Treatment of Ventilator-Associated Pneumonia: Longer Is Not Better

Abstract & Commentary

Synopsis: Antibiotic administration for only 8 days to patients with ventilator-associated pneumonia was not inferior to 15 days of therapy.

Source: Chastre J, et al. Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults. JAMA. 2003;290:2588-2598.

Chastre and colleagues performed a randomized, double-blind trial in 51 French ICUs to compare the efficacy of treatment of ventilator-associated pneumonia (VAP) for a duration of either 8 or 15 days. Patients receiving mechanical ventilation for a minimum of 48 hours were eligible if they had clinical evidence of VAP, significantly positive quantitative cultures of distal pulmonary secretions (BAL or protected brush or catheter), and received appropriate empirical antimicrobial therapy within 24 hours following bronchoscopy. Patients whose pneumonia developed within the first 5 days of mechanical ventilation and who had received no antimicrobial therapy in the 15 days preceding infection were excluded, as were those who were significantly immunocompromised and/or had a SAPS score > 65. Patients were randomized after bronchoscopy to receive antibiotic therapy selected by the clinician for either 8 or 15 days; blinding was maintained until day 8. The sample size selected was designed to demonstrate noninferiority (upper limit of confidence interval < 10% of the difference in outcomes) of the 8-day regimen with regard to mortality and pneumonia recurrence and superiority with regard to total antibiotic use.

A total of 401 patients were enrolled; the 2 treatment groups were similar except that there were significantly more females in the 15-day treatment group. Approximately one-fifth of the pathogens isolated in significant numbers in each group were P aeruginosa, and 7% were MRSA.

Patients assigned 8 days of therapy had, as expected, more antibiotic-free days (13.1 vs 8.7; P < .001) than those randomized to receive antibiotics for 15 days, but there was no significant difference between the 2 treatment groups with regard to 28-day mortality (18.8% vs 17.2%) or recurrent infections (28.9% vs 26.0%). There was also no significant difference with regard to number of days free of mechanical ventilation or days free of organ failure, nor in length of ICU stay. Recurrence of pulmonary infection, however, occurred more frequently in the 8-day than the 15-day group (40.6% vs 25.4%; 90% CI for the difference, 3.9-26.6%) among those whose primary infection was caused by a nonfermenting Gram-negative bacillus.

Table

Suggested General Approach

  1. Make a clinical diagnosis of VAP. Calculate CPIS.
  2. Obtain blood cultures and quantitative cultures of respiratory secretions. Specimens obtained by blind endotracheal aspiration are acceptable.
  3. Start broad-spectrum antibiotic therapy, keeping in mind the local susceptibility patterns, the presence of local pathogens (eg, Legionella spp.), and any antibiotic the patient may have recently received. Do not start vancomycin or linezolid in the absence of Gram-positive organisms seen on Gram stain of respiratory secretions.
  4. At approximately 72 hours, clinically re-evaluate the patient, recalculate the PORT score, and evaluate the microbiological data.  a. If the CPIS score is £ 6 and this low likelihood of VAP is confirmed by good clinical judgment, and if the quantitative microbiologic data fail to meet the appropriate threshold (BAL: > 104 cfu/mL; protected brush: > 103 cfu/mL; ETA: > 105 cfu/mL), discontinue antibiotic therapy. b. If antibiotic therapy continues to be indicated, adjust therapy to reflect the culture and susceptibility results. When possible, de-escalate therapy to a narrower spectrum.
  5. On day 8, discontinue antibiotic therapy if the patient has improved. In the absense of improvement, re-evaluate therapy.

Comment by Stan Deresinski, MD, FACP

"Are minimization of selection of resistant organisms and maximization of individual outcome mutually exclusive?"1 This title of a recent publication establishes the dilemma faced by the clinician in his or her decisions regarding antibiotic therapy. Maintaining this delicate but crucial balance is of prime importance.

While VAP is an infection associated with great morbidity and high mortality, its diagnosis and treatment are fraught with uncertainties. Only approximately one-third of pulmonary infiltrates in surgical ICU patients are due to infection.2 Qualitative cultures of respiratory secretions may be misleading. The initial empiric choice of antibiotic is critical to a favorable outcome. Finally, once antibiotic therapy has been initiated, there has been limited guidance available to the clinician to provide a rational for its discontinuation. There are, in fact, very few infectious diseases for which we know the optimal duration of antibiotic therapy. This is not a trivial issue because unnecessary continuation of antibiotic administration beyond the point of maximal efficacy only contributes to an increased risk of drug-related adverse effects and to an increase in prevalence of antibiotic-resistant organisms. The latter is an especially recalcitrant problem in many ICUs. A recent international conference came to a consensus regarding the management of VAP: "No consensus was reached regarding choices of antimicrobial agents or the optimal duration of therapy."3

The most recent American Thoracic Society consensus statement, published in 1996, recommends that nosocomial pneumonia be treated with antibiotics for 14-21 days.4 This recommendation was not, however, evidence based. Nonetheless, this seems to be the usual answer given to the question concerning the duration of antibiotic therapy for this infection although, in practice, it is not uncommon for antibiotics to be continued for the duration of a patient’s stay in the ICU. It is difficult to argue against the observation that antibiotics are vastly overused in that setting.

Chastre et al acknowledge some of the shortcomings of their investigation, at least 2 of which may be of some importance. Almost two-thirds of the 1171 patients assessed where excluded. Thus, the patients studied represented a highly selected group of all patients. Secondly, the study was not blinded beyond 8 days, opening the door to potential investigator bias. Despite these issues, Chastre et al have made a significant contribution to attempts to rationalize the management of VAP.

Another caveat in the application of these results in the clinic is the finding of a greater rate of recurrence (mostly apparent relapses—no genetic analyses of isolates was performed) among the patients whose primary infection was due to nonfermenting aerobic Gram-negative bacilli, primarily P aeruginosa. This is not terribly surprising, given the difficulty in eradicating this organism. Nonetheless, this result was not reflected in overall outcomes, indicating that these recurrences are manageable.

This and other studies allows a listing of some of the principles that have emerged that allow for better management of VAP, including the following:

1. Early institution of appropriate antibiotic therapy (ie, antibiotics that prove to be active against the bacteria causing the pneumonia) is critical to a successful outcome.5

2. The Clinical Pulmonary Infection Score (CPIS) is reasonably useful in the diagnosis of VAP, especially when combined with microbiological data, in the diagnosis of VAP.6

3. The Gram stain is of value, particularly in excluding the presence of significant numbers of Gram-positive organisms.7

4. Quantitative cultures of respiratory secretions provide useful information in the diagnosis of VAP that may affect outcome.8 While some prefer specimens obtained by BAL, mini-BAL, or protective brush catheter, endotracheal aspirate cultures demonstrate excellent correlation with quantitative cultures obtained by these more technical and expensive methods.9,10

5. The absence of clinical or microbiological data confirmatory of the presence of VAP after 48-72 hours in a patient with a low probability of pneumonia at baseline is an indication to discontinue empiric antibiotic therapy instituted for treatment of presumed pneumonia.11

6. De-escalation of antibiotic therapy (ie, narrowing of the antibacterial spectrum in response to culture and susceptibility data) is indicated when possible.12 "Double coverage" may be warranted in some circumstances (eg, P aeruginosa infections).

7. In most cases, no more than 8 days of antibiotic therapy are required.

These principles can be used in the development of guidelines for the management of VAP. One example, the detailed guidelines in use at the University of Virginia, is available on the Internet.13

Dr. Deresinski, Clinical Professor of Medicine, Stanford; Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center.

References

1. Paterson DL, Rice LB. Are minimization of selection of resistant organisms and maximization of individual outcome mutually exclusive? Clin Infect Dis. 2003; 36:1006-1012.

2. Singh N, et al. Pulmonary infiltrates in the surgical ICU: Prospective assessment of predictors of etiology and mortality. Chest. 1998;114:1129-1136.

3. Rello J, et al. International conference for the development of consensus on the diagnosis and treatment of ventilator-associated pneumonia. Chest. 2001;120: 955-970.

4. Hospital-acquired pneumonia in adults: Diagnosis, assessment of severity, initial antimicrobial therapy, and preventive strategies. A consensus statement, American Thoracic Society. November 1995. Am J Respir Crit Care Med. 1996;153:1711-1725.

5. Iregui M, et al. Clinical importance of delays in the initiation of appropriate antibiotic treatment for ventilator-associated pneumonia. Chest. 2002;122:262-268.

6. Fartoukh M, et al. Diagnosing pneumonia during mechanical ventilation: The clinical pulmonary infection score revisited. Am J Respir Crit Care Med. 2003; 168:173-179.

7. Blot F, et al. Valure of Gram stain examination of lower respiratory tract secretions for early diagnosis of nosocomial pneumonia. Am J Resp Crit Care Med. 2000;162:1731-1737.

8. Fagon JY, et al. Invasive and noninvasive strategies for management of suspected ventilator-associated pneumonia. A randomized trial. Ann Intern Med. 2000;132:621-630.

9. Wood AY, et al. A prospective study assessment of diagnostic efficacy of blind protective bronchial brushings compared to bronchoscope-assisted lavage, bronchoscope-directed brushings, and blind endotracheal aspirates in ventilator-associated pneumonia. J Trauma. 2003;55:825-834.

10. Wu CL, et al. Quantitative culture of endotracheal aspirates in the diagnosis of ventilator-associated pneumonia in patients with treatment failure. Chest. 2002;122:662-668.

11. Singh N, et al. Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit. A proposed solution for indiscriminate antibiotic prescription. Am J Respir Crit Care Med. 2000;162:505-511.

12. Hoffken G, Niederman MS. Nosocomial pneumonial the importance of a de-escalating strategy for antibiotic treatment of pneumonia in the ICU. Chest. 2002; 122:2183-2196.

13. http://hsc.virginia.edu/pharmacy-services/Newsletters/P&T%20Forum/P&T06-02.html. Accessed January 6, 2003.