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Should Pediatric Infectious Diseases Physicians be Proponents of Probiotics?
Can J Infect Dis Med Microbiol
should pediatric infectious diseases physicians be proponents of probiotics?
Joan L Robinson
Pgastrointestinal (GI) tract in an attempt to prevent or treat a disrobiotics are live bacteria or fungi deliberately introduced into the ease state. Probiotics are believed to work using three mechanisms (1,2). The first is a direct antimicrobial effect. Probiotic strains are postulated to 'crowd out' pathogenic GI flora and to compete with them for elements, such as iron, to act as 'decoy binding sites', such that pathogens bind to them rather than to mucosal surfaces and to produce antibacterial products including bacteriocins (bacterial toxins that inhibit other bacteria), hydrogen peroxide and organic acids. The second mechanism is alteration of the GI mucosal barrier. Colonization of probiotic strains may prevent pathogens from damaging the mucosa and invading. The third mechanism is through effects on mucosal immunity, leading to nonspecific humoral immune responses, production of protective cytokines and induction of regulatory T cells, which have an anti-inflammatory effect. Despite decades of use, the efficacy of probiotics for many indications remains unclear. Reasons for this include: 1. There are >100 products worldwide marketed as probiotics. Clinical trials have used myriad products and formulations (based primarily on local availability) and a wide range of doses. Natural health products, including probiotics, are typically not required to meet the same quality standards as pharmaceuticals; therefore, it is possible that the products used in different trials were not uniform, even if they came from the same manufacturer. It is also possible that some formulations did not contain live organisms at the time of ingestion or that probiotic organisms may have been killed by antibiotics given simultaneously (although some believe that even 'dead' probiotics may have some efficacy). In summary, negative trials for any indication do not rule out efficacy of other probiotic regimens for that indication. 2. The United States Food and Drug Administration does not have a definition for 'probiotics' or recognize them as a unique product, and currently requires the same rigour of clinical trial for them as for any new pharmaceutical, including starting with phase I trials. This has led to a marked paucity of probiotic clinical trials in the United States. 3. Clinical trials of probiotics as prophylaxis requires a large sample size because such trials target adverse events that occur for a minority of patients and probiotics are never anticipated to have 100% efficacy. There is overwhelming evidence that probiotics prevent necrotizing enterocolitis and decrease mortality in preterm infants with a birth weight >1000 g (3). Due to safety concerns, there are few clinical trials involving smaller infants, Two recent trials involving 1200 infants with a birth weight of <1000 g showed a trend toward a decrease in the incidence of necrotizing enterocolitis (risk ratio 0.76 [95% CI 0.37 to 1.58]) (3). I calculate a number needed to treat to prevent one case (NNTT) of 47 (95% CI 24 to 693) from these two trials. It is conceivable that probiotics are more effective in newborns than in other populations because their lack of diverse GI flora makes it more likely that a probiotic strain will find a hospitable niche. The following are the main indications related to pediatric infectious diseases for which probiotics are considered.
Primary or secondary prevention of Clostridium difficile-associated diarrhea
Three recent systematic reviews of primarily adult trials concluded
that there is moderate quality evidence that probiotics are effective for
primary prevention of C difficile-associated diarrhea (CDAD) (
4
).
Efficacy was 60% in three pediatric trials (n=605) versus 64% in
19 adult trials (n=3551) in the 2013 Cochrane review (
5
), with the
incidence of CDAD decreasing from 5.5% to 2.0%. The NNTT in all
ages was 29 (95% CI 22 to 43). Separating out the three pediatric trials
(with a mix of inpatients and outpatients) (
6-8
), I calculate a NNTT
that is also 29 (95% CI 15 to 250).
In an adult hospital, when the practice of automatically prescribing
the probiotic Saccharomyces boulardii with broad-spectrum antibiotics
ended, the incidence of hospital-onset CDAD remained at
approximately one per 1000 patient days, suggesting a lack of utility for routine
prophylactic probiotics in a centre with a low incidence of CDAD (
9
).
My conclusion is that one should consider prophylactic probiotics
only in medically fragile children prescribed antibiotics commonly
associated with CDAD (quinolones, clindamycin, cephalosporins
and carbapenems) while admitted to a hospital with a high incidence
of CDAD.
Experts are less optimistic that probiotics can prevent recurrent
CDAD because GI flora is so disrupted in patients with recurrent
CDAD that probiotics may be ineffective (
4
). Two small tri (...truncated)