Comparative Impact of an Optimized PK/PD Target Attainment of Piperacillin-Tazobactam vs. Meropenem on the Trend over Time of SOFA Score and Inflammatory Biomarkers in Critically Ill Patients Receiving Continuous Infusion Monotherapy for Treating Documented Gram-Negative BSIs and/or VAP

Round 1

Reviewer 1 Report

See attachment

Comments for author File: Comments.pdf

Moderate editing of English language required

Author Response

RESPONSE TO REVIEWERS

Manuscript ID: antibiotics-2912599 entitled “Comparative impact of an optimized PK/PD target attainment of piperacillin-tazobactam vs. meropenem on the trend over time of SOFA score and inflammatory biomarkers in critically ill patients receiving continuous infusion (CI) beta-lactam monotherapy for treating documented Gram-negative blood-stream infections and/or ventilator associated pneumonia” by Gatti et al.

Dear Editor,

We would like to thank you for the opportunity to resubmit a revised version of this manuscript. We appreciated the reviewers’ constructive comments. All have been carefully considered and incorporated, where and whenever possible, in the revision.

Our point-by-point responses are provided below.

Q= QUERY; A= ANSWER

Reviewer #1

This manuscript presented a comparative retrospective observational study to compare the PK/PD target attainment, SOFA score, and inflammatory biomarkers of piperacillin-tazobactam vs. meropenem in critically ill patients. The contents of the manuscript fit the scope of the journal. However, the study lacks novelty in general. The study was also conducted with very limited sample size, which might pose challenge to derive meaningful conclusion.

I have a few comments, both major and minor, to further improve the quality of the manuscript.

We thank the reviewer for appreciating our manuscript.

Q1. Table 1, why only present total daily dose for piperacillin-tazobactam, but not for meropenem.

A1. Thank you for this comment. Total daily dose of meropenem is already reported in the third column of Table 1 (median daily meropenem dose equal to 500 mg every 6h).

Q2. The authors should make the layout of Figures 2-4 consistent.

A2. We thank the reviewer for the suggestion. We improved the layout of the figures in the revised version.

Q3. Wouldn’t SOFA score always be positive? (reference: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880479/), not sure why there’s negative values in SOFA score IQR in Table 3 and Figure 2.

A3. We thank the reviewer for this comment, allowing us to better clarify this issue. Both in Table 3 and in Figure 2 are reported delta SOFA score values, and not absolute SOFA score values. Considering that delta SOFA score was calculated as the difference between the SOFA score value at baseline and those reported at 48-hours or at 7-days, the delta SOFA score was negative in case of worsening of clinical conditions. Consequently, negative values of delta SOFA score were found in the IQR reported in Table 3 and in Figure 2. We better specified in Table 3 caption that delta SOFA subscore values are reported.

Q4. In method, the authors said: “Whenever discharge from ICU or death occurred before day 7, delta 7-days SOFA score was assessed by assuming the last day in which SOFA score was assessable.” “Whenever discharge from ICU or death occurred before day 7, delta 7-days for CRP and/or PCT were assessed by assuming the last day in which CRP and/or PCT serum levels were assessable.” Wouldn’t excluding these SOFA scores / other measurements collected not at day 7 a better approach here?

A4. We respectfully disagree with this comment. A recent systematic review with meta-analysis (refer to doi:10.1186/s13054-017-1609-1) aimed at quantifying the relationship between SOFA and mortality in RCTs and at identifying which SOFA derivative best reflected differences between-group mortality. It was found that delta SOFA was significantly associated with mortality and explained 32% of the overall mortality effect. In this context, the SOFA scores assigned to patients discharged from the ICU and to deceased patients should be carefully chosen and clearly described. Non assigning score to discharged or deceased patients will lead to bias that may decrease the validity of the endpoint, as discussed in doi:10.1186/s13054-017-1609-1. Consequently, selecting the last SOFA score observed before the event (i.e., discharge or death) may ensure an effective strategy for avoiding risk of bias, as previously suggested (refer to doi:10.1186/s13054-017-1609-1).

Q5. The authors’ study was conducted with very limited sample size, this poses challenge to derive meaningful conclusions. This might be the reason that the authors used many “may” / “might” throughout the context, even in their major conclusion. The authors should appropriately justify their sample size (probably in the method / discussion section), as this will directly inform how convincing the conclusion is.

A5. As also reported in the response to comment No. 1 of reviewer #2, we added as a limit that sample size calculation for assessing the statistical power of the study was not performed (refer to Discussion section, Line 268-269). The sample size was based on the choice of including only patients having documented Gram-negative BSI or VAP treated with meropenem or piperacillin-tazobactam monotherapy, and of excluding those receiving concomitant anti-Gram-positive or antifungal agents in order to minimize the impact of any potential confounder on SOFA score and/or inflammatory biomarkers trend. This explanation was reported in the Discussion section (refer to Line 269-273).

Q6. Title is too long; the authors should shorten it.

A6. We have shortened the title as suggested.

Q7. The authors should mention somewhere in the introduction, meropenem is one of the carbapenems, piperacillin-tazobactam belongs to betalactam/beta-lactamase inhibitor. This helps the reader to make the connections.

A7. Thank you for this suggestion. We added this information in the Introduction section (refer to Line 64-65).

Q8. Page 2, line 85, “thanks to have” instead of “thanks having”.

A8. Thank you for this suggestion. We modified accordingly.

Q9. This sentence is very hard to understand, please revise. “However, it has still to be assessed which advantages could have an optimized PK/PD target attainment with meropenem monotherapy over that with piperacillin/tazobactam in the treatment of severe documented Gram-negative bacterial infections in the ICU setting.”

A9. Thank you for this suggestion: we revised the sentence for improving readability.

Reviewer 2 Report

Thank you for the opportunity to review the manuscript (antibiotics-2912599) intitled “Comparative impact of an optimized PK/PD target attainment of piperacillin-tazobactam vs. meropenem on the trend over time of SOFA score and inflammatory biomarkers in critically ill patients receiving continuous infusion (CI) beta-lactam monotherapy for treating documented Gram-negative bloodstream infections and/or ventilator associated pneumonia.”.

In this paper, the authors conducted a retrospective observational study comparing critically ill patients receiving treatment with CI meropenem (N = 32) with patients receiving CI piperacillin-tazobactam (N = 43) for documented Gram-negative BSIs or VAP. They found that the decreases in the SOFA score, CRP and PCT serum levels achievable with CI piperacillin-tazobactam at 48-h and at 7-days are similar and as effective as to those achievable with CI meropenem (after optimization on real-time by means of a TDM-based expert clinical pharmacological advice program).

The authors should be commended on their efforts to provide further insights on the best available treatment for management of bloodstream infection and nosocomial pneumonia caused by GNB. This paper is interesting, the methods and findings are well described, and the manuscript is appropriately organized. We recognize the Italian touch of Federico Pea and now that of Milo Gatti, who shows us, paper after paper, that Bologna has turned antibiotic pharmacology into a specialty that rivals Bolognese spaghetti!

I have the following comments: 

-       The statistical analysis is not very robust because it does not take into account potential confounders and concludes equivalence without determining the number of subjects that would have been necessary to detect a difference in prognosis... However, in my opinion, this is not the central focus of the paper. Nevertheless, the discussion could be strengthened by discussing these potential limitations

-       I think the authors should temper their conclusion regarding the utility of TDM for meropenem. Indeed, the use of meropenem in continuous infusion typically yields a median Css to MIC ratio of 92.3 (20.3-166.5). This is mainly due to the fact that MICs for meropenem are often very low, and continuous infusion ensures a very stable and significantly higher Css compared to the MICs of most pathogens. Therefore, there are very few cases where this presents an interest with a genuine clinical impact.

-       There are some areas where the language could be clarified for better readability.

One more time, thank you for the opportunity to review your manuscript.

Minor editing of English language required

Author Response

RESPONSE TO REVIEWERS

Manuscript ID: antibiotics-2912599 entitled “Comparative impact of an optimized PK/PD target attainment of piperacillin-tazobactam vs. meropenem on the trend over time of SOFA score and inflammatory biomarkers in critically ill patients receiving continuous infusion (CI) beta-lactam monotherapy for treating documented Gram-negative blood-stream infections and/or ventilator associated pneumonia” by Gatti et al.

Dear Editor,

We would like to thank you for the opportunity to resubmit a revised version of this manuscript. We appreciated the reviewers’ constructive comments. All have been carefully considered and incorporated, where and whenever possible, in the revision.

Our point-by-point responses are provided below.

Q= QUERY; A= ANSWER

Reviewer #2

Thank you for the opportunity to review the manuscript (antibiotics-2912599) intitled “Comparative impact of an optimized PK/PD target attainment of piperacillin-tazobactam vs. meropenem on the trend over time of SOFA score and inflammatory biomarkers in critically ill patients receiving continuous infusion (CI) beta-lactam monotherapy for treating documented Gram-negative bloodstream infections and/or ventilator associated pneumonia.”.

In this paper, the authors conducted a retrospective observational study comparing critically ill patients receiving treatment with CI meropenem (N = 32) with patients receiving CI piperacillin-tazobactam (N = 43) for documented Gram-negative BSIs or VAP. They found that the decreases in the SOFA score, CRP and PCT serum levels achievable with CI piperacillin-tazobactam at 48-h and at 7-days are similar and as effective as to those achievable with CI meropenem (after optimization on real-time by means of a TDM-based expert clinical pharmacological advice program).

The authors should be commended on their efforts to provide further insights on the best available treatment for management of bloodstream infection and nosocomial pneumonia caused by GNB. This paper is interesting, the methods and findings are well described, and the manuscript is appropriately organized. We recognize the Italian touch of Federico Pea and now that of Milo Gatti, who shows us, paper after paper, that Bologna has turned antibiotic pharmacology into a specialty that rivals Bolognese spaghetti!

We thank the reviewer for appreciating our manuscript.

Q1.      The statistical analysis is not very robust because it does not take into account potential confounders and concludes equivalence without determining the number of subjects that would have been necessary to detect a difference in prognosis... However, in my opinion, this is not the central focus of the paper. Nevertheless, the discussion could be strengthened by discussing these potential limitations.

A1. Thank you for this comment. As suggested, we discussed these issues among potential limitations (refer to Discussion section, Line 268-269). In regard to potential confounders, as already reported in the limitations section, we included in our analysis only patients having documented Gram-negative infections treated with piperacillin-tazobactam or meropenem monotherapy, and excluded those receiving concomitant anti-Gram-positive or antifungal agents for minimizing the impact of any potential confounder on SOFA score and/or inflammatory biomarkers trend.

Q2.      I think the authors should temper their conclusion regarding the utility of TDM for meropenem. Indeed, the use of meropenem in continuous infusion typically yields a median Css to MIC ratio of 92.3 (20.3-166.5). This is mainly due to the fact that MICs for meropenem are often very low, and continuous infusion ensures a very stable and significantly higher Css compared to the MICs of most pathogens. Therefore, there are very few cases where this presents an interest with a genuine clinical impact.

A2. We thank the reviewer for this comment, and we agree with it. Indeed, approximatively 80% of isolated pathogens had an MIC for meropenem of 0.12 mg/L. Consequently, also adopting very low meropenem dosing by continuous infusion (i.e., 125 mg q6-8h) allowed high Css/MIC ratios. In this specific scenario, the TDM-guided approach for optimizing meropenem target attainment could be useful from an ecological point of view, in order to reduce unnecessary meropenem exposure and selective pressure. As suggested, we tempered our conclusions regarding the role of a TDM-guided approach for optimizing meropenem exposure (refer to Discussion section, Line 239-245).

Q3.      There are some areas where the language could be clarified for better readability.

A3. Thank you for this suggestion. We carefully reassessed the text for improving its readability.

Round 2

Reviewer 1 Report

Q1. Table 1, what I asked is that the author reported piperacilin-tazobactam dose as 18g/day but meropenem dose 500 mg q6h, how could reader compare a dose per day to dose q6h directly? The author should convert everything to dose / day to make it consistent, so make it easier for reader to compare.  

Q2. The authors should make the layout of Figures 2-4 consistent. I cannot see the authors improved the layout, the layout of Figure 2 still looks quite different as compared to Figures 3 and 4.  

Q3. The author should write out the equation used to calculate delta SOFA score in the Methods section. 

Q4. The author presented this study with very limited sample size but only provided 4-5 lines of discussion to say this is a limitation of this study. This is inadequate to convince readers why the conclusion of this study is meaningful, especially considering the limited innovation of this study methods. I think this is a major limitation of this study, unless the author provide a more thorough discussion about how the sample size of this study can be comparable to other similar studies / how the sample size will impact the conclusion / interpretation of this study, etc, I will consider reject his manuscript. 

NA

Author Response

Manuscript ID: antibiotics-2912599 entitled “Comparative impact of an optimized PK/PD target attainment of piperacillin-tazobactam vs. meropenem on the trend over time of SOFA score and inflammatory biomarkers in critically ill patients receiving continuous infusion (CI) beta-lactam monotherapy for treating documented Gram-negative blood-stream infections and/or ventilator associated pneumonia” by Gatti et al.

Dear Editor,

We would like to thank you for the opportunity to resubmit a revised version of this manuscript. We appreciated the reviewer’s constructive comments. All have been carefully considered and incorporated, where and whenever possible, in the revision.

Our point-by-point responses are provided below.

Q= QUERY; A= ANSWER

Reviewer #1

Q1. Table 1, what I asked is that the author reported piperacilin-tazobactam dose as 18g/day but meropenem dose 500 mg q6h, how could reader compare a dose per day to dose q6h directly? The author should convert everything to dose / day to make it consistent, so make it easier for reader to compare. 

A1. Thank you for this suggestion, we expressed meropenem dosing per day in Table 1.

Q2. The authors should make the layout of Figures 2-4 consistent. I cannot see the authors improved the layout, the layout of Figure 2 still looks quite different as compared to Figures 3 and 4. 

A2. Thank you for this suggestion, we made the layout of Figure 2 with those of Figures 3-4.

Q3. The author should write out the equation used to calculate delta SOFA score in the Methods section.

A3. Thank you for this suggestion, we specified in the Methods section the equations used for calculating delta SOFA scores (refer to Line 335-341).

Q4. The author presented this study with very limited sample size but only provided 4-5 lines of discussion to say this is a limitation of this study. This is inadequate to convince readers why the conclusion of this study is meaningful, especially considering the limited innovation of this study methods. I think this is a major limitation of this study, unless the author provide a more thorough discussion about how the sample size of this study can be comparable to other similar studies / how the sample size will impact the conclusion / interpretation of this study, etc, I will consider reject his manuscript.

A4. We did our best for meeting the request of this reviewer. We explained in detail how we dealt with sample size calculation (Lines 270-283).