillin-resistant S aureus and P aeruginosa. Their data actually support this exclusion because all preceding cultures with these 2 microorganisms also had the same pathogens isolated subsequently when VAP developed. Inclusion of these patients would have increased the crude agreement rate, although the conclusion may still have been the same.
The other major weakness of the primary study is that, in contrast to the French multicenter trial [2], antibiotic management was not dictated by direct examination of specimens or early culture results, especially in the “invasive” arm. Specifically, although encouraged to, clinicians were not required to stop antibiotics in the 18% of patients with negative cultures or to narrow antibiotic therapy if resistant isolates were not cultured, and streamlining actually occurred late in the course of therapy. Lost in the debates about the optimal diagnostic strategy for VAP is the fact that the diagnostic technique itself does not affect outcome of patients. Any effect of a diagnostic strategy on outcome is dependent on its impact on physicians' decision making, in this instance, antibiotic management. The Table 1 lists various antibiotic management strategies based on diagnostic testing. When comparing 2 diagnostic strategies, if antibiotic management is not correspondingly altered, it is unlikely that outcome will be affected. The 4 studies in which subsequent antibiotic management was not driven by results of diagnostic testing all demonstrated no difference in outcome [1], [12], [13], [14]. The CCCTG study itself, however, confirms that discontinuing antibiotics in patients with negative cultures is not only safe [15], [16], [17] but also suggests that continuing Gram-negative coverage in patients with monomicrobial S aureus VAP may be associated with increased mortality [18].
Table 1. Antibiotic management strategies in randomized controlled trials of diagnostic testing in ventilator-associated pneumonia
| 1. Test; treat based only on cultures |
 Baker [27] |
| 2. Test; screen and start empirical; stop or modify based on cultures |
| Fagon and Chastre [2] |
| 3. Test; start empirical; stop or modify based on cultures |
| Singh et al [28] |
| 4. Test; start empirical; modify only based on cultures |
| Sanchez-Nieto et al [13] |
| Ruiz et al [12] |
| Sole-Violan [14] |
| CCCTG [1] |
| 5. Test; start empirical; escalate only based on cultures |
Given the above limitations, and the selected population enrolled in the CCCTG study, the guidelines proposed for diagnostic and antibiotic management of patients suspected of VAP should be taken with caution and adapted to specific patient populations.
Despite the expected high activity of the drug regimens used, antibiotic failure occurred in a distressingly high number of patients, even those without high risk of MDR pathogens treated aggressively [19]. The lack of improvement in oxygenation as a marker of clinical failure is again confirmed [20]. The association of Candida colonization and increased mortality is also confirmed [21], [22]. These both suggest that patients with suspected VAP are truly immunocompromised [23]; they are unable to protect themselves from either bacterial or fungal challenge and have adverse outcomes despite appropriate antimicrobial therapy. The possibility that antibiotics themselves contribute to this immunoparalysis is supported by the CCCTG study [9], [18], [19], [21]. Until the immunoparalysis issue is addressed, clinicians will need to walk the tightrope between appropriate antibiotic therapy and excessive antibiotic use.
Our therapeutic dilemmas can hopefully be reduced by preventive efforts. An important move forward in this regard is progress toward improving our understanding of the risk factors for VAP and effective methods for its prevention, thanks to a number of clinical trials performed in this area in the recent years. The CCCTG, building on a previous version [24], has now updated an evidence-based guideline for prevention of VAP [25]. Substantial changes or additions from this previous version include new recommendations regarding use of oral antiseptic agents, strengthening the recommendation regarding subglottic secretion drainage, no recommendation regarding the type of humidification (heat-moisture exchangers or heated humidifiers), and using semi-recumbent positioning with head elevated to 45° when feasible.
Recent studies show that providing education on management and prevention of VAP and feedback to personnel are associated with reduced infection rates. However, numerous challenges exist with implementing guidelines and having these adopted and adhered to on a long-term basis, as reviewed by Sinuff [26]. Although multifaceted interventions included in a guideline (“bundles”) are likely to be more effective than a single-focused one, the key for success lies in the ways the guideline is implemented, involving continued efforts from the intensive care unit leadership, education, reminders and feedback, and similarly to steps followed in a quality improvement program. Recent experience with this approach suggests that VAP rates can be reduced by about half.
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PII: S0883-9441(08)00026-9
doi:10.1016/j.jcrc.2007.12.020
© 2008 Elsevier Inc. All rights reserved.
