Multidrug-Resistant Bacteria in Children and Adolescents with Cystic Fibrosis

Round 1

Reviewer 1 Report

The paper "Multidrug-Resistant Bacteria in Children and Adolescents with Cystic Fibrosis" written  by Dr.Fainardi et al. is well written and results are clearly presented. The authors realized an interesting work unfortunately, based on a small number of patients as admitted by authors.

I would suggest some minor and major revisions detailed as follow.

1)      As far as I have well understood, authors collected data at time of first detection of infection, at time of enrolment (jan 2022) and in the following 12 months after the first detection for all patients and controls. However, it is difficult to understand where to fit the “time of enrolment” in relation to the other timelines (for istance time of infection, probably different between patients). I believe it would be important to better highlight and make clearer these data and timelines that are important to reinforce the final message and hypothese the correlation between clinical data and MD bacteria infection (patients’ conditions before the infection, at time of infection and in the 12 months follow-up after the infection). For istance, I would suggest to create a 3rd Table with the same available data referred to the period after 12 months of infection. Another idea could be to consider as time zero, the data at time of infection and not at time of enrolment. I hope the authors will understand my point and find the better solution.

To better clarify my point, there are 4 different timepoints reffered in the text, with the 1st infection being different between patients:

12 months before infect.__________1st infect._______enrollement________12 months after infect

2) I would suggest to include Pex data to tables or eventually generate a new table with Pex data at different available timelines.

3) Another possible option, always to reinforce authors’ message that MDR bacteria infection correlates with worse clinical condition/parameters is to calculate the “delta” changes between different timelines (for istance between first infection and after 12 months). This would allow to explore a possible increased rate of decline in MDR bacteria patients vs controls.

4) In the abstract authors missed to include data of 12 months after infection. I believe it should be added.

5) Authors describe that 4 patients were treated immediately with a course of 14 days of antibiotics. Could they specify if that treatment allowed treating the infection (eradicated the infection) or patients still were colonized? It could be interesting to understand if those patients went better compare to those patients that were not treated.

6) I believe that authors cannot state that patients with MDR bacteria have worse pulmonary function with not significant differences in FEV1 and FVC. Possibly they can just suggest that they seem to have a more “obstructive lung condition” (correlated with worse FEV1/FVC).

7) Authors speculate that more severe patients might be more predisposed to be colonized by MDR. However, to understand if the infection correlates with an increased rate of decline I believe we need the “delta” between infection and 6 or 12 months after. Otherwise those patients can just be more severe and stay the same irrelevantly to infection.

Author Response

)      As far as I have well understood, authors collected data at time of first detection of infection, at time of enrolment (jan 2022) and in the following 12 months after the first detection for all patients and controls. However, it is difficult to understand where to fit the “time of enrolment” in relation to the other timelines (for istance time of infection, probably different between patients). I believe it would be important to better highlight and make clearer these data and timelines that are important to reinforce the final message and hypothese the correlation between clinical data and MD bacteria infection (patients’ conditions before the infection, at time of infection and in the 12 months follow-up after the infection). For istance, I would suggest to create a 3rd Table with the same available data referred to the period after 12 months of infection. Another idea could be to consider as time zero, the data at time of infection and not at time of enrolment. I hope the authors will understand my point and find the better solution.

To better clarify my point, there are 4 different timepoints reffered in the text, with the 1st infection being different between patients:

12 months before infect.__________1st infect._______enrollement________12 months after infect

We thank the reviewer for this useful comment. We clarified in different parts the 3 time points (both in the method section and in the results) and we added Table n 3.

2) I would suggest to include Pex data to tables or eventually generate a new table with Pex data at different available timelines.

Thanks for this clarification. This datum has been added to the Tables.

3) Another possible option, always to reinforce authors’ message that MDR bacteria infection correlates with worse clinical condition/parameters is to calculate the “delta” changes between different timelines (for istance between first infection and after 12 months). This would allow to explore a possible increased rate of decline in MDR bacteria patients vs controls.

Thank you for the comment. We added the delta change for the patients colonized as suggested.

4) In the abstract authors missed to include data of 12 months after infection. I believe it should be added.

This has been added to the abstract.

5) Authors describe that 4 patients were treated immediately with a course of 14 days of antibiotics. Could they specify if that treatment allowed treating the infection (eradicated the infection) or patients still were colonized? It could be interesting to understand if those patients went better compare to those patients that were not treated.

Patients were still colonized (unsuccessful eradication).

6) I believe that authors cannot state that patients with MDR bacteria have worse pulmonary function with not significant differences in FEV1 and FVC. Possibly they can just suggest that they seem to have a more “obstructive lung condition” (correlated with worse FEV1/FVC).

We changed the text accordingly.

7) Authors speculate that more severe patients might be more predisposed to be colonized by MDR. However, to understand if the infection correlates with an increased rate of decline I believe we need the “delta” between infection and 6 or 12 months after. Otherwise those patients can just be more severe and stay the same irrelevantly to infection.

We believe that patients with severe disease may be more susceptible to MDR bacteria because of the underlying severe lung condition and that infection may not influence their outcome. However, lung function decline was greater for patients colonized by MDR bacteria and this was added to the text highlighting that this can be ascribed both to the severity of CF and to MDR bacteria.

Author Response File: Author Response.docx

Reviewer 2 Report

The manuscript tried to clarify when and how to treat patients with cystic fibrosis (CF) and multidrug-resistant (MDR) bacteria. The authors showed that children and adolescents with CF colonized by MDR bacteria experience more exacerbations, had lower lung function and lower BMI than controls even before being colonized. Thus, these findings will be useful for CF and MDR. 

 Comments

(1) All CF patients colonized by MDR bacteria were males. Why?

(2) Adolescents have biological defense ability more developed than children. There seemed little pathological difference between children and adolescents with CF colonized by MDR bacteria. Why?

(3) Did MDR bacteria induce CF?

(4) When bacteria have resistance to new antibiotics, how will the treatment be done?

That is all.

Author Response

The manuscript tried to clarify when and how to treat patients with cystic fibrosis (CF) and multidrug-resistant (MDR) bacteria. The authors showed that children and adolescents with CF colonized by MDR bacteria experience more exacerbations, had lower lung function and lower BMI than controls even before being colonized. Thus, these findings will be useful for CF and MDR. 

 Comments

• All CF patients colonized by MDR bacteria were males. Why?

It is a surprising finding since in CF women have usually a more severe spectrum of the disease and therefore may be more susceptible to colonization with aggressive bacteria.

• Adolescents have biological defense ability more developed than children. There seemed little pathological difference between children and adolescents with CF colonized by MDR bacteria. Why?

Most children got the MDR bacterium in childhood (10 years) but we did not find a significant difference between younger subjects and adolescents. Adolescents are usually more compromised than younger kids since the decline of the disease is higher.

(3) Did MDR bacteria induce CF?

CF predispose to bacterial colonization due to the thick mucus and therefore MDR bacteria can sometimes affect the lung of the patient with CF.

(4) When bacteria have resistance to new antibiotics, how will the treatment be done?

Different combinations of antibiotics (15 days courses) can be tried on the basis of the antibiograms. If the bacterium is resistant to most

Author Response File: Author Response.docx