VAIL, COLO. – The strategy of a short course of probiotics prescribed to prevent development of Clostridium difficile–associated diarrhea in patients on antibiotic therapy for any of myriad indications is attracting serious attention in both pediatrics and adult medicine.
Interest in this low-cost and demonstrably low-risk preventive strategy has been driven by a recent favorable meta-analysis by the Cochrane Collaboration.
Dr. Samuel Dominguez
The Cochrane analysis included all 23 randomized controlled trials of probiotics for the prevention of C. difficile–associated diarrhea in adults or children taking antibiotics. The trials, three of which were conducted in children, included 4,213 subjects, none of whom were immunocompromised, severely ill, or had an underlying gastrointestinal disorder.
The incidence of C. difficile–associated diarrhea was 2.0% in patients randomized to probiotics, compared with 5.5% in controls, for a highly significant 64% reduction in risk. Moreover, the risk of adverse GI events such as abdominal cramping, nausea, fever, taste disturbance, or flatulence was reduced by 20% in the probiotics group (Cochrane Database Syst. Rev. 2013 May 31 [doi: 10.1002/14651858.CD006095.pub3]).
The benefit of prophylactic probiotics was similar in magnitude in children and adults.
"Moderate-quality evidence suggests that probiotics are both safe and effective for preventing C. difficile–associated diarrhea when used along with antibiotics in patients who are not immunocompromised or severely debilitated," the Cochrane investigators concluded.
Neither the current American College of Gastroenterology practice guidelines on C. difficile–associated diarrhea (Am. J. Gastroenterol. 2013;108:478-98) nor the Infectious Diseases Society of America guidelines (Infect. Control Hosp. Epidemiol. 2010;31:431-55) recommend using prophylactic probiotics. However, both guidelines were published before the Cochrane meta-analysis was released, Dr. Samuel R. Dominguez pointed out at a conference on pediatric infectious diseases sponsored by the Children’s Hospital Colorado.
"Interestingly, a larger effect size was seen in studies of probiotics that contained multiple species compared to a single species, although the data set wasn’t large enough for investigators to be able to look at different specific formulations," added Dr. Dominguez, a pediatric infectious diseases specialist at the University of Colorado, Denver.
He noted that the incidence, severity, and mortality of C. difficile infections have increased dramatically since 2000. Even in children, a population traditionally considered at low risk, a recent population-based study conducted in Olmsted County, Minn., by investigators at the Mayo Clinic concluded that the age- and gender-adjusted incidence of C. difficile infection jumped nearly 13-fold from 1991 to 2009, when it reached 32.6 per 100,000 persons. Three-quarters of the 92 cases were community acquired. Prior studies of C. difficile disease in children may have underestimated the incidence because they were largely based on hospital-acquired cases (Clin. Infect. Dis. 2013;56:1401-6).
Another recent study highlights the serious nature of C. difficile in children, Dr. Dominguez continued. This retrospective cohort study conducted at 41 children’s hospitals included 4,474 patients hospitalized with C. difficile infection and 8,821 matched controls. The in-hospital mortality rate was 1.43% in children with C. difficile infection, compared with 0.66% in controls. In the subgroup of children with hospital-onset C. difficile infection, the mortality risk was an adjusted 6.7-fold higher than in matched controls.
Patients with community-onset C. difficile infection had a mean hospital length of stay that was 5.6 days longer and total hospital costs that were $18,900 greater than those of controls. In patients with hospital-onset C. difficile infection, the differences were even more dramatic: a mean 21.6-day longer length of stay than for controls, and a $93,600 greater hospital cost (Clin. Infect. Dis. 2013;57:1-8).
Dr. Dominguez said that although there is no set policy at Children’s Hospital, his own practice is to recommend probiotics to healthy children who are going to be taking antibiotics.
At a separate conference devoted to adult medicine, Dr. Mel L. Anderson cited both the Cochrane Collaboration meta-analysis and a separate one led by investigators at Toronto’s Hospital for Sick Children that concluded probiotics reduced the incidence of C. difficile–associated diarrhea by 66% (Ann. Intern. Med. 2012;157:878-88).
"If you look at these randomized controlled trials, I think the evidence is fairly convincing. And it’s not an expensive treatment. We use a lot of it in our inpatient service to reduce the risk of antibiotic-associated diarrhea, and C. difficile in particular," said Dr. Anderson, chief of the hospital medicine section at the Denver VA Medical Center.
Prophylactic probiotics are not for the surgical patient who is merely getting a dose or two of perioperative antibiotic coverage. But the preventive therapy is worth at least considering in pretty much everybody else getting a prescription for antibiotics. The randomized trials included in the two meta-analyses basically included patients receiving 3 days or more of antibiotics. Classes of antibiotics identified in previous work as posing an increased risk of C. difficile–associated diarrhea included the beta-lactams, cephalosporins, fluoroquinolones, and clindamycin – "pretty much everything you prescribe" – Dr. Anderson observed in Estes Park, Colo., at a conference on internal medicine sponsored by the University of Colorado.