Fluoroquinolones Are Useful as Directed Treatment for Complicated UTI in a Setting with a High Prevalence of Quinolone-Resistant Microorganisms

Round 1

Reviewer 1 Report

The author has done a great effort in this study. This work will be of interest in term of AMR. However, this work needs a major revision and need to add more data. I have few questions and comments:

The introduction section is too short. The authors are recommended to add more background. The mechanism of fluoroquinolones, background to UTIs will add an impact to the study.

Line 28: replace gram negative with Gram-negative.

Line 9-10 and 27-28: The sentences are repetitive. Please modify.

Line 12: Rather then to use us/we/our, authors are recommended to use this/current/present study.

Line 29: The authors are recommended to not mention here specifically P. aeruginosa, as there are many other important UTI pathogens. Also, it is not their specific study target.

Line 48: which protocol?

Line 73-74 can be moved at the beginning of material and methods.

Line 90-91: there should be spaces in the figure legend. The words are combined. Might be because of format errors.

Line 101-102: Change the sentence as “8.6% of the patients were found infected with two of more type of bacterial isolates at once”.

In table 1,2 and 3, the authors mentioned only females and age group >75 years, is it means there was no male or transgender patient and also is there no other age group patients?

In table 1, 2, remove word “sex” after female.

The authors are recommended to use specific antibiotics in the group fluoroquinolones. This data will significantly help to understand the specific scenario at study location, that which antibiotic specifically was used and which was more resistant.

The authors are also encouraged to add the prevalence of bacterial isolates, the samples from which these were isolated and the ward in which the patients were admitted.

Because more data is needed for the study, I will recommend for a major revision.

Author Response

Thank you to the reviewers for their comments and suggestions, which have been most helpful and useful for improving the quality of the text and the readers’ comprehension.

I will answer the reviewers’ questions point by point.

Reviewer 1:

1. The introduction section is too short. The authors are recommended to add more background. The mechanism of fluoroquinolones, background to UTIs will add an impact to the study.

- The background to UTIs has been extended (lines 28-32). “Urinary tract infections (UTIs) are amongst the most frequent bacterial infections in the community with considerable morbidity [1] and require antibiotic treatment. Fluoroquinolones (FQ) have been extensively used as empirical treatment for UTI [2], that is, before the confirmation of the etiology and antibiogram, since their spectrum of activity includes enteric Gram-negative bacilli [3]. They are recommended as directed treatment [2], once the bacteria that causes the infections and its antibiogram is known, since they have many beneficial pharmacokinetic properties [3].”

- A paragraph about the mechanism of fluoroquinolones has been added to the introduction (lines 38-46). “Resistance to fluoroquinolones is multifactorial and can be via one or a combination of target-site gene mutations, increased production of efflux pumps, modifying enzymes and/or target-protection proteins [9]. The most common mechanism of resistance is the mutation in one or more of the genes that encode type II topoisomerases (which include DNA gyrase and topoisomerase IV) and alter the fluoroquinolones binding affinity of the enzyme [10]. Although fluoroquinolones preferentially target either DNA gyrase or topoisomerase IV for Gram-negative or Gram-positive bacteria respectively, they will bind to the secondary target, which in turn becomes a target once the primary binding is mutated [11].”

2. Line 28: replace gram negative with Gram-negative.

- It has been done.

3. Line 9-10 and 27-28: The sentences are repetitive. Please modify.

- Lines 27-28 have been modified. “Urinary tract infections (UTIs) are amongst the most frequent bacterial infections in the community with considerable morbidity [1] and require antibiotic treatment.”

4. Line 12: Rather than to use us/we/our, authors are recommended to use this/current/present study.

- It has been changed: “A prospective observational study of patients with the diagnosis of community-acquired UTI was conducted, in which their outcomes according to whether they had FQ or not in their empirical and directed treatments were compared. A multivariate analysis was performed to identify risk factors for UTIs due to ciprofloxacin-resistant microorganisms.”

5. Line 29: The authors are recommended to not mention here specifically P. aeruginosa, as there are many other important UTI pathogens. Also, it is not their specific study target.

- Following the reviewer’s recommendation P. aeruginosa is not mentioned in line 29.

6. Line 48: which protocol?

The protocol is explained more accurately in Madrazo, M. 2020. Aplicación de los criterios de sepsis-3 en la infección urinaria. Universitat de València, València. The reference has been included.

7. Line 73-74 can be moved at the beginning of material and methods.

It has been done.

8. Line 90-91: there should be spaces in the figure legend. The words are combined. Might be because of format errors.

It was a format error; it has been corrected.

9. Line 101-102: Change the sentence as “8.6% of the patients were found infected with two of more type of bacterial isolates at once”.

It has been changed.

10. In table 1,2 and 3, the authors mentioned only females and age group >75 years, is it means there was no male or transgender patient and also is there no other age group patients?

All patients were cisgender; therefore, patients which were not female, were male.

Median age as 78 [70-86]; age as quantitative variable has been added to table 1 and table 2. Age group ≥75 years old was considered as variable “old patient” with a common definition. We analyze it because it was a common risk factors in some studies.

11. In table 1, 2, remove word “sex” after female.

Sex has been removed from table 1 and 2.

12. The authors are recommended to use specific antibiotics in the group fluoroquinolones. This data will significantly help to understand the specific scenario at study location, that which antibiotic specifically was used and which was more resistant.

“One hundred and sixty-two (38.7%) patients were treated with FQ, 27 (6.4%) were given FQ as empirical treatment (20 patients were treated with levofloxacin and 7 with ciprofloxacin) and 135 (32.2%) as directed treatment (21 patients with levofloxacin and 114 with ciprofloxacin).” was added in lines 79-81.

Due to the differences in the use of ciprofloxacin and levofloxacin in empiric and directed treatment, both quinolones were grouped up in the analysis, since separately, the statistical power of the analysis would be less. Due to its characteristics, ciprofloxacin is more suitable for the treatment of urinary tract infection. Due to the nature of resistance mechanisms, bacteria responsible for a urinary infection that are resistant to ciprofloxacin will presumably also be resistant to levofloxacin at the clinical level; and in any case, the use of levofloxacin would hardly be justified if it is resistant to ciprofloxacin. Therefore, we only recorded resistances to ciprofloxacin.

13. The authors are also encouraged to add the prevalence of bacterial isolates, the samples from which these were isolated and the ward in which the patients were admitted.

The prevalence of bacterial isolates is reported in lines 102-104.

The specification of the samples (all were urine cultures, as noted in line 102) is added in line 52. As may be seen in Figure 1, patients with contaminated or negative urine cultures, or without urine cultures, were excluded.

All patients were admitted to an internal medicine ward (lines 42-43).

Reviewer 2 Report

Revision report

Manuscript ID: antibiotics-2153368; “Usefulness of fluoroquinolones for complicated community-acquired urinary tract infection in a setting with a high prevalence of quinolone-resistant microorganisms”

In the present study the authors aim to know the usefulness of fluoroquinolones (FQ) for treatment of community-acquired UTI in a  setting with a high  prevalence of fluoroquinolone-resistant microorganisms. They conducted a prospective observational study of patients with the diagnosis of community-acquired UTI. The authors compared outcomes according to having FQ or not in empirical and directed treatments. In addition, a multivariate analysis was performed to identify risk factors  for UTIs due  to ciprofloxacin-resistant microorganisms. The results show that  both in-hospital mortality and 30-day mortality were lower in the group of patients directly treated with FQ, however no difference when FQ were used as empirical treatment. The authors concluded that; in a setting with a high prevalence of  community-acquired UTI caused by quinolone-resistant microorganisms, FQ as directed treatment for community–acquired UTI were associated with better outcomes  than other antibiotics, but  their use as empirical  treatment  is not  indicated, even in those cases without risk factors for quinolones resistance. 

Comments:

- Title: I think the title needs to be modified in order to be more informative and reflective for the study major findings.

- Introduction:

- The introduction is so short. The introduction section should be modified to be more informative, focusing more on previous studies, the rationale for this study needs to be represented better.

- The difference between empirical and directed treatment should be briefly explained

-  Material and methods:

- Line 44-45: Intensive Care Unit (ICU)……. intensive care unit (ICU)

- Results: the results are well written, concise and informative.

- Just the authors need to mention the results ± standard errors or standard deviation both in the results section and the discussion where ever mentioned.

- Discussion

The authors need to avoid using we, our, ……and could be replaced by the current or present study….

- The study should mention the ethical approval and the institution review board (IRB) approval numbers as it carried on human subjects.

Author Response

Thank you to the reviewers for their comments and suggestions, which have been most helpful and useful for improving the quality of the text and the readers’ comprehension.

I will answer the reviewers’ questions point by point.

REVIEWER 2

1. Title: I think the title needs to be modified in order to be more informative and reflective for the study major findings.

The title has been changed to “Fluoroquinolones are Useful as Directed Treatment for Com-plicated Community-Acquired Urinary Tract Infection in a Setting with a High Prevalence of Quinolone-Resistant Microorganisms”

2. The introduction is too short. The introduction section should be modified to be more informative, focusing more on previous studies, the rationale for this study needs to be represented better.

The introduction has been extended, with more information and supporting the rationale for this study.

3. The difference between empirical and directed treatment should be briefly explained

Both concepts have been explained in the introduction (lines 30-34): “Fluoroquinolones (FQ) have been extensively used as empirical treatment for UTIs [2], that is, before the confirmation of the etiology and antibiogram, since their spectrum of activity includes enteric Gram-negative bacilli [1]. They are recommended as directed treatment [2], once the bacteria that causes the infections and its antibiogram is known, since they have many beneficial pharmacokinetic properties [1].”

4. Line 44-45: Intensive Care Unit (ICU)……. intensive care unit (ICU)

The use of capital letters has been corrected.

5. The authors need to mention the results ± standard errors or standard deviation both in the results section and the discussion where ever mentioned.

The interquartile range was added (line 120-121) “… and those with other antibiotics (DTQ 5 [3-7] days vs. DTOA 5 [3-7] days, p 0.328).”

6. The authors need to avoid using we, our, ……and could be replaced by the current or present study….

In the present study (line 163)

The findings (line 164)

In the present study (line 176)

The results show that (line 184)

the present study study (line 187)

When patients with or without a history of prior use of quinolones or an HCA-UTI regarding resistance to quinolones were compared (lines 193-194)-

In the present study (line 199)

These findings (line 202)

Therefore, to consider empirical treatment with carbapenems for complicated UTIs in patients with risk factors for MDR pathogens should be noted [29]., (lines 204-206)

In the present study (line 208)

it could not be analyzed (line 216)

The present study (line 217)

the antecedent of recurrent UTI was not recorded in the protocol; it has been pointed out (lines 219-220)

7. The study should mention the ethical approval and the institution review board (IRB) approval numbers as it carried on human subjects.

The approval number was added (line 67). “(code 85/16, September 2016)”

Round 2

Reviewer 1 Report

The authors have made great efforts to revise the manuscript. I have some minor concerns which can be considered to make it better for the reader:

1. The title is too long. Make it concise.

2. In the material and methods section, authors are encouraged to put subheadings, e.g., statistical analysis.

3. Italicize the "n" (n=number) and "p" (p-values)

Author Response

Thank you to the reviewers for their comments and suggestions, which have been most helpful and useful for improving the quality of the text and the readers’ comprehension.

I will answer the reviewers’ questions point by point.

Reviewer 1:

1. The title is too long. Make it concise.

The title has been changed, following the reviewer’s recomendation: Fluoroquinolones are Useful as Directed Treatment for Com-plicated UTI in a Setting with a High Prevalence of Quinolone-Resistant Microorganisms

2. In the material and methods section, authors are encouraged to put subheadings, e.g., statistical analysis.

It has been done.

3. Italicize the "n" (n=number) and "p" (p-values)

Following te reviewer’s suggestion all  "n" (n=number) and "p" (p-values) have been italicized in table 1, 2 and 3.

Reviewer 2 Report

The authors have modified the manuscript following the reviewers suggestions. 

Author Response

Thank you for your words

Author Response File: Author Response.pdf