Abstract & Commentary
Ventilator-associated pneumonia (VAP) remains a difficult problem in critically ill patients, both in diagnosis and treatment. Recent improvements in diagnosis include using quantitative culture methods to help differentiate colonization from active infection. Once the diagnosis of VAP is confirmed, appropriate antibiotics are usually given for 14-21 days. This prolonged exposure to antibiotics may contribute to the development of bacterial resistance and may not improve resolution of the pulmonary infection. Some clinicians (myself included) believe that a shorter course of therapy is appropriate. In this multi-institutional, prospective study, an 8-day antibiotic treatment course was compared to a 15-day treatment in patients with VAP. Diagnosis of VAP was made using conventional criteria, but it was confirmed with quantitative cultures obtained by protected brush samples (at least 103 colony-forming units [cfu]/mL) or from bronchoalveolar lavage (at least 104 cfu/mL) in adult patients receiving mechanical ventilation for at least 48 hours. There was no difference in mortality (18.8% in 8-day group vs 17.2% in 15-day group), length of stay, or relapse rate, but those patients receiving 15 days of therapy had a much higher chance of having a multiresistant organism if they relapsed or developed a secondary infection (62% vs 42.1%).
This large study screened more than 1100 patients and enrolled 402 patients from 51 ICUs in France between May 1999 and June 2002. Entrance criteria excluded those with early onset VAP (which may be more sensitive to antibiotics), those expected to die from other causes, those who were immunosuppressed from disease or medication, those on long-term antibiotic treatment for extrapulmonary indications, and those who were made DNR by their attending physicians. VAP was diagnosed based on a new and persistent infiltrate on chest radiograph following at least 48 hours of mechanical ventilation and the presence of at least 1 of the following: purulent tracheal secretions, temperature of 38.3°C, and/or leukocyte count greater than 10,000. Empiric therapy had to be appropriate as confirmed by sensitivity testing several days later to be continued to randomization. One patient withdrew consent, and 401 patients completed the study: 197 were randomized to the 8-day treatment group and 204 to the 15-day group. All completed the trial.
The primary study outcomes were death from any cause, documented pulmonary infection recurrence, and number of antibiotic-free days from diagnosis of VAP until day 28. Secondary outcome measures were mechanical ventilation-free days, organ failure-free days, multiple measures of lung failure daily, emergence of resistant infections during the entire ICU stay, and mortality at 60 days.
The groups were well matched at admission to the ICU and entry into the study (8 vs 15 days): average age (60 vs 61), male predominance (77% vs 68%), SAPS II score (45 both), duration of MV prior to VAP (13.4 vs 13.8 days), and previous exposure to antibiotics (84% vs 83%). There were fewer surgery patients in the 8-day group (31.5% vs 37.3%), but this difference was not statistically significant. Organisms responsible for the VAP were similar in both groups.
Mortality at 28 days following VAP treatment was 18.8% in the 8-day group and 17.2% in the 15-day group; at 60 days mortality, 25.4% vs 27.9%, and at hospital discharge, 32% vs 30%. There was a higher recurrence in the 8-day group if the causative organism was Pseudomonas aeruginosa (40.6% vs 23.8%), but this had no effect on length of stay, ventilator-free days, or mortality. Antibiotic-free days were about 50% less (no surprise) in the 8-day group over the first 28 days of treatment. Of the patients who developed recurrent pulmonary or other infections, more of the causative organisms were resistant to multiple antibiotics in the 15-day group (62.3% vs 42.1%; P = .04) (Chastre J, et al. Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults. A randomized trial. JAMA. 2003;290:2588-2598).
Comment by Charles G. Durbin, Jr., MD
The major conclusion of this large, complicated, well-designed study is that a short course of appropriate antibiotics (8 days) is no worse than a longer one (15 days). Antibiotic usage was less, and the development of resistance was lower. The possible exception was if the infective agent was Pseudomonas aeruginosa, in which the shorter course was associated with a higher recurrence rate but no difference in important outcomes. The similarities between the groups in mortality, ICU length of stay, ventilator-free days, organ failure-free days, lung injury scores, oxygenation indices, and other measured variables suggest that a shorter treatment course for VAP is appropriate. In fact, treatment for less than 7 days may be even more desirable. Courses of antibiotic treatment of 48-72 hours for VAP should be studied now that this study confirms no additional benefit and a rise in risk of resistance from 15 days of treatment.
One of the strengths of this study is the use of bronchoscopic culture techniques and quantitative bacterial analysis to confirm the diagnosis of VAP. While no method appears to be perfect in this regard and controversy abounds, the quantitative methods hold the most sway among clinicians and investigators to confirm the presence of VAP. This fact and the contemporaneousness of the data make this study’s findings important to current care choices. Limiting the duration of antibiotic therapy to 1 week for VAP is something that can be implemented immediately, with little concern about patient harm. Reducing unnecessary antibiotic use is an important issue for all those practicing or receiving treatment in an ICU.
Dr. Durbin, Jr. is Professor of Anesthesiology Medical Director of Respiratory Care University of Virginia.