Efficacy of Cloxacillin Versus Cefazolin for Methicillin-Susceptible

BMJ Open: first published as 10.1136/bmjopen-2018-023151 on 1 September 2018. Downloaded from

PEER REVIEW HISTORY

BMJ Open publishes all reviews undertaken for accepted manuscripts. Reviewers are asked to complete a checklist review form (http://bmjopen.bmj.com/site/about/resources/checklist.pdf) and are provided with free text boxes to elaborate on their assessment. These free text comments are reproduced below.

This paper was submitted to a another journal from BMJ but declined for publication following peer review. The authors addressed the reviewers’ comments and submitted the revised paper to BMJ Open. The paper was subsequently accepted for publication at BMJ Open.

(This paper received three reviews from its previous journal but only two reviewers agreed to published their review.)

ARTICLE DETAILS

TITLE (PROVISIONAL) Efficacy of cloxacillin versus cefazolin for methicillin-susceptible Staphylococcus aureus bacteremia (CloCeBa): study protocol for a randomized, controlled, non-inferiority trial

AUTHORS Burdet, Charles; Loubet, Paul; Le Moing, Vincent; Vindrios, William; Esposito-farese, Marina; Linard, Morgane; Ferry, Tristan; Massias, Laurent; Tattevin, P.; Wolff, Michel; Vandenesch, François; Grall, Nathalie; Quintin, Caroline; Mentré, France; Duval, Xavier; Lescure, François-Xavier

VERSION 1 – REVIEW

REVIEWER Nathaniel J. Rhodes

Chicago College of Pharmacy, Midwestern University, USA http://bmjopen.bmj.com/ REVIEW RETURNED 23-Apr-2018

GENERAL COMMENTS Burdet and colleagues propose to conduct a randomized open- label non inferiority study of cloxacillin versus cefazolin for MSSA bacteremia. The authors are to be commended for attempting to address this important problem and fill a gap in the literature regarding the comparative efficacy of these compounds directly for

serious MSSA infections. My comments are focused on on September 27, 2021 by guest. Protected copyright. maximizing the generalizability and robustness of the authors study and ensuring full transparency of the study.

Major comments:

1. The protocol presented herein was compared to the clinicaltrials.gov entry for "Non-inferiority Trial Comparing Cloxacillin vs Cefazolin in Methicillin-susceptible Staphylococcus Aureus Bacteremia (CLOCEBA) NCT03248063." Important differences exist. Oral switching is discussed in the protocol but not at clinicaltrials.gov in the treatment intervention. This is important as many clinicians will need to know what the protocol is before referring patients for enrollment.

6 weeks of IV antibiotics for serious complex staph infections. Thus, it is unclear what role there is for oral therapy and how the authors envision oral conversion taking place. Currently, it is unsatisfyingly described as "at the discretion of the clinician in charge."

7. The non-inferiority assumptions appear somewhat optimistic. Retrospective studies suggest that cefazolin is categorically better that ASPs under many circumstances. However, there is inherent biases in these studies as the authors rightly point out: namely selection bias for less severely ill patients with less complex infections. If the success rates differ from the authors' initial forecasts, a sample size of up to 1000 patients may be necessary. on September 27, 2021 by guest. Protected copyright. Minor comments: English copy editing and grammatical edits needed throughout.

Trial status: the dates of enrollment are to be included per journal requirements. Please add this from the clinicaltrials.gov entry 6/2018-6/2022.

REVIEWER Joseph Rindone VA Medical Center Prescott, Arizona USA REVIEW RETURNED 01-May-2018

GENERAL COMMENTS This review of this important trial is complete and straightforward. The only section I am not sure about is the non-inclusion section, # 6. Are all patients with endocarditis excluded?

BMJ Open: first published as 10.1136/bmjopen-2018-023151 on 1 September 2018. Downloaded from

VERSION 1 – AUTHOR RESPONSE Reviewer: 1 Burdet and colleagues propose to conduct a randomized open-label non inferiority study of cloxacillin versus cefazolin for MSSA bacteremia. The authors are to be commended for attempting to address this important problem and fill a gap in the literature regarding the comparative efficacy of these compounds directly for serious MSSA infections. My comments are focused on maximizing the generalizability and robustness of the authors study and ensuring full transparency of the study.

Major comments: 1. The protocol presented herein was compared to the clinicaltrials.gov entry for "Non-inferiority Trial Comparing Cloxacillin vs Cefazolin in Methicillin-susceptible Staphylococcus Aureus Bacteremia (CLOCEBA) NCT03248063." Important differences exist. Oral switching is discussed in the protocol but not at clinicaltrials.gov in the treatment intervention. This is important as many clinicians will need to know what the protocol is before referring patients for enrollment. Indeed the presentation of the protocol made on the clinicaltrials.gov website was not precise enough. We detailed the possibility of an oral switching on clinicaltrials.gov and added the following sentence on the description of the intervention (lines 208-211): “As currently recommended, investigators will be encouraged to use the intravenous route for the entire duration of treatment. However, in order to interfere as little as possible with usual practice in each center, the antimicrobial therapy will be let to the choice of the physician in charge of the patient after a minimum of 7 days of intravenous treatment.”

2. Oral therapy is not defined or described in the protocol. Oral beta-lactams are only acceptable under very limited circumstances. The clinical standard of practice is to administer 4-6 weeks of IV antibiotics for serious complex staph infections. Thus, it is unclear what role there is for oral therapy and how the authors envision oral conversion taking place. Currently, it is unsatisfyingly described as "at the discretion of the clinician in charge." Indeed we did not describe the oral switch of antimicrobial treatment in the protocol. The present trial aims at comparing the effectiveness of cefazolin and cloxacillin for the treatment of MSSA infections. Although current recommendations are to treat by the intravenous route for the entire treatment duration, it is common in France to switch to oral therapy after 7-10 days of intravenous treatment. There are many oral antibiotic treatment might be given for treatment of MSSA infections, and it appeared quite complicated to define an algorithm for oral switch. Indeed, various resistance profiles

could be exhibited by the bacterial strain isolated, and the patients himself could exhibit numerous http://bmjopen.bmj.com/ medical conditions and / or co-treatment that precluded to specify all possible cases for switching from cloxacillin or cefazolin. In addition, we wanted to constraint as little as possible the physician in charge of the patients in order to mimic the usual practice of each center. However, we agree that the sentence was not detailed enough and we added the following sentences (lines 208-211): “As currently recommended, investigators will be encouraged to use the intravenous route for the entire duration of treatment. However, in order to interfere as little as possible with usual practice in each center, the antimicrobial therapy will be let to the choice of the physician in charge of the patient on September 27, 2021 by guest. Protected copyright. after a minimum of 7 days of intravenous treatment.”

3. The earliest time that oral switching can occur is at day 7 of therapy in the protocol. This is not consistent with standard management of the vast majority of complex MSSA infections in the U.S. and likely not in many countries. If a significant fraction of patients receive early (i.e., before day 14) oral therapy, there will be questions about the severity of illness of the population and generalizability of the results. No severity of illness assessments or scoring is proposed, limiting generalizability further. We agree with this remark, however it is quite common in France to switch intravenous treatment for oral treatment when the clinical condition of the patient improves. For instance, uncomplicated MSSA bacteremia or arthritis are commonly switched to oral treatment after 7-10 days of IV treatment. As noted in the 4th remark of the reviewer, we tried to homogenize the patients’ population by excluding patients with complex MSSA infections, such as infections involving the central nervous system or intravascular implants. Including all MSSA infections whatever their complexity would have resulted in a very heterogeneous patients populations with the risk of being inconclusive.

BMJ Open: first published as 10.1136/bmjopen-2018-023151 on 1 September 2018. Downloaded from

4. The inclusion and exclusion, while pragmatic, also necessitate that many endocarditis and dialysis patients are excluded due to possible CNS involvement or intravascular devices or CRCL cutoffs. Thus, a gap will remain in these patient populations. Discussion of the ethics of not evaluating/including these patients who suffer the most from MSSA infections is warranted. Based on data we have previously published (V Le Moing, Plos One 2015) on a cohort of 2 081 Staphylococcus aureus bacteremia patients, the rate of patients with endocarditis and or hemodialysis is around 20%.We agree that excluding these patients will reduce the external validity of our results. However, we think that these conditions are highly specific and need specific studies. We have acknowledged this limitation in the “limitation” section of the manuscript.

5. The evidence linking cefazolin to low CNS concentrations is quite poor. The authors should seriously re-consider whether CNS infections will be excluded. They have an opportunity to dispel old myths in this domain. It should certainly be considered because equipoise still exists in this population. Based on the study mentioned above, the rate of central nervous infections excluding those related to IE, is low (1%). Given this rate, and the severity of the infection, we preferred to exclude these patients. We have also acknowledged this limitation in the “limitations” section of the manuscript.

6. The stated rational for not blinding study personnel and patients is based on the number of infusions. This has been resolved and dealt with by the BLING investigators (e.g., Roberts and Lipman et al.). Running both drugs as continuous infusions would ameliorate this issue. The evidence would be greatly strengthened by allocation concealment and blinding. We agree that a continuous infusion of both drugs would alleviate the issue of blinding. However, we decided to use intermittent infusion after consulting all participating centers on the possibility for them to administer the antibiotic treatment by continuous infusion. Only a few centers responded positively, and we thus decided to continue with intermittent infusion. In addition, the trial is now opening and changing the mode of infusion would necessitate an amendment to the protocol to obtain a new agreement from the health authorities and the ethics committee, which had both been already obtained.

7. The non-inferiority assumptions appear somewhat optimistic. Retrospective studies suggest that cefazolin is categorically better that ASPs under many circumstances. However, there is inherent biases in these studies as the authors rightly point out: namely selection bias for less severely ill patients with less complex infections. If the success rates differ from the authors' initial forecasts, a http://bmjopen.bmj.com/ sample size of up to 1000 patients may be necessary. Yes that’s true, however we used available data for computing the sample size and did not find data for the exact patient’s population that is studied in the CloCeBa trial.

Minor comments: English copy editing and grammatical edits needed throughout. Thank you for this advice, this has been verified.

Trial status: the dates of enrollment are to be included per journal requirements. Please add this from on September 27, 2021 by guest. Protected copyright. the clinicaltrials.gov entry 6/2018-6/2022. This has been added (line 378).

Reviewer: 2 This review of this important trial is complete and straightforward. The only section I am not sure about is the non-inclusion section, # 6. Are all patients with endocarditis excluded? We agree with the reviewer that this criterion was not precise enough. As explained in the response to the remarks of Nathaniel J. Rhodes, we aimed at excluding from the trial patients with complex MSSA infections, such as those with CNS involvement. Patients with endocarditis will be eligible if they do not present with central neurological symptoms at the time of enrollment.

VERSION 2 – REVIEW

REVIEWER Nathaniel J. Rhodes, PharmD, MSc Midwestern University, Chicago College of Pharmacy USA REVIEW RETURNED 25-Jun-2018

BMJ Open: first published as 10.1136/bmjopen-2018-023151 on 1 September 2018. Downloaded from

GENERAL COMMENTS Burdet and colleagues present their revised methods description for CloCeBa, a randomized comparison of cloxacillin and cefazolin for MSSA bloodstream infections. As the study appears to be underway and the investigators are unable to make substantive revisions at this stage, I will focus comments on just a few aspects of the work. Overall, the work is important and will produce meaningful insights into MSSA therapy and optimal treatment.

Major comments: how will patients undergoing oral switching after 7 days be handled in analysis? Will they be treated as eligible for PP? Currently, the PP population is defined by 14 days of therapy but it is not clear if a minimum of 7 or 14 days of IV is required for PP inclusion. A more conservative approach would be to exclude IV to oral switches from the PP analysis.

Minor comments: Line 113: unsure of use of valorization here. Perhaps another word was intended.

Line 224: "let to the choice of the investigator" should be "left to the choice of the investigator"

Line 218 and 261, Consensual should be consensus

VERSION 2 – AUTHOR RESPONSE

Reviewer: 1 Burdet and colleagues present their revised methods description for CloCeBa, a randomized comparison of cloxacillin and cefazolin for MSSA bloodstream infections. As the study appears to be underway and the investigators are unable to make substantive revisions at this stage, I will focus comments on just a few aspects of the work. Overall, the work is important and will produce meaningful insights into MSSA therapy and optimal treatment. http://bmjopen.bmj.com/ Major comments: how will patients undergoing oral switching after 7 days be handled in analysis? Will they be treated as eligible for PP? Currently, the PP population is defined by 14 days of therapy but it is not clear if a minimum of 7 or 14 days of IV is required for PP inclusion. A more conservative approach would be to exclude IV to oral switches from the PP analysis. We agree with the reviewer that this definition of the per protocol population requires clarification. Following the experimental design of the CloCeBa trial, the antimicrobial therapy will last at least 14 days, and will be left to the choice of the physician in charge of the patient after a minimum of 7 days of the intravenous treatment assigned by randomization. A full course of antibiotic treatment by the on September 27, 2021 by guest. Protected copyright. intravenous route will be encouraged, however, an oral switch is common in France after 7-10 days of intravenous treatment. We thus changed the sentence defining the per protocol population for the following : “The per protocol population is defined by all patients treated by antimicrobial for at least 14 days, including intravenous cefazolin or cloxacillin for the first 7 days following inclusion, irrespective of the randomization arm.” (lines 311-313).

Minor comments: We thank the reviewer for his corrections that were all taken into consideration.

Line 113: unsure of use of valorization here. Perhaps another word was intended. Indeed this sentence was unclear. We changed the word “valorization” for ‘publication” (line 134).

Line 224: "let to the choice of the investigator" should be "left to the choice of the investigator". This has been modified (lines 210 and 219).

Line 218 and 261, Consensual should be consensus. This has been modified (lines 213 and 256).