SAN DIEGO (EGMN) – Giving the probiotic Lactobacillus GG to critically ill patients on mechanical ventilation resulted in markedly reduced rates of ventilator-associated pneumonia and Clostridium difficile disease in a double-blind, placebo-controlled study.

“Probiotic therapy looks like it may provide us with a novel, inexpensive, and – most importantly – nonantibiotic opportunity for prevention of VAP [ventilator-associated pneumonia]. It may also provide us with an opportunity to prevent other nosocomial infections,” Dr. Lee E. Morrow said at the annual meeting of the American College of Chest Physicians.

He reported on 138 patients admitted to a tertiary-center intensive care unit (ICU) with an anticipated need for more than 72 hours of mechanical ventilation, placing them at high risk for VAP. Participants were stratified on the basis of APACHE II (Acute Physiology and Chronic Health Evaluation II) scores, and randomized to double-blind administration of 10⁹ CFU of the commercially available probiotic Lactobacillus GG (68 patients) or placebo (70 patients) every 12 hours. The first daily dose was delivered in a slurry to the oropharynx, the second in sterile water via nasogastric tube to the stomach.

The primary end point was the incidence of microbiologically confirmed VAP, which was 19% in the probiotic group and 40% in the control patients, a significant difference, according to Dr. Morrow of Creighton University, Omaha, Nebraska.

The rate of clinically diagnosed VAP using the American College of Chest Physicians (ACCP) criteria was 25% in the probiotic group, compared with 47% with placebo. The ACCP criteria consist of a new infiltrate on chest x-ray plus any two of the following three clinical criteria: fever, purulent sputum, or leukocytosis.

The incidence of C. difficile disease as diagnosed by cytotoxic assay was 6% in the probiotic group and 19% in controls. The duration of ICU-associated diarrhea also was significantly lower in the probiotic group: a mean of 3.1 days, compared with 6.2 days in controls.

Patients who received the probiotic received antibiotics for pneumonia for a mean of 5.6 days, significantly less than the 8.6 days in controls. They received antibiotics specifically for C. difficile infection for a mean of 0.5 days, compared with 2.1 days in controls.

Hospital charges averaged U.S.$66,000 more per patient in the placebo arm because of their longer ICU and overall hospital lengths of stay, along with their additional need for expensive antibiotics. Hospital cost data weren’t available.

Several secondary end points showed intriguingly consistent trends, albeit statistically nonsignificant, in favor of probiotic prophylaxis. For example, the probiotic group had a 12% hospital mortality rate, compared with 17% in controls. They also had a 38% incidence of bacteremia and a 21% urinary tract infection (UTI) rate, compared with rates of 73% and 33%, respectively, with placebo.

“I’d take the bacteremia and UTI data with a grain of salt, because those conditions were diagnosed based on clinical criteria, not rigorous microbiologic criteria. But those are some strong trends,” Dr. Morrow observed.

Probiotic prophylaxis had no side effects at all.

Serial cultures using oral swabs and gastric aspirates showed a clear trend toward preservation of a normal mixed upper respiratory flora in the probiotic group, with less appearance of potentially pathogenic species than in controls.

“When you compare the gastric aspirates, the difference isn’t as clear. But it certainly looks like there’s something going on up in the oropharynx,” Dr. Morrow noted.

The probiotic treatment concept adopts measures to modify the gut flora in order to replace harmful microbes with useful ones. The mechanisms of benefit aren’t fully understood, but immunomodulation appears to figure prominently. Ligands on the commensal organisms interact with toll-like receptors on gut-associated lymphatic tissue, which releases signals promoting immune system homeostasis, Dr. Morrow explained.

Session chair Dr. Muthiah P. Muthiah said that probiotic prophylaxis against VAP is an appealing strategy directed at a common and expensive problem in the ICU.

“VAP is costly not only to the economy, but also to human life. If the VAP happens to involve a multidrug-resistant gram-negative organism like some of the Pseudomonas or Acinetobacter, the attributable mortality can be as high as 60%-70%,” observed Dr. Muthiah of the University of Tennessee, Memphis.

“The average rate of VAP nationally is about 35 cases per 1,000 mechanical ventilation days. We’d like to see it at 1 or less per 1,000,” he added.

Dr. Morrow disclosed that the probiotic study was funded entirely by noncommercial entities, including the U.S. National Institutes of Health and the American College of Chest Physicians. He called this a proof-of-concept study, given that it was single center and restricted to a select patient population at very high risk for VAP.

The next logical step, he said, would be a large multicenter trial powered to show whether the favorable mortality trend observed in the Omaha trial is real.

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