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News about Probiotics


kbarrington

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A few things have been happening recently: first of all, the big news was that Solgar recalled ABCDophilus as a result of some contamination of the product. As many of you will probably know, there was fungal contamination of the final product which was associated with a preterm infant developing intestinal mucormycosis, which was fatal.

Quality control and highly reliable products are essential for preterm infants. Complications, expected (at least in retrospect) and unexpected, have been frequent in the brief history of neonatology. I am on record as having suggested that ABCDophilus might be an appropriate preparation for use in the NICU, it certainly appears to be effective, it was the preparation used in the Australian Pro-Prems trial. Solgar, the company that supplies ABCDophilus, do not I think, produce the organisms themselves, they appear to be responsble for the final compounding, which is the stage that seems to have been contaminated. This case emphasizes how essential good quality control is. In order to ensure that the benefits of probiotics are maximized, we have to avoid such risks.

As most things in medicine and in neonatology, an intervention should be used based on the balance of risks and benefits, and how those risks and benefits are valued by the patient or their family. Avoidable risks such as this one should of course be avoided. It would be a great mistake to suggest that this is a valid reason to avoid introducing probiotics. Previous problems in manufacture of medical devices or medications have led to withdrawal, correction, and re-introduction. We need reliable and safe products for preterm infants, the one we use in Montreal certainly seems to fit those criteria.

In other news, the Pips trial has been presented, although not yet published. This large high quality multi-center trial from the UK randomized 1000 babies to placebo or to a single species probiotic (a Bifidobacterium Breve). The primary outcome variable was survival without NEC or late onset sepsis. NEC stage 2 or worse occurred in 10% of controls and 9.4 % of treated babies. In isolation such a small change could easily be due to random chance alone.

Why the benefits of probiotics in this trial should be less (or absent) is not immediately clear. Among the possibilities, this study avoided biases that exaggerated the benefits in other studies: this study suffered from biases that reduced the benefits: the organism chosen was less effective for this purpose (or less effective at colonizing the infants' intestines): random variation in efficacy across numerous studies.

The 95% CI of the relative risk from this individual trial are from 0.68 to 1.27. Which means that although this was a high quality trial, it cannot with confidence exclude a substantial benefit (or indeed harm) or probiotics.

Two other trials have also recently been published. Sanjay Patole and colleagues performed a small study with the primary objective of ensuring that their preparation and strain of B breve succesfully colonized their babies, without adverse effects. They had about 80 babies per group (with or without probiotics) and had only one case of NEC, in the placebo group.

In another trial, this time from Turkey, probiotics were administered to 2 of their 4 groups, either with or without inulin, a prebiotic molecule. The other two groups were either control, or received only inulin. The 400 babies were eligible if they were under 32 weeks, and less than 1500 grams, and fed before 7 days of age. The controls had an 18% incidence of NEC, which was a little lower in the prebiotic group (12%), and much lower in the probiotic group (2%) and combined group (4%). The probiotic organism they used was a Bifidobacterium Lactis.

I haven't seen any other RCTs, so if we add all these data, Pips and the other studies, to the meta-analysis we get a Forest plot which looks like this: (I must emphasize that this is not the same as an updated systematic review: much more methodologic rigour is required, but I think it gives an indication how the data currently stand).:

forest-plot.png?w=640

What I think this means is that we now sorely need comparative trials. We have to find out if the differences in efficacy are due to random variation, or is there a real difference in the efficacy of the organisms used.

I think it might well turn out that some probiotic organisms, perhaps because of differences in their utilisation of prebiotic molecules (I will come back to this) are less effective at preventing NEC. The only way we will know is if we perform very large comparative trials. NEC is such a devastating disease, with long-term consequences, that we have to find out.

Finally, the other news is that a case series of bifidobacterial bacteremias has been published. Two of the 3 cases were transient bacteremias requiring no therapy, the third was an infant who develoepd NEC despite prophylaxis and grew B longum which is the strain found in Infloran, which all 3 affected infants were being given.

In contrast to the avoidable contamination of ABCDophilus with a fungus, this complication is, I would think, an unavoidable cost of using probiotics. At some point, after treatment of many thousands of infants with probiotics, it was inevitable that this type of complication would arise. This is not to say that we should ignore this risk, but it must be weighed against the enormous proven benefits.

Remember that if you use unpasteurized breast milk in your infants, you are already giving them bifidobacteria, of varying species and strains. B breve, B longum and B bifidum have all been found in breast milk, and probably others also. We do not have the choice to leave an infants gut sterile, in any case it would not be a good idea! Giving a nudge in the right direction with a reliable probiotic preparation is about the best we can do at present.

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Thanks for the great update!

In our tertiary unit in Puerto Montt, Chile, we were using Biogaia ® but we stopped doing so after the Solgar report, plus Dr. Josef Neu's recommendation to wait for more studies in http://www.eneonatalreview.org/newsletters/2014/volume10_issue01.html

We still use it in selected cases, usually >1500 g babies, but we are still not sure which preparation is safer: Biogaia comes in liquid form, but there are others that are in powder form... Should these be reconstituted in sterile water? What is the appropriate dose? Refrigeration? 

 

We really wish we could start safely using probiotics again!

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Guest charris

Posted

From Canada - in our NICU we use FloraBaby which is the same product that Dr. Barrington uses.  A few weeks ago I talked with Thomas Bedford who is the president of the company that makes Florababy ® - Renewlife.

(email Thomas@renewlife.ca ; direct phone (cell) 1-416-817-5924; or company number 1-800-485-0960 ext. 3 -   and will call back )

 

He's had to field quite a few questions about the contaminated product in the US, and how his company compares in terms of possibility of cross-contamination. This is what I found out:

 

1) Evidently the source of the fungus that contaminated ABC Dophilus was that it was used as a growth medium for the digestive enzymes  (or used in the process of making digestive enzymes) that were also made in the same facility as their probiotic.

 

At the RenewLife company facility that makes probiotics such as Florababy® - there are only  bacteria there, no fungal products at all.  That facility is in Montreal.  They do have another site remote to that one that deals with other biologicals.  Therefore in his estimation there is no possibility that the Florababy® could be contaminated with fungal elements.

 

2) The bacteria produced for Florababy are grown on a medium including  sugar/dairy/soy medium as part of the fermentation process.  The bacteria are removed.  The quality assurance piece includes testing for presence of proteins of soy or dairy origin  (or absence of, rather), among other tests.

 

I think that the Solgar contamination  incident was specific to that product and that situation. There is enough evidence of the benefit of probiotics to "safely use probiotics again" - just check into the company and their processes.  Maybe the govt of your country needs to demand higher levels of quality assurance - in Canada for natural health (NHP) products it's pretty good  (these are not under the Food act, but NHP have a higher level of quality control.)

re: powder forms - this one in particular, the RNs mix with a few mLs of EBM and give it once daily. THe powder is kept in the fridge.

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RenewLife don't produce the probiotic organisms themselves, they are produced by a company called Harmonium International, who have their facilities in Mirabel just north of Montreal. In fact there are only a few manufacturers of these organisms in the world, and unfortunately in many parts of the world a company selling a probiotic preparation to the public, can change suppliers, change formulation and which strains are involved, without changing the packaging or informing consumers. 

One of the advantages of the Canadian Natural Products Number system, is to put a stop to that. in order to maintain their NPN, companies have to stick with all the details that are on file with Health Canada. 

 

It is certainly important that a safe product is given to our tiny babies, a discussion with manufacturers and regulatory authorities may help you to know what the situation si in your own country. 

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