Author s response to reviews

Transcription

1 Author s response to reviews Title: Outcome of patients with streptococcal prosthetic joint infections with special reference to rifampicin combinations Authors: Elise Fiaux (elise.fiaux@hotmail.fr) Marie Titecat (m.titecat@orange.fr) Olivier Robineau (orobineau@ch-tourcoing.fr) Jaime Lora-Tamayo (sirsilverdelea@yahoo.com) Youssef ElSamad (elsamad.youssef@chu-amiens.fr) Manuel Etienne (Manuel.Etienne@chu-rouen.fr) Noelle Frebourg (noelle.frebourg@chu-rouen.fr) Nicolas Blondiaux (nblondiaux@ch-tourcoing.fr) Benoit Brunschweiler (Brunschweiler.Benoit@chu-amiens.fr) Franck Dujardin (franck.dujardin@chu-rouen.fr) Eric Beltrand (ebeltrand@ch-tourcoing.fr) Caroline Loïez (Caroline.LOIEZ@chru-lille.fr) Vincent Cattoir (cattoir-v@chu-caen.fr) Patrice Mertl (mertl.patrice@chu-amiens.fr) Michel Valette (mvalette@ch-toucoing.fr) Sophie Nguyen (snguyen@ch-tourcoing.fr) François Caron (Francois.Caron@chu-rouen.fr) Henri Migaud (Henri.MIGAUD@chru-lille.fr) Eric Senneville (senneric670@gmail.com) Version: 1 Date: 19 May 2016

2 Author s response to reviews: Dear Editor-in-Chief, Many thanks for giving us the opportunity to revise the manuscript of our study on streptococcal prosthetic joint infections. We greatly appreciated the remarks and comments of Reviewer 1, 2 and 3. We have responded point by point to all the questions and demands of clarifications or modifications in the presentation of the data. Thanks to the Reviewers remarks, we think that our revised manuscript is now much better than the original version. We provide two documents attached to the present letter: the detailed responses to the three Reviewers and a revised version of our manuscript taking into account all the Reviewers' remarks. As we mention in the first document we were unable to answer the second question of Reviewer 2 simply because we did not understand the sense of the question; however, we could provide the required numeric data in Figure 1, as required. I am looking forward to hearing from you. Best regards, Éric Senneville, MD, PhD, on behalf of the co-authors Reviewer reports: Reviewer #1: This is an interesting article providing supplementary data on streptococcal PJI Is suitable for publication however the authors need to revise their manuscripts providing answers for theses questions: - In the Abstract: section results: provide the multivariate analysis We have added the following sentence in the Abstract section: The only independent variable significantly associated with the patients outcomes was the location of the prosthesis (i.e., hip versus knee) (OR = 0.19; 95%CI ; p value 0.04). - results: does patient with others rifampicin combinations failed in the same proportion as levofloxacin -rifampicin combinations : if so why is the hypothesis

3 The data are reported in Figure 1 but as the numeric data are not reported, we have added the following sentence in the Results section: Patients treated with rifampicin-levofloxacin and other rifampicin combinations had comparable remission rates [20/24 (16.7%) and 16/20 (20%), respectively; P=0.09)]. We are sorry but we do not understand the sentence" if so why is the hypothesis" and are therefore unable to give an answer - How was defined malnutrition? provide the definitions in the text not only in table(foot note) We have added the following sentence in the methods section:.., malnutrition defined as albuminemia under 35 mg/l,.. - In the discussion section: can you give a theorytical mechanism to explain the efficacy of rifampicin combinations on Streptococcal PJI We must admit that the rational for using rifampicin combinations for the treatment of prosthetic joint infections is limited. We have data coming from the experimental studies conducted by Holmberg et al. showing the beneficial effect of rifampin in an experimental model mimicking PJI due to Enterococcus spp. especially in young biofilms (ref 17 of the paper). No equivalent studies are available for streptococci. However, enterococci are like staphylococci and enterococci Gram positive cocci and it is notable that the beneficial role of fluoroquinolones for the treatment of Gram negative bacilli-related PJIs is admitted without questioning the influence of the type of strain involved, provided it is susceptible to fluoroquinolones. We have added the following sentence in the Discussion section: The rational for using rifampicin-combinations in patients with streptococcal PJIs is limited. Holmberg et al. have shown the beneficial effect of rifampin in an experimental model mimicking PJI due to Enterococcus spp., especially in young biofilms (17). No equivalent studies are currently available for streptococci. However, enterococci are like staphylococci and enterococci Gram positive cocci and it is notable that the beneficial role of fluoroquinolones for the treatment of Gram negative bacilli-related PJIs is admitted without questioning the influence of the type of strain involved, provided it is susceptible to fluoroquinolones. - in conclusions give perspective: how can we proceed to demonstrate that really rifampicin in useful in streptococcal PJI

4 Authors' response: We have added the following sentence in the Conclusions section (last sentence) However, prospective randomized controlled studies would be needed to assess with certainty the role of rifampicin combinations for the treatment of patients with streptococcal PJIs. Reviewer #2: Page 4, lines 8-10: The authors should review the percentages that come with the reference 1. We thank Reviewer 2 for his remark and have corrected the data coming from Reference 1. The sentence is now: Streptococcus spp. are responsible for 9 to 10% of PJIs and represent the second cause of PJIs due to Gram-positive cocci (1). Page 4, lines 53-58: The authors should consider rewriting the sentence because the relationship between streptococci antimicrobial therapy with Enterococci is not made clear. We agree with this remark and have modified the sentence as follows: Although enterocci and streptococci are not quite similar in terms of virulence and antimicrobial susceptibility, it is however notable that a recent in vitro study showed the superiority of rifampicin-ciprofloxacin combination when compared to amoxicillin or linezolid rifampicin combinations on Enterococcus faecalis biofilms formed on plastic (17). Page 8, line 58: The authors should include the year of the guide used. We added the year of the guide from the CASFM recommendations ni the following sentence: The diffusion agar technique was used in each case, and the procedure and interpretation of the susceptibility tests were performed in accordance with CA-SFM (Comité de l Antibiogramme de la Société Française de Microbiologie; annual guides from 2001 to 2011) recommendations ( sfm.asso.fr). Page 8, lines 40-60: The authors should include the different types of samples processed and the microbiologic diagnosis employed to obtain the bacterial isolation, because it may influence the microbiological profitability. For example, conventional culture method or sonication.

5 We have added the following sentence: In each case, at least 5 peroperative samples were taken and transported within two hours to the microbiology laboratory. Solid specimens were beforehand crushed by vortexing (in 1 ml of sterile saline solution for 1 min) with sterile glass beads in order to extract bacteria from biofilm. Gram staining was performed for standard samples. After direct examination, standard samples (fluid specimens and tissue homogenate samples) were inoculated onto chocolate agar plus PolyViteX (biomérieux, Marcy l'etoile, France), into brain heart broth at 35 C for 15 days. Sonication of the samples including removed implants was not used. Page 10, line 6: The authors should include the specific microbiological identification, genus and specie, for the "β-hemolitic streptococci separate from the group B streptococci". We agree and have modified the sentence as follows: Among the 95 episodes of streptococcal PJIs, 37 were identified as (38.9%) group B streptococci, 31 (32.6%) as viridans group streptococci separate from the milleri-group, 15 (15.8%) as millerigroup streptococci, and 12 (12.6%) as β-hemolytic streptococci separate from the group B, including 4 of group A, 2 of group C and 6 of group G. Page 10, line 15: The authors should identify the microorganisms involved in the episodes related with concomitant bacteremia. We agree and have modified the sentence as follows: Nineteen (20%) episodes were associated with concomitant bacteremia due to the same streptococcal strain (i.e., 5 S. anginosus, 1 S. bovis, 5 S. constellatus, 2 S. mitis, 2 S. durans and 4 S. oralis) including 6 episodes of infective endocarditis (i.e., 1 S. bovis, 2 S. mitis, 2 S. durans and 1 S. oralis). Page 14, line 18: The authors should include the French guidelines reference for the treatment of PJI

6 We have added the corresponding reference and have modified the numbering of the following references in the texte and in the reference list Recommendations for clinical practice. Osteo-articular infection therapy according to materials used (prosthesis, implants, osteosynthesis).société de Pathologie Infectieuse de Langue Française (SPILF); Collège des Universitaires de Maladies Infectieuses et Tropicales (CMIT); Groupe de Pathologie Infectieuse Pédiatrique (GPIP); Société Française d'anesthésie et de Réanimation (SFAR); Société Française de Chirurgie Orthopédique et Traumatologique (SOFCOT); Société Française d'hygiène Hospitalière (SFHH); Société Française de Médecine Nucléaire (SFMN); Société Française de Médecine Physique et de Réadaptation (SOFMER); Société Française de Microbiologie (SFM); Société Française de Radiologie (SFR-Rad); Société rançaise de Rhumatologie (SFR-Rhu). Med Mal Infect 2009; 39: References: The authors should review the reference 9. The complete title it is not included We thank Reviewer 2 for his helpful remark and have corrected the reference N 9 as : Zimmerli W, Widmer A, Blatter M, Frei R, Ochsner PE. Role of rifampin for treatment of orthopedic implant-related staphylococcal infections: a randomized controlled trial. Foreign- Body Infection (FBI) Study Group. JAMA. 1998;279: Reviewer #3: The article entitled: "Outcome of patients with streptococcal prosthetic joint infections with special reference to rifampicin combinations" is a large retrospective revision of PJI due to Streptococcus spp. The article is clear and there are important new concepts that are of great interest for the readers about the management of these infections. Some comments: 1.- in table 2, fever was present in 5 patients but in table 3 in 35+17, please clarify. Fifty-two patients had fever; we have corrected the typing error in Table 2 as: Fever 52 (54.7) 2.- DAIR was clearly associated with failure and also there was a trend in haematogenous infections (table 3). How many patients in DAIR group had an haematogenous PJI? And which was the outcome in these patients in comparison to post-op cases? There are reports showing that haematogenous cases have significantly worse outcome (Rodriguez D, et al Clin Microbiol Infect 2010; 16: 1789).

7 We agree with this remark as of 4 patients with haematogenous infection who were treated with DAIR, 3 (75%) failed which is consistent with the results of the study from Rodriguez et al. We have added the following sentences: - In the results section: and 3 in 4 patients (75%) with PJIs of haematogenous origin treated with DAIR failed. - In the discussion section: The high failure rate recorded in our patients with streptococcal PJIs of haematogenous origin treated with DAIR is consistent with the study from Rodriguez et al. showing a worse outcome of haematogenous PJIs treated with DAIR in comparison to postoperative cases (26). and have added the corresponding reference: Rodríguez D, Pigrau C, Euba G, Cobo J, García-Lechuz J, Palomino J, et al.; REIPI Group (Spanish Network for Research in Infectious Disease). Acute haematogenous prosthetic joint infection: prospective evaluation of medical and surgical management. Clin Microbiol Infect 2010; 16: DAIR meant only 1 debridement? Or some patients required more than 1 debridement? Do you have this information? Yes; we have added the data in the Resulst section: 4 patients treated with DAIR required two debridements. 4.- Rifampin was added after a period of iv treatment, probably with a b-lact in monotherapy. It would be possible that some patients fail during iv therapy before switching to oral treatment. In order to evaluate the benefit of rifampin combinations, it would be interesting to describe the outcome of those patients that started oral treatment with different regimens. No patients failed during the treatment period prior to the oral switch; all the failures were recorded after 20 days of pos-operative antibiotic treatment 5.- Do you have the time from surgery to failure/remission, it would be interesting to see the survival curve for DAIR vs implant removal. We performed a survival curve (Kaplan-Meier) comparing DAIR patients with those treated with removal of the infected implants :

8 We agree with Reviewer 3 that the representation is more accurate than the data reported in Table 3; we take this opportunity to thank Reviewer 3 for his comment and helpful proposition Figure 2 : Kaplan-Meier curves of the probability of failure-free period according to the surgical strategy (i.e., Debridement, Antibiotics and Implant Retention-DAIR versus removal of the implants) of 95 episodes of streptococcal prosthetic joint infections *: Log-rank test