The Importance of Quality in Probiotic Products

The tragic death of an infant from GI mucormycosis was linked to a fungus from a contaminated probiotic product (see here). This catastrophe reminds us that care must be taken when using probiotics (or any supplements) for vulnerable populations.

Some probiotic studies have targeted vulnerable subjects. Examples include children with AIDS (Trois et al. 2008), adults with severe, acute pancreatitis (Besselink, et al. 2008), cervical cancer patients undergoing radiation therapy (Chitapanarux et al. 2010), very low birth weight infants (Alfaleh et al 2011) and infants with necrotizing enterocolitis (Zampieri et al. 2013). Most such studies have not resulted in serious adverse effects, although in the case of the Besselink et al. (2008) study, increased mortality was observed in the probiotic treatment group. In this case, death did not result from infection caused by the probiotic, but due to ischemic bowel thought to be caused by nasal:jejunal administration of the mass of dairy carrier fermented in situ by the probiotic.

Use of a contaminated product that led to this infant’s death should not be interpreted as a caution against probiotic use per se. It is a caution against researchers or clinicians using products of poor quality. The probiotic strains did not cause the fatal infection; although still under investigation, it appears that the opportunistic pathogen contaminating the product did. Proper adherence to strict quality control guidelines should prevent such an occurrence.

When in 1982, 7 people died as a result of cyanide-laced Tylenol, the conclusion wasn’t that Tylenol wasn’t safe. The response was focused on how to improve product packaging to make tampering more apparent.

Similarly, this case does not reveal anything about the safety of probiotics for premature infants. But it does emphasize the importance of use of high quality products in this population.

December 9, 2014 the FDA issued a letter to healthcare providers warning about use of probiotic dietary supplements in vulnerable populations. It is a reminder that dietary supplements are not regulated as drugs, including that dietary supplements are not subject to “the agency’s rigorous manufacturing and testing standards for drugs, including testing for extraneous organisms.”  The letter does not point out the legal requirement for dietary supplements to be manufactured under dietary supplement Good Manufacturing Practices, which includes the requirement that manufacturers take any precaution necessary to protect against contamination with microorganisms. However, zero tolerance is not the standard for yeast/mold in even properly manufactured dietary supplements.  It will be important to discern for this case if regulations were in place to prevent this tragic event and what failed was compliance to and enforcement of those regulations; or if regulations were followed and a low level of contamination with a pathogenic mold slipped through detection.

Many researchers and clinicians see the numerous studies and meta-analyses showing that probiotics can prevent morbidity and mortality associated with necrotizing enterocolitis in premature infants and call for more placebo-controlled efficacy studies to confirm what the best probiotic product and dose should be. This case of death of a probiotic-treated infant may convince these experts that safety, not efficacy, studies should be the focus, or perhaps that probiotics should not be used at all. But other experts (Shane et al. 2013) consider that with the current level of evidence, probiotic efficacy studies should proceed, with high quality, defined probiotics and using a comparative effectiveness design, not a placebo-controlled design. In fact, some clinical researchers have moved ahead with clinical implementation of probiotic administration to premature infants as a standard of care, but have done so only under strict control and guidelines (Deshpande et al. 2011). A Montreal hospital has been using probiotics in their neonatal intensive care unit since July 2011, with no evidence of safety concerns (Janvier et al. 2014).

Key points from this unfortunate incident are:

  • Poor quality probiotic foods or supplements should not be on the market nor used in research. Probiotic identity and purity should be determined using best available methods and with rigorous standards appropriate to product usage.
  • Probiotic dietary supplements and foods must be manufactured according to Good Manufacturing Practices, and failure to do so can have serious outcomes.
  • This fatal case of GI mucormycosis does not reflect on the safety of properly manufactured supplements that meet quality standards.
  • The regulatory category for probiotic dietary supplements and foods dictates that these products are intended for use in the general population. Even a properly manufactured, high quality supplement might be a risk for certain vulnerable populations. Such “off label use” should be considered carefully by healthcare professionals and consumers.