Abstract & Commentary: Aerosolized Antibiotics in the Management of Ventilator-Associated Pneumonia
Abstract & Commentary
Aerosolized Antibiotics in the Management of Ventilator-Associated Pneumonia
By David J. Pierson, MD, Editor, Professor Emeritus, Pulmonary and Critical Care Medicine, University of Washington, Seattle, is Editor for Critical Care Alert.
Synopsis: This retrospective review of patients with ventilator-associated pneumonia caused by Pseudomonas aeruginosa or Acinetobacter baumannii at the authors' institution found that survival, ventilator days, and lengths of stay were better among those who had received aerosolized tobramycin or colistin in addition to systemic antibiotic therapy. The numbers were small, however, and the potential use of adjunctive aerosolized antibiotic therapy comes with a number of important caveats.
Source: Arnold HM, et al. Use of adjunctive aerosolized antimicrobial therapy in the treatment of Pseudomonas aeruginosa and Acinetobacter baumannii ventilator-associated pneumonia. Respir Care 2012; Feb 17. [Epub ahead of print.]
Arnold and colleagues at Barnes-Jewish Hospital in St. Louis performed a 6-year retrospective cohort study of patients with bronchoalveolar lavage (BAL) documented ventilator-associated pneumonia (VAP), diagnosed by accepted clinical and quantitative culture criteria, that was caused by either Pseudomonas aeruginosa (PA) and Acinetobacter baumannii(AB). The purpose of the study was to compare outcomes among patients who had received adjunctive aerosolized antibiotics (AAA) to those in patients who were treated with only systemic antibiotics (NAAA). Included in the study were all adult patients without cystic fibrosis who were ventilated for at least 48 hours, had new or progressive infiltrates on chest X-ray, had at least two of three clinical indicators (fever/hypothermia, leukocytosis/leukopenia, and purulent secretions), had at least 104 colony-forming units/mL of one of the target organisms on BAL fluid culture, and received at least 72 hours of treatment with antibiotics to which the recovered organism was sensitive. In addition to microbiologic data and clinical outcomes, the authors recorded patient age, comorbidities, APACHE II score on the day of bronchoscopy, and modified Clinical Pulmonary Infection Score.
During the 2004-2009 period covered by the study, 150 patients initially met the authors' criteria for inclusion. After exclusion of 57 of these for a priori reasons such as withdrawal of life support, antibiotic treatment for less than 72 hours, and missing data, there were 19 patients who received AAA and 74 who did not (NAAA). All patients received systemic antibiotics to which their organisms were sensitive. Of the 19 patients treated with AAA, 10 received tobramycin, 300 mg twice daily for 11.0 ± 3.9 days, and 9 received colistin, 150 mg twice daily for 8.9 ± 6.7 days. AAA patients had higher initial APACHE II scores. NAAA subjects experienced a shorter time from VAP onset to appropriate intravenous antibiotic initiation (0.5 ± 0.9 vs 2.6 ± 5.4 days, P = 0.038), but the length of intravenous therapy was similar in the two groups (12.8 ± 8.5 vs 17.8 ± 13.3 days, P = 0.163). Other aspects of the patients' demographics and management were similar.
Thirty-day mortality was 0.0% in the AAA group vs 17.6% among NAAA patients (P = 0.063). When patients transitioned to palliative care were included in the mortality analysis, this suggested difference in hospital mortality disappeared (32.1% vs 33.3%; P = 0.907). However, Kaplan-Meier curves depicting the probability of 30-day survival from VAP onset demonstrated that patients receiving AAA had a statistically greater survival (P = 0.030 by the log rank test). Patients who received AAA spent fewer days on the ventilator (18.9 ± 15.9 vs 38.4 ± 32.4 days, P < 0.001), in the ICU (37.5 ± 42.5 vs 56.3 ± 31.3 days, P = 0.001), and in the hospital (39.0 ± 42.5 vs 58.3 ± 33.4 days, P = 0.001), and these differences persisted after excluding those who died. No outcome differences were found in AAA patients who received tobramycin vs colistin. The authors conclude that patients with VAP due to PA or AB may experience improved survival when AAA is added to the antibiotic regimen. However, they also refer to recent reports of increased microbial resistance to both tobramycin and colistin when administered by aerosol, and call for large randomized clinical trials to settle the issue of whether AAA is beneficial in VAP.
Commentary
Like all studies based on a retrospective chart review, this report tells us what clinicians did in managing a series of patients but not why they did it. That is, why some patients with VAP due to the organisms in question received AAA and others did not is unknown, although it is unlikely that the treatment assignment was random. And while the patients were similar according to the factors the authors examined, there may have been other important aspects of their underlying health status, the acute illness, or the ways in which they were managed that varied enough to cast doubt on whether the findings reflected effects of the treatment of interest. However, this article focuses attention on an important topic — the role of aerosolized antibiotics in intubated, critically ill patients.
Despite ongoing administrative and clinical efforts to decrease the incidence of VAP, it is exceedingly unlikely that this complication of critical illness can ever be completely eliminated because of its predispositions and pathogenesis. In most instances, VAP develops in patients who require at least several days of intubation and whose lower airways have been colonized by bacteria not normally found there. These organisms gain entry around or through the endotracheal or tracheostomy tube, and their proliferation in the lower airways precedes tissue invasion and clinical illness. It therefore stands to reason that antimicrobial agents delivered to the airways would be useful in preventing bacteria from proliferating there, and potentially also in treating tissue invasion and clinical illness when they occur. Antibiotics have been administered via aerosol for these purposes for 40 years, but whether they are clinically effective remains far from certain.
In a thoughtful discussion of the pros and cons of using AAA to prevent or treat VAP,1 MacIntyre and Rubin list a number of reasons why this should be beneficial:
- Airway colonization precedes clinical infection in the great majority of cases.
- Reducing airway bacterial load reduces the development of VAP.
- Aerosolized antibiotics deposit directly in the airways and kill bacteria there.
- Aerosolized and other topically-applied antibiotics have been shown to decrease airway infections in certain settings (as, for example, with selective decontamination of the digestive tract).
- Numerous case reports and small series suggest clinical effectiveness.
However, these authors also point out numerous potential adverse effects and other disadvantages of using aerosolized antibiotics for VAP:
- Antibiotics applied to the airway mucosa penetrate poorly to the deeper tissues.
- Airway bacteria are typically encased in biofilms, into which the agents may not penetrate.
- Resistance develops rapidly when antibiotics are applied topically.
- Bronchospasm, hypersensitivity pneumonitis, and systemic toxicity may occur.
- There are numerous technical aspects to delivering these drugs via artificial airways that may greatly reduce their effectiveness.
- No drugs or delivery systems are currently FDA-approved for this use.
The practical technical difficulties involved in aerosolizing drug preparations that are not intended to be applied in this manner deserve special mention. Using the wrong diluent or concentration, or mixing agents for nebulization, can result in ineffective particle sizes, drug precipitation, and other problems. The literature on optimal administration of aerosols during mechanical ventilation is extensive. Many types and brands of nebulizers are in current use, and their aerosol delivery characteristics vary dramatically. Large quantities of drug typically deposit in the artificial airway, greatly reducing the delivered dose. Drug delivery is decreased by rapid inspiratory flows and also by humidification of the inspired gas, both of which are typically needed in ventilating critically ill patients with VAP. Reducing the inspiratory flow rate improves aerosol delivery but increases the risk of expiratory air trapping and hyperinflation, while turning off the humidification system facilitates aerosol delivery but can lead to airway drying and the inspissation of secretions; the consequences of forgetting to readjust these variables after each treatment could be dire.
With the emergence of multiple drug resistance among the organisms that may cause VAP, and the relative dearth of new, effective antibiotics, the increasing interest in AAA is understandable. Recent reviews2,3 emphasize the sound rationale for using AAA in VAP, particularly when resistance limits the systemic agents that can be used, but conclude that insufficient evidence currently exists to support this approach for managing patients. The potential role for AAA remains uncertain, and the availability of data from well-designed, large clinical trials in this important area of critical care would be of great value. n
References
- MacIntyre NR, Rubin BK. Respiratory therapies in the critical care setting. Should aerosolized antibiotics be administered to prevent or treat ventilator-associated pneumonia in patients who do not have cystic fibrosis? Respir Care 2007;52:416-421; discussion 421-422.
- Chastre J, Luyt CE. Other therapeutic modalities and practices: Implications for clinical trials of hospital-acquired or ventilator-associated pneumonia. Clin Infect Dis 2010;51(Suppl 1):S54-S58.
- Palmer LB. Aerosolized antibiotics in the intensive care unit. Clin Chest Med 2011;32:559-574.
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