Pivmecillinam for Uncomplicated Lower Urinary Tract Infections Caused by Staphylococcus saprophyticus—Cumulative Observational Data from Four Recent Clinical Studies
, Marianne Bollestad 3,4, Ingvild Vik 4, Morten Lindbæk 4, Lars Bjerrum 5, Niels Frimodt-Møller 2 and Jenny Dahl Knudsen 1,2Round 1
Reviewer 1 Report
Jansaker et al presents the results of four studies on the efficacy of pivmecillinam in treating lower urinary infections produced by S. saprophyticus.
The scientific name of some bacterial species must be written in italic (lines 30, 31, 39, 86, 92, 102, 104, 108, 109, 114, 117, 123, 126, 129,130)
Latin statements such "bona fide" (line 37), "in vitro" (line 123) etc, should be written in italic
Line 39: after "Enterobacteriaceae", they should (could) add "sp".
Authors could write more about advantages of using pivmecillinam (resistance, side effects, etc)
Line 64: add "the" before "study four"
How did you ensure that the patients did not omit to administer some antibiotic doses?
It is mandatory to present your results in another manner to make them more explicit. For example in percents
Author Response
PEER-REVIEW nr 1
General response: Thank you for your peer-review and helpful comments.
Open Review
(x) I would not like to sign my review report
( ) I would like to sign my review report
English language and style
( ) Extensive editing of English language and style required
( ) Moderate English changes required
( ) English language and style are fine/minor spell check required
(x) I don't feel qualified to judge about the English language and style
Yes | Can be improved | Must be improved | Not applicable | |
Does the introduction provide sufficient background and include all relevant references? | ( ) | (x) | ( ) | ( ) |
Is the research design appropriate? | (x) | ( ) | ( ) | ( ) |
Are the methods adequately described? | (x) | ( ) | ( ) | ( ) |
Are the results clearly presented? | ( ) | ( ) | (x) | ( ) |
Are the conclusions supported by the results? | ( ) | (x) | ( ) | ( ) |
Comments and Suggestions for Authors
Jansaker et al presents the results of four studies on the efficacy of pivmecillinam in treating lower urinary infections produced by S. saprophyticus.
The scientific name of some bacterial species must be written in italic (lines 30, 31, 39, 86, 92, 102, 104, 108, 109, 114, 117, 123, 126, 129,130)
Response: Thank you for noticing this. In our file they are in italic. This must be a technical problem with the transformation of our document. We will make sure that before any possible publication that the final proof copy has all bacterial species in italic.
Latin statements such "bona fide" (line 37), "in vitro" (line 123) etc, should be written in italic
Response: As above.
Line 39: after "Enterobacteriaceae", they should (could) add "sp".
Response: Amended to: “…effect against several species of Enterobacteriaceae.”
Authors could write more about advantages of using pivmecillinam (resistance, side effects, etc)
Response: Amended. Several sections has been added to the introduction and marked in yellow.
Line 64: add "the" before "study four"
Response: We are not quite sure if this is most suitable in this sentence, but we added a “comma” to separate the specific details about the test from the first section of the sentence: “MIC of mecillinam was determined in thirteen isolates from study four [16], by E-test according…”
How did you ensure that the patients did not omit to administer some antibiotic doses?
Response: The adherence rates were high in each of the separate RCTs. The specific adherence rates can be viewed in each RCT article.
It is mandatory to present your results in another manner to make them more explicit. For example in percents
Response: Thank you for your comment. We have looked through the result section thoroughly. Unfortunately, we are not quite sure that we understand this comment. We have presented the results with percentages for each study respectively, and cumulatively for all studies. However, we have now moved the percentages up to immediately after the case data (eg. “26 out of 33 (79%”). Please, if we have misunderstood this comment; specify more and we will be glad to amend to it.
Reviewer 2 Report
The manuscript entitled "Pivmecillinam for uncomplicated lower urinary tract infections caused by Staphylococcus saprophyticus–cumulative observational data from four recent clinical studies," describe the outcomes of treatment of the lower urinary tract infection caused by S. saprophyticus, with a prodrug-pivmecillinam.
This reviewer has some minor questions/comments.
1. The organic structures of the pivmecillinam and mecillinam should be included in the paper.
2. Why was pivmecillinam chosen over other drugs targeting gram +ve pathogens?
3. In the case of study no. 4, did authors try synergy/combination therapy with different drugs for the cases where relapse/failure is the outcome?
4. The drug name and unit is not mentioned for MIC in SI table
5. In case study 4, why MIC against mecillinam was determined instead of pivmecillinam?
6. How three times daily conc./dose of pivmecillinam was determined?
7. Line 124-126, the sentence ‘On the other hand, high urine….…S. saprophyticus” is not clear.
Author Response
PEER-REVIEW nr 2
General response: Thank you for your peer-review and helpful comments.
Open Review
(x) I would not like to sign my review report
( ) I would like to sign my review report
English language and style
( ) Extensive editing of English language and style required
( ) Moderate English changes required
(x) English language and style are fine/minor spell check required
Response: Thank you. Minor spell and grammatical corrections have now been done.
( ) I don't feel qualified to judge about the English language and style
Yes | Can be improved | Must be improved | Not applicable | |
Does the introduction provide sufficient background and include all relevant references? | ( ) | ( ) | (x) | ( ) |
Is the research design appropriate? | (x) | ( ) | ( ) | ( ) |
Are the methods adequately described? | ( ) | (x) | ( ) | ( ) |
Are the results clearly presented? | ( ) | (x) | ( ) | ( ) |
Are the conclusions supported by the results? | ( ) | (x) | ( ) | ( ) |
Comments and Suggestions for Authors
The manuscript entitled "Pivmecillinam for uncomplicated lower urinary tract infections caused by Staphylococcus saprophyticus–cumulative observational data from four recent clinical studies," describe the outcomes of treatment of the lower urinary tract infection caused by S. saprophyticus, with a prodrug-pivmecillinam.
This reviewer has some minor questions/comments.
1. The organic structures of the pivmecillinam and mecillinam should be included in the paper.
Response: We have added information on the pharmacological properties in the introduction (marked with yellow).
2. Why was pivmecillinam chosen over other drugs targeting gram +ve pathogens?
Response: Treatment was initiated on symptoms alone (ie. empirically), and a urine sample was secured simultaneously.
3. In the case of study no. 4, did authors try synergy/combination therapy with different drugs for the cases where relapse/failure is the outcome?
Response: The primary physicians switched to another class of antibiotics. Synergism would be a good idea and something that is interesting to investigate in the future.
4. The drug name and unit is not mentioned for MIC in SI table
Response: Amended to MIC Mecillinam (mg/L)
5. In case study 4, why MIC against mecillinam was determined instead of pivmecillinam?
Response: Pivmecillinam (amdinocillin pivoxil) is the oral antimicrobial inactive prodrug of the antimicrobial active agent mecillinam (amdinocillin). Thus, MIC is determined for mecillinam since pivmecillinam lacks antimicrobial activity before the enzymatic hydrolysis of the pivoxil ester.
6. How three times daily conc./dose of pivmecillinam was determined?
Response: Three times daily is the customary dosing interval of pivmecillinam in Denmark and Norway. This is supported by theoretical considerations on PK/PD, based on PK data (Ref 5 in manuscript), clinical efficacy in ESBL (ref. 9-10 in manuscript) and E. coli susceptibility to mecillinam. Thus, the four randomized controlled trials used this interval.
7. Line 124-126, the sentence ‘On the other hand, high urine….…S. saprophyticus” is not clear.
Response: The section in yellow was added to make this sentence clearer. “On the other hand, high urine concentrations of mecillinam might alone explain the beneficiary effect of the antibiotic against S. saprophyticus, since MICs seem to be well below the peak urine concentration.”
