Review for 10.1186/s12876-018-0831-x (2018)

Reviewer ’s report  
 
Title: A practical guide for probiotics applied to the case of antibiotic -associated diarrhea in The 
Netherlands  
 
Version: 0 Date: 04 Jan 2018  
 
Reviewer: Lynne Vernice McFarland  
 
Reviewer's report:  
 
A paper on this subject is much needed, as there exists a great deal of confusion for clinicians 
and patients on how to choose an appropriate probiotic for their specific disease condition.  The 
authors have put in a great deal of work into this paper, but  it fails currently to meet its goal of 
providing any practical advice.  
 
Major comments:  
1. Main Outcome. The data is poorly presented, often incorrect and the outcomes that should 
have been presented in the main paper are buried in supplementary excel spre adsheets, which 
are so poorly formatted, the text is often hidden and illegible. The main outcome (efficacy for 
preventing AAD by different types of probiotics) in theory is given in Figure 3, but the figure 
is so blurry, you can't read what the probiotics  are.  In addition the labelling is poor (for 
example, what does "et alia (1)" refer to? -this does not do justice to a complete description of 
either the strains contained in the probiotic products and does not describe all the studies 
within one probiotic  group. What does (1) refer to? It's not the reference #1, so the readers 
will not understand what this refers to.  Indeed some of the classifications are wrong. For 
example, Gao 2010 is described as a dietary supplement, but the same product is also 
descr ibed as a 'dairy product' (Beasoleil 2007 and Sampalis 2010). This product [Bio -K+] is 
actually a mixture of three Lactobacilli strains, not just two and the strain designations for the 
L. casei is not given. A better analysis would be to have the first co lumn as the subgroup of 
specific probiotics, then give all the studies under that one type of probiotic, along with a 
pooled RR for that probiotic. Then you can easily see which probiotics are effective and 
which are not. The current Figure 3 does not help  at all. Pooling by 'dairy product' vs 'food 
supplement' does not provide any useful clinical summary.  
 
2. Methods. The methods are poorly described.  It is not apparent from the abstract if this is just 
a systematic review or a meta -analysis or what ?  The  methods section is lacking any 
description of recommended methods for meta -analysis or reviews (no PRISMA statements 
or descriptions), exclusion criteria are not described, inclusion criteria are poorly presented. 
The authors present their methods as "a 4  step work -flow" which is not helpful and is not 
very applicable to how they really did the paper. EVERY review should start with prevent vs 
treatment, reviewing articles, etc. Were the exclusion criteria stated a priori, etc. were the 
reasons 96 studies w ere excluded in the protocol?  The first time they appear to be described 
is in the figure 2 (and not in the Methods section).   There is no description of the methods 
they used for their meta -analyses in the Methods section (for example, heterogeneity 
measurements, risk of bias, etc).  
 
3. Introduction. The introduction reads like a paper all about AAD by itself (with 61 references, 
even before we get into the review itself!). Re -focus this and shorten dramatically. Three 
short paragraphs should do it.  
 
4. Results are incorrect.  The three main RRs reported in the text (page 13, lines 1 -24) do not 
match the pooled RR in Figure 3. Why is this?  
 
5. The true value of this paper is to give a practical guide to probiotic products, but the most 
glaring result is that not all probiotic types pooled within Figure 3 are equally effective. Also, 
the authors consistently use the term "shows an effect" when 'an effect' could be either a 
significant reduction in efficacy for AAD' or 'a non -significant finding of efficacy ' or 
'reduction in adverse reactions'.  Please be more precise.  
 
6. One of the big problems I found with this paper is that the authors state in the text that some 
studies 'showed an effect', (assuming once again they mean a significant effect of AAD 
efficacy) but do not present of how many studies were reviewed in total?  For example, for L. 
rhamnosus GG, (page 13, line 39 -41), they state 'there is an effect in at least three... studies' 
and provide citations for (Arvola 1999, Szajewsak 2009 and Vanderhoof  1999), but how 
many other studies with non -significant efficacy findings were reviewed?  I know there are 
more studies than these three!  It is impossible to find this out from Figure 3 (those 
references/studies not given) and the studies may be buried in  the supplementary data 
(assuming you can decipher those spreadsheets), but this data is not given in the text, where it 
is sorely needed.  In addition, in the Discussion (page 14, line 19) where this is discussed, the 
authors quote the incorrect reference s (#39,60,63) do not refer to Lactobacillus rhamnosus 
GG studies at all!  
 
7. The authors do not seem to follow their own 'star' recommendation scheme. In the results 
under Recommendations (page 13, lines 43 -50), the state that "A number of multi -strain 
formulations led to a two -star recommendation, including those with an effect in only 
selected study".  But in their Methods sections, they stated that in order to achieve a 'two -star' 
recommendation rating, there had to be at least two studies with a [signif icant I assume] 
effect.   
 
8. The authors also state that Saccharomyces boulardii achieved only a trend from 5 studies, but 
where is the data for this? A frustrating search through the long supplementary data tables 
appears to have included five studies wit h this probiotic (Kotowska 2005, Lewis 1998, 
McFarland 1995, Pozzoni 2012 and Surawicz 1989). However, how can they explain that 
other meta -analyses looking at this same probiotic continually finds a significant reduction in 
AAD risk? Goldenberg JA 2013 ha d 9 trials and found significant efficacy for S. boulardii 
and well as Szajewska H 2015 with 21 RCTs! Why does their review differ so dramatically 
from others?  
 
9. There are too many numerous other errors in the text to list here (for example, page 4, line  
24) "Nevertheless, in the past decade (2004 -2009)…"   It's 2017! The past decade would be 
2007 -2017!  
 
10. Where was the data on the doses and duration of probiotic therapy given? This might help to 
provide some guidance. Little of this was covered in the D iscussion section also.  
 
11. Table 1. Need to clearly describe the Table so that it can stand alone and be understandable. 
For example, what odes "category" refer to?  Isn't this "Recommendation level"? Also, 
column labaeled "Product" should be "Brand nam e" and the column labeled "Brand name" 
should be the manufacturer!  Define all abbreviations.  
 
12. Figure 1 is interesting, but could as easily be described in the Introductory section of the 
paper.  
 
13. Figure 3. This is horrible. Can't read it, sub -group s are inappropriate, same type of products 
are included as dairy products and food supplement. Do not use 'et alia' -list the studies! List 
of species/strains! what do the numbers in the () refer to? Not references, but what?  Very 
hard to evaluate this fig ure, as even when it is on zoom, the text is blurry and incomplete.  
 
14. Supplement Tables are even worse. Excel spreadsheets are not appropriate, especially when 
the cells have hidden text and when published, they will be not able to be uncovered.  Take 
the time to do presentable Tables.  In addition, the value of supplement table 1 (side effects 
of antibiotics) is not worth the space.  Tables in file 2 and 3 are valuable, but need to be 
legible. Re -do.  Additional file 4 (Figure of probiotics for AAD fro m 32 studies listed in 
chronological order). Why? The lack of sub -groups by  type of probiotic is needed, not by the 
year they were published. No valuable conclusion or inference was made from this figure, so 
why is it here? File 5 (products available in T he Netherlands) is interesting and almost 
understandable but not well formatted —use wrap text for cells.  
Although it would be valuable to have a practical guide, this paper completely fails to provide 
one. I do appreciate the thoroughness of the search and  presenting the types of probiotic products 
available in The Netherlands is a valuable. This papers needs to be refocused, trimmed and 
checked for accuracy. Consider the types of what types of Figures need to be presented, the data 
that your readers will a ctually need to see in a paper of this type, etc.  
Are the methods appropriate and well described?  
If not, p lease specify what is required in your comments to the authors.  
 
No 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the d ata shown?  
If not, please explain in your comments to the authors.  
 
No 
 
Are you able to assess any statistics in the manuscript or would you recommend an  
additional statistical review?  
If an additional statistical review is recommended, please specify what a spects require further  
assessment in your comments to the editors.  
 
I recommend additional statistical review  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Needs some language corrections before being published  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an  
organisation that may in any way gain  or lose financially from the publication of this  
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose  
financially from the publication of this manuscript, either now or in the fut ure? 
 
3. Do you hold or are you currently applying for any patents relating to the content of the  
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds  or has applied for patents relating to the content of  the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?   
 
If you can answer no to all of the above, write 'I declare that I have no competing interests' 
below.  If your reply is yes to any, please give details below.  
 
I declare I have the following potential conflicts of interest: I am a paid member of an Advisory  
Board for Bio -K+, I am a paid lecturer for Biocodex and Lallemand.  
 
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