Reviewer ’s report  
 
Title: Probiotics use for antibiotic -associated diarrhea: a pragma tic participatory evaluation in 
nursing homes  
 
Version: 0 Date: 22 Nov 2019  
 
Reviewer: Lynne v McFarland  
 
Reviewer's report:  
 
. 
Abstract  
 
Than  when no probiotics was used (36% vs 20%; p=0,022, Chi -square). [comment: I believe the 
two red % are reversed?]  
 
BACKGROUND  
 
Probiotics are li ve microorganisms that when administered in adequate amounts confer a health 
benefit on the host (6),(7). [comment: Specify which probiotics, not all probiotics are equally 
effective] Probiotics appear to be safe and effective in reducing AAD overall (8), as shown in 
outpatients (9), as well as free -living adults and children (10). No serious adverse events have 
been found to be attributed to probiotics, and the risk for adverse events has been similar to that 
of control groups (9,10). Systematic reviews an d meta -analyses show better effects for 
multispecies probiotics compared with mono -strain probiotics in reducing AAD (11,12). 
[comment, #11 Souza A 2002 review is ok, but #12 McFarland is just on a single strain probiotic 
and does not comment on multiple s train probiotics. These two references do not support that 
statement that multispecies probiotics are more effective] A pragmatic participatory evaluation 
(PPE) design was chosen as a suitable approach for implementation of probiotics (14), as well as 
to study its effectiveness in daily nursing home practice (15,16). [comment: please define shortly 
what a 'pragmatic participatory evaluation design is']  
 
The aims of this PPE were threefold: 1) development of a procedure for the implementation of 
probiotics to  prevent AAD in nursing homes, 2) evaluation of changes in the occurrence of AAD 
by administrating multispecies probiotics to nursing home residents, and 3) evaluation of the 
implementation process of probiotics in daily nursing home practice. [comment: Ai m #1 is not 
really an aim of the study. Every study first develops a protocol for implementation. Therefore 
all the information on the implementation protocol should be more correctly in the Methods 
section. You can't do a study if you don't have an a prio ri protocol first. I would suggest that Aim 
#1 is to evaluate the efficacy of the multi -species probiotic for the prevention of AAD in nursing 
home residents and Aim#2 is to evaluate the implementation process of the new protocol itself]  
 
 
 
 
METHODS  
Design  
 
Implementation of probiotics  
The probiotic that were implemented and evaluated in the three nursing homes was the 
multispecies probiotics Ecologic® AAD (Winclove Probiotics B.V.)(17). Ecologic AAD 
consists of 9 different bacterial species, the total daily do se being 1010 cfu (B. bifidum W23, B. 
longum W51, E. faecium W54, L. acidophilus W37 and W55, L. paracasei W20, L. plantarum 
W62, L. rhamnosus W71, and L. salivarius W24).  
[My comments: Please note, genus and species names should be in italics. Also, plea se include 
all description of probiotic administration here: 5 g sachet/d . How long probiotic given (duration 
of antibiotics? Was probiotic continued for any time after antibiotics were discontinued? Was 
there patient follow -up for delayed onset AAD?]  
 
RESULTS  
Implementation procedure  
 
[comment This paragraph describes methods and should be in the Methods section, not Results].  
A protocol was developed for the nursing staff with instructions about the probiotic 
administration procedure, who it should be adm inistered to, with which food substances it could 
be mixed, and instructions about special situations such as problems with swallowing, or probe 
feeding. Although probiotics are usually considered dietary supplements, the project team 
decided that the elde rly care physicians should prescribe probiotics as standard additional 
treatment to the antibiotic prescription. Therefore, probiotics were listed on the medication list of 
the respective nursing home resident. The medication list is used by the nursing st aff to keep 
track of all given medication and requires that the staff checks off the use of both antibiotics and 
probiotics, which guarantees administration of the probiotics. Based on previous publications 
(20) as well as the most frequently used antibiot ics at Rivas zorggroep, amoxicillin/clavulanic 
acid and ciprofloxacin were selected for which concomitant probiotics intake was considered 
useful.  
 
Therefore, all residents requiring antibiotics amoxicillin/clavulanic acid or ciprofloxacin received 
probio tics as part of standard care, except in specific cases were residents were not physically 
able to consume the probiotics. [This should be in Methods as an exclusion criteria?] [Please 
include here whether any compliance data was collected, as in, # reside nts received Probiotic/# 
residents started on amx/clavulanic acid or ciprofloxacin].  
 
[This paragraph should be in the Methods section] The protocol prescribed that for each 
administration one 5 g sachet of probiotics should be mixed with 100 ml water, mil k or (drink) 
yoghurt by the nursing staff. Mixing with fruit juice, fruit compote, soft drinks or warm drinks 
was not allowed. The probiotics were administered twice daily, at least two to three hours before 
or after the administration of antibiotics to pr event inhibition of the probiotic bacterial species by 
the antibiotics (21). The probiotics were given to residents at the start of an antibiotics treatment 
until one week after finishing the treatment, as suggested in a meta -analysis (22). [Do you 
collect ed any data post -antibiotic/probiotic administration to determined delayed -onset AAD?] 
The dietician was designated as the main contact person for questions regarding the protocol and 
administration of probiotics and monitored the actual administration of probiotics together with 
the nursing staff.  
 
[This paragraph should be in the Methods section] Adaptations to the developed protocol were 
needed, in order to provide better instructions to the nursing staff on how to administer the 
probiotics to nursing ho me residents. Nursing staff required specific information whether 
probiotics could be combined with laxatives, whether probiotics had possible interactions with 
other medication, and whether probiotics could be administered to residents with gluten 
intoler ance. Additionally, the nursing staff required recommendations on administering 
probiotics in a more individualized manner to residents. For example, adjusting the dosage and 
starting moment of the probiotics, or changing the administration time (earlier o r later on the 
day). All feedback was taken into account in the development of a final version of the protocol 
(see S1 Appendix).  
 
Outcome evaluation  
As shown in Figure 2, data on 167 episodes of antibiotics use were collected from a total of 93 
residents, including 84 episodes that were supplemented with probiotics and 83 episodes with no 
probiotics supplementation (see S2 Data). Data from the 83 episodes [Clarify: episodes of AAD 
or episodes of antibiotic exposure?] with no probiotics were derived from 49 residents. Data 
from the 84 [antibiotic?] episodes with probiotics use were derived from 71 residents.  
 
 
 [Please revise Table 2 title to clarify what episodes refer to, such as  '…in antibiotic episodes 
with…"  
 
From 27 residents data were collected from both episodes with and episodes without probiotics 
supplementation. In Figure 2, the occurrence of AAD from these 27 residents during antibiotics 
episodes without and with probiotics is depicted. [This is not corr ect, Figure 2 does not provide 
data on AAD, please revise.]  
 
[The following sentences are confusing. Can you revise to something like: In 27 residents with 
multiple antibiotic episodes, AAD occurred in 15% of ?# residents on the probiotic compared to 
AAD i n ?% of ?# residents when antibiotics were given without the probiotic administration.]  
This allows readers to directly compare AAD rates in those with and without the probiotic. In 13 
out of 27 residents, AAD did not occur when using antibiotics without probiotics. One of those 
13 residents actually developed AAD when using probiotics during a later episode. Another 13 
out of 27 residents developed AAD during antibiotics treatment. Of those 13 residents, the 
majority (85%) did not develop AAD when taking probiotics in combination with antibiotics 
treatment.  
Process evaluation [This section is very good]  
. 
[How many eligible residents received the probiotic? Compliance rate?]  
 
DISCUSSION  
.  
 
These findings are in line with earlier studies that demonstrated reduction of AAD upon 
probiotic administration in older populations (23 -25). [Comment: please note, reference #23 
Beausoleil, #24 Gao and #25 Hickson, refer to DIFFERENT probiotics. It is not valid to refer to 
all probiotics, as efficacy of probiotics are strain -specific (see reference below), so not all 
probiotics that contain some Lactobacilli should be lumped together. In your discussion, specify 
which probiotic (give strains) have been found to be effective to prevent AAD in elderly. Do not 
lump togethe r as generic 'probiotic'. Also, suggest adding reference below to your discussion]  
 
McFarland LV, Evans CT, Goldstein EJC. Strain -specificity and disease -specificity of probiotic 
efficacy: a systematic review and meta -analysis. Frontiers in Medicine 2018; 5(124):1 -14. [doi: 
10.3389/fmed.2018.00124]  
 
A previous study showed no difference between multistrain probiotics (L acidophilus, B. 
bifidum, B. lactis) versus placebo in the prevention of AAD in older (≥65 years) hospital patients 
(3). However, probiotic s were administered to patients when diarrhea occurred, and not at the 
start of antibiotics treatment as in the present PPE. [Comment: I believe this is incorrect. 
Reference #3 by Allen gave this 3 -strain probiotic mixture for the prevention of AAD and gav e 
the probiotic with antibiotics, not for treatment of existing diarrhea]. This may explain the lack 
of effect in the study by Allen et al. Furthermore, the administration of probiotics to nursing 
home residents with somatic and/or psychogeriatric conditio ns was found to be safe. [By 
whom?] Adverse events where only reported in 2.8% of cases, and were not likely to be caused 
by probiotics intake and no serious adverse events were reported. Previous studies have 
demonstrated that the use of probiotics is saf e in older populations (26), [comment: again, this 
study refers only to one strain of probiotic L. rhamnosus GG, not all probiotics!] but that 
probiotic treatment is contraindicated for critically ill patients with an immune compromised 
state, an impaired intestinal barrier function such as occurs with multi organ failure and severe 
acute pancreatitis, and a central venous catheter (27,28). [Incorrect reference cited, #28 does not 
address safety of probiotics in AAD?]  
 
[Comment: this section is well presen ted] This pragmatic participatory evaluation had several 
limitations that need further discussion and reflection.  
in the occurrence of AAD in nursing home residents with somatic and/or psychogeriatric 
conditions. Further studies are recommended to investi gate whether probiotic use for prevention 
of AAD is cost -effective and whether it can prevent recurrent infections in older people.  
 
Please correct reference #17 Stockbr??gger  
17. Koning CJM, Jonkers DMAE, Stobberingh EE, Mulder L, Rombouts FM,  
Stockbr??gg er RW. The effect of a multispecies probiotic on the intestinal microbiota  
and bowel movements in healthy volunteers taking the antibiotic amoxycillin. Am J  
Gastroenterol. 2007;102(1):1 -12. 
 
Are the methods appropriate and well described?  
If not, please 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 data shown?  
If not, please explain in your comme nts to the authors.  
 
Yes 
 
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 aspects require further  
assessment in your comments to the editors.  
 
I am able to assess the statistics  
 
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, f ees, funding, or salary from an 
organisation that may in any way gain or lose financially from the public ation of this 
manuscript, either now or in the future?  
2. Do you hold any stocks or shares in an organisation t hat may in any way gain or lose 
financially from the publication of this manuscript, either now or in the future?  
3. Do you hold or are you curre ntly 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 g ive details below.  
 
LVM is on advisory boards of two probiotic companies: Bio codex and Bio -K PLUS. Also paid 
lecturer for Biocodex. Does not own stock or equity in either company.  
 
 
 
 
I agree to the open peer review policy of the journal. I understand that my n ame will be included 
on my report to the authors and, if the manuscript is accepted f or public ation, my named report 
including any attachments I upload will be posted on the website along with the authors' 
responses. I agree for my report to be made availa ble under an Open Access Creative Commons 
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments 
which I do not wish to be included in my named report can be in cluded as confidential comments 
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
Reviewer ’s report  
 
Title: Probiotics use for antibiotic -associated diarrhea: a pragma tic participatory evaluation in 
nursing homes  
 
Version: 0 Date: 22 Nov 2019  
 
Reviewer: Lynne v McFarland  
 
Reviewer's report:  
 
. 
Abstract  
 
Than  when no probiotics was used (36% vs 20%; p=0,022, Chi -square). [comment: I believe the 
two red % are reversed?]  
 
BACKGROUND  
 
Probiotics are li ve microorganisms that when administered in adequate amounts confer a health 
benefit on the host (6),(7). [comment: Specify which probiotics, not all probiotics are equally 
effective] Probiotics appear to be safe and effective in reducing AAD overall (8), as shown in 
outpatients (9), as well as free -living adults and children (10). No serious adverse events have 
been found to be attributed to probiotics, and the risk for adverse events has been similar to that 
of control groups (9,10). Systematic reviews an d meta -analyses show better effects for 
multispecies probiotics compared with mono -strain probiotics in reducing AAD (11,12). 
[comment, #11 Souza A 2002 review is ok, but #12 McFarland is just on a single strain probiotic 
and does not comment on multiple s train probiotics. These two references do not support that 
statement that multispecies probiotics are more effective] A pragmatic participatory evaluation 
(PPE) design was chosen as a suitable approach for implementation of probiotics (14), as well as 
to study its effectiveness in daily nursing home practice (15,16). [comment: please define shortly 
what a 'pragmatic participatory evaluation design is']  
 
The aims of this PPE were threefold: 1) development of a procedure for the implementation of 
probiotics to  prevent AAD in nursing homes, 2) evaluation of changes in the occurrence of AAD 
by administrating multispecies probiotics to nursing home residents, and 3) evaluation of the 
implementation process of probiotics in daily nursing home practice. [comment: Ai m #1 is not 
really an aim of the study. Every study first develops a protocol for implementation. Therefore 
all the information on the implementation protocol should be more correctly in the Methods 
section. You can't do a study if you don't have an a prio ri protocol first. I would suggest that Aim 
#1 is to evaluate the efficacy of the multi -species probiotic for the prevention of AAD in nursing 
home residents and Aim#2 is to evaluate the implementation process of the new protocol itself]  
 
 
 
 
METHODS  
Design  
 
Implementation of probiotics  
The probiotic that were implemented and evaluated in the three nursing homes was the 
multispecies probiotics Ecologic® AAD (Winclove Probiotics B.V.)(17). Ecologic AAD 
consists of 9 different bacterial species, the total daily do se being 1010 cfu (B. bifidum W23, B. 
longum W51, E. faecium W54, L. acidophilus W37 and W55, L. paracasei W20, L. plantarum 
W62, L. rhamnosus W71, and L. salivarius W24).  
[My comments: Please note, genus and species names should be in italics. Also, plea se include 
all description of probiotic administration here: 5 g sachet/d . How long probiotic given (duration 
of antibiotics? Was probiotic continued for any time after antibiotics were discontinued? Was 
there patient follow -up for delayed onset AAD?]  
 
RESULTS  
Implementation procedure  
 
[comment This paragraph describes methods and should be in the Methods section, not Results].  
A protocol was developed for the nursing staff with instructions about the probiotic 
administration procedure, who it should be adm inistered to, with which food substances it could 
be mixed, and instructions about special situations such as problems with swallowing, or probe 
feeding. Although probiotics are usually considered dietary supplements, the project team 
decided that the elde rly care physicians should prescribe probiotics as standard additional 
treatment to the antibiotic prescription. Therefore, probiotics were listed on the medication list of 
the respective nursing home resident. The medication list is used by the nursing st aff to keep 
track of all given medication and requires that the staff checks off the use of both antibiotics and 
probiotics, which guarantees administration of the probiotics. Based on previous publications 
(20) as well as the most frequently used antibiot ics at Rivas zorggroep, amoxicillin/clavulanic 
acid and ciprofloxacin were selected for which concomitant probiotics intake was considered 
useful.  
 
Therefore, all residents requiring antibiotics amoxicillin/clavulanic acid or ciprofloxacin received 
probio tics as part of standard care, except in specific cases were residents were not physically 
able to consume the probiotics. [This should be in Methods as an exclusion criteria?] [Please 
include here whether any compliance data was collected, as in, # reside nts received Probiotic/# 
residents started on amx/clavulanic acid or ciprofloxacin].  
 
[This paragraph should be in the Methods section] The protocol prescribed that for each 
administration one 5 g sachet of probiotics should be mixed with 100 ml water, mil k or (drink) 
yoghurt by the nursing staff. Mixing with fruit juice, fruit compote, soft drinks or warm drinks 
was not allowed. The probiotics were administered twice daily, at least two to three hours before 
or after the administration of antibiotics to pr event inhibition of the probiotic bacterial species by 
the antibiotics (21). The probiotics were given to residents at the start of an antibiotics treatment 
until one week after finishing the treatment, as suggested in a meta -analysis (22). [Do you 
collect ed any data post -antibiotic/probiotic administration to determined delayed -onset AAD?] 
The dietician was designated as the main contact person for questions regarding the protocol and 
administration of probiotics and monitored the actual administration of probiotics together with 
the nursing staff.  
 
[This paragraph should be in the Methods section] Adaptations to the developed protocol were 
needed, in order to provide better instructions to the nursing staff on how to administer the 
probiotics to nursing ho me residents. Nursing staff required specific information whether 
probiotics could be combined with laxatives, whether probiotics had possible interactions with 
other medication, and whether probiotics could be administered to residents with gluten 
intoler ance. Additionally, the nursing staff required recommendations on administering 
probiotics in a more individualized manner to residents. For example, adjusting the dosage and 
starting moment of the probiotics, or changing the administration time (earlier o r later on the 
day). All feedback was taken into account in the development of a final version of the protocol 
(see S1 Appendix).  
 
Outcome evaluation  
As shown in Figure 2, data on 167 episodes of antibiotics use were collected from a total of 93 
residents, including 84 episodes that were supplemented with probiotics and 83 episodes with no 
probiotics supplementation (see S2 Data). Data from the 83 episodes [Clarify: episodes of AAD 
or episodes of antibiotic exposure?] with no probiotics were derived from 49 residents. Data 
from the 84 [antibiotic?] episodes with probiotics use were derived from 71 residents.  
 
 
 [Please revise Table 2 title to clarify what episodes refer to, such as  '…in antibiotic episodes 
with…"  
 
From 27 residents data were collected from both episodes with and episodes without probiotics 
supplementation. In Figure 2, the occurrence of AAD from these 27 residents during antibiotics 
episodes without and with probiotics is depicted. [This is not corr ect, Figure 2 does not provide 
data on AAD, please revise.]  
 
[The following sentences are confusing. Can you revise to something like: In 27 residents with 
multiple antibiotic episodes, AAD occurred in 15% of ?# residents on the probiotic compared to 
AAD i n ?% of ?# residents when antibiotics were given without the probiotic administration.]  
This allows readers to directly compare AAD rates in those with and without the probiotic. In 13 
out of 27 residents, AAD did not occur when using antibiotics without probiotics. One of those 
13 residents actually developed AAD when using probiotics during a later episode. Another 13 
out of 27 residents developed AAD during antibiotics treatment. Of those 13 residents, the 
majority (85%) did not develop AAD when taking probiotics in combination with antibiotics 
treatment.  
Process evaluation [This section is very good]  
. 
[How many eligible residents received the probiotic? Compliance rate?]  
 
DISCUSSION  
.  
 
These findings are in line with earlier studies that demonstrated reduction of AAD upon 
probiotic administration in older populations (23 -25). [Comment: please note, reference #23 
Beausoleil, #24 Gao and #25 Hickson, refer to DIFFERENT probiotics. It is not valid to refer to 
all probiotics, as efficacy of probiotics are strain -specific (see reference below), so not all 
probiotics that contain some Lactobacilli should be lumped together. In your discussion, specify 
which probiotic (give strains) have been found to be effective to prevent AAD in elderly. Do not 
lump togethe r as generic 'probiotic'. Also, suggest adding reference below to your discussion]  
 
McFarland LV, Evans CT, Goldstein EJC. Strain -specificity and disease -specificity of probiotic 
efficacy: a systematic review and meta -analysis. Frontiers in Medicine 2018; 5(124):1 -14. [doi: 
10.3389/fmed.2018.00124]  
 
A previous study showed no difference between multistrain probiotics (L acidophilus, B. 
bifidum, B. lactis) versus placebo in the prevention of AAD in older (≥65 years) hospital patients 
(3). However, probiotic s were administered to patients when diarrhea occurred, and not at the 
start of antibiotics treatment as in the present PPE. [Comment: I believe this is incorrect. 
Reference #3 by Allen gave this 3 -strain probiotic mixture for the prevention of AAD and gav e 
the probiotic with antibiotics, not for treatment of existing diarrhea]. This may explain the lack 
of effect in the study by Allen et al. Furthermore, the administration of probiotics to nursing 
home residents with somatic and/or psychogeriatric conditio ns was found to be safe. [By 
whom?] Adverse events where only reported in 2.8% of cases, and were not likely to be caused 
by probiotics intake and no serious adverse events were reported. Previous studies have 
demonstrated that the use of probiotics is saf e in older populations (26), [comment: again, this 
study refers only to one strain of probiotic L. rhamnosus GG, not all probiotics!] but that 
probiotic treatment is contraindicated for critically ill patients with an immune compromised 
state, an impaired intestinal barrier function such as occurs with multi organ failure and severe 
acute pancreatitis, and a central venous catheter (27,28). [Incorrect reference cited, #28 does not 
address safety of probiotics in AAD?]  
 
[Comment: this section is well presen ted] This pragmatic participatory evaluation had several 
limitations that need further discussion and reflection.  
in the occurrence of AAD in nursing home residents with somatic and/or psychogeriatric 
conditions. Further studies are recommended to investi gate whether probiotic use for prevention 
of AAD is cost -effective and whether it can prevent recurrent infections in older people.  
 
Please correct reference #17 Stockbr??gger  
17. Koning CJM, Jonkers DMAE, Stobberingh EE, Mulder L, Rombouts FM,  
Stockbr??gg er RW. The effect of a multispecies probiotic on the intestinal microbiota  
and bowel movements in healthy volunteers taking the antibiotic amoxycillin. Am J  
Gastroenterol. 2007;102(1):1 -12. 
 
Are the methods appropriate and well described?  
If not, please 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 data shown?  
If not, please explain in your comme nts to the authors.  
 
Yes 
 
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 aspects require further  
assessment in your comments to the editors.  
 
I am able to assess the statistics  
 
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, f ees, funding, or salary from an 
organisation that may in any way gain or lose financially from the public ation of this 
manuscript, either now or in the future?  
2. Do you hold any stocks or shares in an organisation t hat may in any way gain or lose 
financially from the publication of this manuscript, either now or in the future?  
3. Do you hold or are you curre ntly 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 g ive details below.  
 
LVM is on advisory boards of two probiotic companies: Bio codex and Bio -K PLUS. Also paid 
lecturer for Biocodex. Does not own stock or equity in either company.  
 
 
 
 
I agree to the open peer review policy of the journal. I understand that my n ame will be included 
on my report to the authors and, if the manuscript is accepted f or public ation, my named report 
including any attachments I upload will be posted on the website along with the authors' 
responses. I agree for my report to be made availa ble under an Open Access Creative Commons 
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments 
which I do not wish to be included in my named report can be in cluded as confidential comments 
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
Please review this paper.
user
Reviewer ’s report  
 
Title: Probiotics use for antibiotic -associated diarrhea: a pragma tic participatory evaluation in 
nursing homes  
 
Version: 0 Date: 22 Nov 2019  
 
Reviewer: Lynne v McFarland  
 
Reviewer's report:  
 
. 
Abstract  
 
Than  when no probiotics was used (36% vs 20%; p=0,022, Chi -square). [comment: I believe the 
two red % are reversed?]  
 
BACKGROUND  
 
Probiotics are li ve microorganisms that when administered in adequate amounts confer a health 
benefit on the host (6),(7). [comment: Specify which probiotics, not all probiotics are equally 
effective] Probiotics appear to be safe and effective in reducing AAD overall (8), as shown in 
outpatients (9), as well as free -living adults and children (10). No serious adverse events have 
been found to be attributed to probiotics, and the risk for adverse events has been similar to that 
of control groups (9,10). Systematic reviews an d meta -analyses show better effects for 
multispecies probiotics compared with mono -strain probiotics in reducing AAD (11,12). 
[comment, #11 Souza A 2002 review is ok, but #12 McFarland is just on a single strain probiotic 
and does not comment on multiple s train probiotics. These two references do not support that 
statement that multispecies probiotics are more effective] A pragmatic participatory evaluation 
(PPE) design was chosen as a suitable approach for implementation of probiotics (14), as well as 
to study its effectiveness in daily nursing home practice (15,16). [comment: please define shortly 
what a 'pragmatic participatory evaluation design is']  
 
The aims of this PPE were threefold: 1) development of a procedure for the implementation of 
probiotics to  prevent AAD in nursing homes, 2) evaluation of changes in the occurrence of AAD 
by administrating multispecies probiotics to nursing home residents, and 3) evaluation of the 
implementation process of probiotics in daily nursing home practice. [comment: Ai m #1 is not 
really an aim of the study. Every study first develops a protocol for implementation. Therefore 
all the information on the implementation protocol should be more correctly in the Methods 
section. You can't do a study if you don't have an a prio ri protocol first. I would suggest that Aim 
#1 is to evaluate the efficacy of the multi -species probiotic for the prevention of AAD in nursing 
home residents and Aim#2 is to evaluate the implementation process of the new protocol itself]  
 
 
 
 
METHODS  
Design  
 
Implementation of probiotics  
The probiotic that were implemented and evaluated in the three nursing homes was the 
multispecies probiotics Ecologic® AAD (Winclove Probiotics B.V.)(17). Ecologic AAD 
consists of 9 different bacterial species, the total daily do se being 1010 cfu (B. bifidum W23, B. 
longum W51, E. faecium W54, L. acidophilus W37 and W55, L. paracasei W20, L. plantarum 
W62, L. rhamnosus W71, and L. salivarius W24).  
[My comments: Please note, genus and species names should be in italics. Also, plea se include 
all description of probiotic administration here: 5 g sachet/d . How long probiotic given (duration 
of antibiotics? Was probiotic continued for any time after antibiotics were discontinued? Was 
there patient follow -up for delayed onset AAD?]  
 
RESULTS  
Implementation procedure  
 
[comment This paragraph describes methods and should be in the Methods section, not Results].  
A protocol was developed for the nursing staff with instructions about the probiotic 
administration procedure, who it should be adm inistered to, with which food substances it could 
be mixed, and instructions about special situations such as problems with swallowing, or probe 
feeding. Although probiotics are usually considered dietary supplements, the project team 
decided that the elde rly care physicians should prescribe probiotics as standard additional 
treatment to the antibiotic prescription. Therefore, probiotics were listed on the medication list of 
the respective nursing home resident. The medication list is used by the nursing st aff to keep 
track of all given medication and requires that the staff checks off the use of both antibiotics and 
probiotics, which guarantees administration of the probiotics. Based on previous publications 
(20) as well as the most frequently used antibiot ics at Rivas zorggroep, amoxicillin/clavulanic 
acid and ciprofloxacin were selected for which concomitant probiotics intake was considered 
useful.  
 
Therefore, all residents requiring antibiotics amoxicillin/clavulanic acid or ciprofloxacin received 
probio tics as part of standard care, except in specific cases were residents were not physically 
able to consume the probiotics. [This should be in Methods as an exclusion criteria?] [Please 
include here whether any compliance data was collected, as in, # reside nts received Probiotic/# 
residents started on amx/clavulanic acid or ciprofloxacin].  
 
[This paragraph should be in the Methods section] The protocol prescribed that for each 
administration one 5 g sachet of probiotics should be mixed with 100 ml water, mil k or (drink) 
yoghurt by the nursing staff. Mixing with fruit juice, fruit compote, soft drinks or warm drinks 
was not allowed. The probiotics were administered twice daily, at least two to three hours before 
or after the administration of antibiotics to pr event inhibition of the probiotic bacterial species by 
the antibiotics (21). The probiotics were given to residents at the start of an antibiotics treatment 
until one week after finishing the treatment, as suggested in a meta -analysis (22). [Do you 
collect ed any data post -antibiotic/probiotic administration to determined delayed -onset AAD?] 
The dietician was designated as the main contact person for questions regarding the protocol and 
administration of probiotics and monitored the actual administration of probiotics together with 
the nursing staff.  
 
[This paragraph should be in the Methods section] Adaptations to the developed protocol were 
needed, in order to provide better instructions to the nursing staff on how to administer the 
probiotics to nursing ho me residents. Nursing staff required specific information whether 
probiotics could be combined with laxatives, whether probiotics had possible interactions with 
other medication, and whether probiotics could be administered to residents with gluten 
intoler ance. Additionally, the nursing staff required recommendations on administering 
probiotics in a more individualized manner to residents. For example, adjusting the dosage and 
starting moment of the probiotics, or changing the administration time (earlier o r later on the 
day). All feedback was taken into account in the development of a final version of the protocol 
(see S1 Appendix).  
 
Outcome evaluation  
As shown in Figure 2, data on 167 episodes of antibiotics use were collected from a total of 93 
residents, including 84 episodes that were supplemented with probiotics and 83 episodes with no 
probiotics supplementation (see S2 Data). Data from the 83 episodes [Clarify: episodes of AAD 
or episodes of antibiotic exposure?] with no probiotics were derived from 49 residents. Data 
from the 84 [antibiotic?] episodes with probiotics use were derived from 71 residents.  
 
 
 [Please revise Table 2 title to clarify what episodes refer to, such as  '…in antibiotic episodes 
with…"  
 
From 27 residents data were collected from both episodes with and episodes without probiotics 
supplementation. In Figure 2, the occurrence of AAD from these 27 residents during antibiotics 
episodes without and with probiotics is depicted. [This is not corr ect, Figure 2 does not provide 
data on AAD, please revise.]  
 
[The following sentences are confusing. Can you revise to something like: In 27 residents with 
multiple antibiotic episodes, AAD occurred in 15% of ?# residents on the probiotic compared to 
AAD i n ?% of ?# residents when antibiotics were given without the probiotic administration.]  
This allows readers to directly compare AAD rates in those with and without the probiotic. In 13 
out of 27 residents, AAD did not occur when using antibiotics without probiotics. One of those 
13 residents actually developed AAD when using probiotics during a later episode. Another 13 
out of 27 residents developed AAD during antibiotics treatment. Of those 13 residents, the 
majority (85%) did not develop AAD when taking probiotics in combination with antibiotics 
treatment.  
Process evaluation [This section is very good]  
. 
[How many eligible residents received the probiotic? Compliance rate?]  
 
DISCUSSION  
.  
 
These findings are in line with earlier studies that demonstrated reduction of AAD upon 
probiotic administration in older populations (23 -25). [Comment: please note, reference #23 
Beausoleil, #24 Gao and #25 Hickson, refer to DIFFERENT probiotics. It is not valid to refer to 
all probiotics, as efficacy of probiotics are strain -specific (see reference below), so not all 
probiotics that contain some Lactobacilli should be lumped together. In your discussion, specify 
which probiotic (give strains) have been found to be effective to prevent AAD in elderly. Do not 
lump togethe r as generic 'probiotic'. Also, suggest adding reference below to your discussion]  
 
McFarland LV, Evans CT, Goldstein EJC. Strain -specificity and disease -specificity of probiotic 
efficacy: a systematic review and meta -analysis. Frontiers in Medicine 2018; 5(124):1 -14. [doi: 
10.3389/fmed.2018.00124]  
 
A previous study showed no difference between multistrain probiotics (L acidophilus, B. 
bifidum, B. lactis) versus placebo in the prevention of AAD in older (≥65 years) hospital patients 
(3). However, probiotic s were administered to patients when diarrhea occurred, and not at the 
start of antibiotics treatment as in the present PPE. [Comment: I believe this is incorrect. 
Reference #3 by Allen gave this 3 -strain probiotic mixture for the prevention of AAD and gav e 
the probiotic with antibiotics, not for treatment of existing diarrhea]. This may explain the lack 
of effect in the study by Allen et al. Furthermore, the administration of probiotics to nursing 
home residents with somatic and/or psychogeriatric conditio ns was found to be safe. [By 
whom?] Adverse events where only reported in 2.8% of cases, and were not likely to be caused 
by probiotics intake and no serious adverse events were reported. Previous studies have 
demonstrated that the use of probiotics is saf e in older populations (26), [comment: again, this 
study refers only to one strain of probiotic L. rhamnosus GG, not all probiotics!] but that 
probiotic treatment is contraindicated for critically ill patients with an immune compromised 
state, an impaired intestinal barrier function such as occurs with multi organ failure and severe 
acute pancreatitis, and a central venous catheter (27,28). [Incorrect reference cited, #28 does not 
address safety of probiotics in AAD?]  
 
[Comment: this section is well presen ted] This pragmatic participatory evaluation had several 
limitations that need further discussion and reflection.  
in the occurrence of AAD in nursing home residents with somatic and/or psychogeriatric 
conditions. Further studies are recommended to investi gate whether probiotic use for prevention 
of AAD is cost -effective and whether it can prevent recurrent infections in older people.  
 
Please correct reference #17 Stockbr??gger  
17. Koning CJM, Jonkers DMAE, Stobberingh EE, Mulder L, Rombouts FM,  
Stockbr??gg er RW. The effect of a multispecies probiotic on the intestinal microbiota  
and bowel movements in healthy volunteers taking the antibiotic amoxycillin. Am J  
Gastroenterol. 2007;102(1):1 -12. 
 
Are the methods appropriate and well described?  
If not, please 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 data shown?  
If not, please explain in your comme nts to the authors.  
 
Yes 
 
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 aspects require further  
assessment in your comments to the editors.  
 
I am able to assess the statistics  
 
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, f ees, funding, or salary from an 
organisation that may in any way gain or lose financially from the public ation of this 
manuscript, either now or in the future?  
2. Do you hold any stocks or shares in an organisation t hat may in any way gain or lose 
financially from the publication of this manuscript, either now or in the future?  
3. Do you hold or are you curre ntly 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 g ive details below.  
 
LVM is on advisory boards of two probiotic companies: Bio codex and Bio -K PLUS. Also paid 
lecturer for Biocodex. Does not own stock or equity in either company.  
 
 
 
 
I agree to the open peer review policy of the journal. I understand that my n ame will be included 
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which I do not wish to be included in my named report can be in cluded as confidential comments 
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
assistant