Criteria abstracted from The Users' Guide to Medical Literature, from the Health Information Research Unit and Clinical Epidemiology and Biostatistics, McMaster University

Highlighted lines and questions below provide links to the pertinent description of criteria in The EBM User's Guide, now available at the Canadian Centres for Health Evidence

Article Reviewed:

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Comparison of 8 vs 15 Days of Antibiotic Therapy for Ventilator-Associated Pneumonia in Adults: A Randomized Trial.

Chastre J, Wolff M, Fagon J-Y, et al.

JAMA 2003;290 2588-2598 [abstract]

Reviewed by Jose Cortes MD, Baylor College of Medicine and Texas Children's Hospital, Houston TX

Review posted October 28, 2004

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I. What is being studied?:

The study objective:

To determine equivalency between 8 and 15 days of antibiotic coverage to treat microbiologically proven ventilator associated Pneumonia (VAP).

The study design:

Prospective, randomized, double blind clinical trial.

The patients included:

Patients (n=402) from 51 French ICU's that were intubated, mechanical ventilated for at least 48 hr and met the Inclusion criteria:

• Older than 18 years
• Clinical suspicion of VAP (new and persistent Infiltrate on CXR associated with at least of the following. 1) purulent tracheal secretions, 2) Temperature ≥ 38.3C, 3) leukocyte count > 10,000)
• Positive quantitative culture of distal pulmonary secretions obtained by fiberoptic bronchoscopy
• Use of empiric antibiotic that had adequate coverage against the microorganism found during bronchoscopy.
  The patients excluded:

  • Pregnant patients
  • Enrolled In another trial
  • Patient with a small chance of survival (Simplified Acute Physiologic Score > 65 points)
  • Neutropenia
  • Stage 3 acquired immunodeficiency syndrome
  • Use of immunosupresants
  • Had a concomitant extrapulmonary Infection diagnosed between day 1 and 3 that required longer than 8-day antibiotic coverage
  • Attending physician decision about restricted life support
  • Patients with early onset pneumonia and no antibiotic use during 15days preceding the infection.

  The interventions compared:

  An 8 vs. 15 day course of antibiotics.

  The outcomes evaluated:

  The main outcomes evaluated in the two groups were: 1) Death, 2) Microbiologic documented infection recurrence and 3) Antibiotic free days. These outcomes were assessed 28 days after VAP onset and analyzed on an intent-to-treat basis.

  They also evaluated secondary outcomes: 1) Number of mechanical ventilation free days, 2) Number of organ failure free days, 3) Length of ICU stay, 4) Rate of unfavorable outcomes, 5) Mortality at day 60, 6) Percentage of emerging multiresistant bacteria during the ICU stay.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes, patients were randomly assigned to receive antibiotics for 8 or 15 days.

Randomization occurred three days after diagnostic bronchoscopy and after patients were started on a broad-spectrum empiric antibiotic and inclusion/exclusion criteria was verified. Patients were randomized only if the pathogen isolated at a predetermined concentration was appropriately covered by the initial empiric regimen. The randomization was performed centrally using an Interactive answering service. This was stratified by center in blocks of 4 according to a computer generated random number.

2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?

Was followup complete?

Yes, 402 patients were randomized in the study. One hundred ninety-seven were assigned to the 8-day antibiotic regime and 205 were assigned to the 15-day antibiotic regime. No patients were lost to follow-up. One patient was not accounted in the analysis of the 15-day antibiotic regimen due to withdrawal of consent.

Were patients analyzed in the groups to which they were randomized?

Yes, statistical analysis was based on intention-to-treat was used.

Secondary questions:

3. Were patients, health workers, and study personnel "blind" to treatment?

Yes, the investigators were blind from the time of randomization until day 8. All patients, medical and nursing staff and pharmacists remained also blinded during the first 8 days.

4. Were the groups similar at the start of the trial?

Yes. Both groups were compared based on clinical characteristics at enrollment and both groups were similar with the exception of the percentage of females in the 15-day antibiotic regimen group, 32% vs 23% (p=0.046). On a broader basis, I don't think this gender difference made a difference in the outcome of the study.

5. Aside from the experimental intervention, were the groups treated equally?

There is no information provided on other aspects of patients' care.

III. What were the results?

1. How large was the treatment effect?

The primary outcomes analyzed in the study were:

• Death
• Microbiological documented pulmonary infection recurrence
• Antibiotic free days

Please note that this analysis uses a more liberal one-sided confidence interval of 90% because this is a non-inferiority trial (to prove that 8 days of therapy is not worse than 15 days).

Death	8-day regimen (n=197)	15-day regimen (n=204)	RRR/RRI (95%CI)
Death from all causes	37/197 (18.8%)	35/204 (17.2%)	RRI 0.095 (-0.280 to 0.664)
Non-fermenting GNB	15/64 (23.4)	19/63 (30.2)	RRR 0.223 (-0.389 to 0.565)
MRSA	6/21 (28.6)	5/21 (23.8)	RRI 0.200 (-0.568 to 2.332)
Other	16/112 (14.3)	11/120 (9.2)	RRI 0.558 (-0.244 to 2.212)

Treating ventilator-associated pneumonia in adults for 8 days versus 15 days does not increase or reduce the risk of death among the patients.

Pulmonary infection recurrence	8-day regimen (n=197)	15-day regimen (n=204)	RRR/RRI (95%CI)
All patients	57/197 (28.9%)	53/204 (26%)	RRI 0.114 (-0.190 to 0.532)
Non-fermenting GNB	26/64 (40.6)	16/63 (25.4)	RRI 0.600 (-0.046 to 1.681)
MRSA	7/21 (33.3)	9/21 (42.9)	RRR 0.222 (-0.698 to 0.644)
Other Bacteria	24/112 (21.4)	28/120 (23.3)	RRR 0.082 (-0.485 to 0.432)

Treating ventilator-associated pneumonia in adults for 8 days versus 15 days does not increase or reduce the risk of pulmonary infection recurrence among the patients. The only exception may be the patients infected with non-fermenting GNB in which treating for 8 days has a relative risk increase of 0.6 compare to the 15-day regimen.

The analysis of the third primary outcome is evaluating the difference between two means.

No. of antibiotic-free days	8-day regimen Mean (SD)	15-day regimen Mean (SD)	Mean Difference (95%CI)
All patients	13.1 (7.4)	8.7 (5.2)	4.4 (3.1 to 5.6)
Non-fermenting GNB	12.0 (7.4)	7.5 (5.4)	4.5 (2.2 to 6.7)
MRSA	12.9 (7.0)	4.9 (5.7)	8.0 (4.6 to 12.1)
Other bacteria	13.7 (7.5)	10.0 (4.6)	3.7 (2.1 to 5.3)

None of the secondary outcomes measures differed significantly between patients in the two groups. They express but not show data supporting, that among patients who developed recurrent pulmonary infections, multiresistant pathogens emerged significantly less frequently in those who had received 8 days of antibiotics (42.1 vs 62.3% of recurrent infections; p=0.04).

2. How precise was the estimate of the treatment effect?

Not very precise. All confidence intervals are wide and are not significant. In my analysis using 95%CI, I found that the two primary outcomes (death and pulmonary infection recurrence) cross 1 in all the variables. The intervals using 95%CI are broader; they are more likely to cross unity than the 90% CI analysis performed by the researchers. The pulmonary infection recurrence outcome for non-fermenting GNB is significant higher in the group treated for 8 days - the relative risk increase is 60%. The 95% CI does cross 1 but just barely.

Since a primary goal of this study was to reduce unnecessary antibiotic use, it was important to actually demonstrate an increase in antibiotic-free days in the short course group. Overall the difference was a mean of 4.4 days; the 95% CI's tell us that the true mean difference could have been as short as 3.1 days. We are then left to ask whether this is a clinically important decrease in antibiotic-free days.

IV. Will the results help me in caring for my patients?

1. Can the results be applied to my patient care?

Even though, the study was conducted in adults and one of the criteria was to be older than 18 years, it may be applied to my patient population. In our hospital, we already use a short duration of treatment for VAP (10-day course), which is closer to the 8 days studied here.

2. Were all clinically important outcomes considered?

Yes.

3. Are the likely treatment benefits worth the potential harms and costs?

It is difficult to determine this question due to lack of information from infection control about the potential benefit that this short treatment had against the emergence of multi-resistant bacteria. There were no apparent harms and is easy to deduce that less antibiotics should result in even less resistance, not more. One could argue that a definite benefit in costs exists while shortening antibiotic treatment.

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