Berbari, Elie F.

Berendt, Anthony R.

Hanssen, Arlen

Lew, Daniel

Osmon, Douglas R.

Rao, Nalini

Steckelberg, James M.

Wilson, Walter R.

Zimmerli, Werner

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Reply to Eisen and Denholm,Dauchy et al, Fierer, andNguyen and JonesWe appreciate the opportunity to replyto the letters of Fierer [1], Eisen andDenholm [2], Dauchy et al [3], andNguyen and Jones [4]. We are also gladthat the publication of the Infectious Dis-eases Society of America (IDSA) guide-lines on prosthetic joint infection (PJI)has prompted additional discussion andhope that this eventually manifests asfurther research [5].Fierer [1] raises the important questionof rifampin dosing in PJI due to suscepti-ble staphylococci treated with debride-ment and retention. We recommendedthe dose as outlined in the only random-ized clinical trial to address this issue [6].In that trial, a dose of 450 mg orallytwice daily was used initially and de-creased to 300 mg orally twice daily iftoxicity occurred that did not requiredrug discontinuation. With oral rifampindoses of 300 mg or 450 mg, peak concen-trations of 4.0 µg/mL or 6 µg/mL, respec-tively, are reached. The trough level ofboth doses is >0.25 µg/mL at 12 hours(half-life: 2.5 hours). The 600-mg doseresults in a peak of 10 µg/mL, with atrough level at 24 hours of about 0.08 µg/mL (half-life: 3 hours) [7]. In view ofthe minimum inhibitory concentration(MIC) values of Staphylococcus aureus(0.008–0.15 µg/mL, MIC 90% [MIC90]:0.015 µg/mL) and Staphylococcus epider-midis (0.004–0.15 µg/mL, MIC90: 0.015µg/mL), all these regimens may be ade-quate [8]. The dose of 300–450 mg orallytwice daily as well as 600 mg orally oncedaily was also recently recommended in162 • CID 2013:57 (1 July) • CORRESPONDENCEthe IDSA guidelines for treatment ofmethicillin-resistant S. aureus [9].Eisen and Denholm [2] raise the ques-tion of the A1-level ranking of the recom-mendation for the use of rifampin forstaphylococcal PJI treated with debride-ment and retention. We followed theranking system as recommended by IDSAand the Canadian Task Force on the Pe-riodic Health Examination [5]. Thatdocument states there must be at least 1randomized trial to give it a rank of A1.We regret the typographical error intable 1 of the PJI guidelines [5], whichstates >1 rather than ≥1. The panel be-lieves there is ample evidence to supportthe use of rifampin for this indication asoutlined in the PJI guidelines.Dauchy et al [3] raise multiple ques-tions. The panel did not recommendcutoffs for C-reactive protein and sedi-mentation rate, as different authors haveused different cutoffs. We believe what isabnormal for these tests should be left tothe clinician and the laboratory they areutilizing. We state in the footnote of table2 [5] that the vancomycin dose should bebased on serum levels and that optimalserum levels will depend on the patho-gen. In addition, optimal serum levels areunknown if local antimicrobial therapy isused, such as when a spacer is usedduring 2-stage exchange or when vanco-mycin is used in conjunction with rifam-pin. We believe we clariﬁed the issue ofduration of therapy as best we couldbased on the available evidence andexpert opinion. We clearly stated wherethere was and was not consensus regard-ing the use of chronic oral suppressiongiven the data available for the varioussurgical procedures including debride-ment and retention and 1-stage ex-change. We think more research iswarranted to clarify this issue further andstated so in the “research gaps” section ofthe guidelines. It is true we did not makea deﬁnitive recommendation for 1-stageexchange for joint arthroplasties otherthan for hip arthroplasty. We agree withthe authors that, since our literaturereview was completed, additional infor-mation has become available to suggestthat 1-stage exchange for total knee ar-throplasty infection may be useful [10,11]. We look forward to additional infor-mation becoming available.Last, Nguyen and Jones [4] raise theimportant question about the optimaldose of ceftriaxone for the treatmentof oxacillin- and ceftriaxone-susceptiblestaphylococci based on the oxacillinMIC. We understand the argument forthe 2- to 4-g dose of ceftriaxone every12–24 hours as outlined by the authorsin their letter but also recognized, basedon the references cited by the authors aswell as additional references included inthe PJI guidelines [12, 13], that a dose of1–2 g every 24 hours has been success-fully used by investigators to treat PJIdue to susceptible staphylococci. It wason the basis of this information that werecommended a dosing range of 1–2 gevery 24 hours. We also clearly state thatwe could not reach consensus about theuse of ceftriaxone in general for the treat-ment ofmethicillin-sensitive, ceftriaxone-susceptible staphylococci. Certainlywhereceftriaxone has formed a signiﬁcant com-ponent of intravenous antibiotic therapy,we are aware that it was commonly usedto support outpatient parenteral antibi-otic therapy (OPAT) and would mainlyhave been preceded by a period of high-dose anti-staphylococcal penicillin thera-py in the immediate postoperative periodand for some days prior to patient dis-charge into a OPAT program. Initiatingtreatment with ceftriaxone in the face ofhigh bacterial burdens may pose differ-ent risks to doing so after a formal surgi-cal debridement either as part ofa debridement and implant retention(DAIR) procedure or at revision surgery,when the bacterial burden has been dra-matically reduced. Furthermore, whenused as part of a DAIR strategy, ceftriax-one was itself followed by extendedtherapy with, usually, a ﬂuoroquinoloneand rifampin. These complexities, andthe fact that failures of treatment havebeen seen to occur both during therapy(of any kind) and when antibiotics arestopped, do make it hard to be certainwhether the theoretical concerns fromNguyen and Jones, based as they aremainly on MIC data, give a genuinecause for concern in the real world.We agree that clinicians should con-sider all information, including theguidelines and the information outlinedby Nguyen and Jones [4] (as well as thefact that pharmacokinetic/pharmacody-namic predications may not reﬂect thedosage of a particular drug required inthe setting of the use of combinationtherapy with rifampin or procedureswhere antibiotic-impregnated spacers areused), when they are making treatmentdecisions for individual patients.As with many aspects of the diagnosisand treatment of PJI, there may be multi-ple ways to successfully manage thesemost difﬁcult infections; additional re-search is needed to deﬁne optimal treat-ment strategies.NotePotential conﬂicts of interest. The followinglist is a reﬂection of what has been reported toIDSA. In order to provide thorough transparen-cy, IDSA requires full disclosure of all relation-ships, regardless of relevancy to the guidelinetopic. The reader of these guidelines should bemindful of this when the list of disclosures is re-viewed.D. R. O. has received research grants fromCubist Pharmaceuticals and Ortho-McNeil.E. F. B. has received funding from Cubist Phar-maceuticals, Ortho McNeil, Orthopedic Re-search, and Education Foundation and Mayo.A. H. has received royalties from Stryker Corpfor hip/knee design. W. Z. has served as a boardmember of Pﬁzer and on the speakers’ bureaus ofPﬁzer and Synthes, Inc. D. L. is a member of theBoard of Basilea. A. R. B. was awarded a PﬁzerVisiting Professorship to the Department ofAllergy and Infectious Diseases at the Universityof Washington, Seattle. All other authors reportno potential conﬂicts.All authors have submitted the ICMJE Formfor Disclosure of Potential Conﬂicts of Interest.Conﬂicts that the editors consider relevant to thecontent of the manuscript have been disclosed.CORRESPONDENCE • CID 2013:57 (1 July) • 163Douglas R. Osmon,1 Elie F. Berbari,1 AnthonyR. Berendt,2,3 Daniel Lew,4 Werner Zimmerli,5James M. Steckelberg,1 Nalini Rao,6,7Arlen Hanssen,8 and Walter R. Wilson11Division of Infectious Diseases, Mayo Clinic Collegeof Medicine, Rochester, Minnesota; 2Bone InfectionUnit, Nufﬁeld Orthopaedic Centre, and 3UniversityHospitals NHS Trust, Oxford, United Kingdom;4Division of Infectious Diseases, Department ofInternal Medicine, University of Geneva Hospitals, and5Basel University Medical Clinic, Liestal, Switzerland;6Division of Infectious Diseases, Department ofMedicine and 7Department of Orthopaedic Surgery,University of Pittsburgh School of Medicine,Pennsylvania; and 8Department of Orthopedics, MayoClinic College of Medicine, Rochester, MinnesotaReferences1. Fierer J. Dosing rifampin. Clin Infect Dis2013; 57:161.2. Eisen DP, Denholm JS. Recommendationsfor rifampicin therapy of staphylococcal in-fection in Infectious Diseases Society ofAmerica prosthetic joint infection guidelinesare not supported by available literature. ClinInfect Dis 2013; 57:159–60.3. Dauchy FA, Dutronc H, Cazanave C, DuponM. Infectious Diseases Society of Americaguidelines for the diagnosis and manage-ment of prosthetic joint infection: what is thecorrect duration of antibiotic treatment? ClinInfect Dis 2013; 57:160–1.4. Nguyen HM, Jones RN. Treatment ofmethicillin-susceptible Staphylococcus aureusosteoarticular and prosthetic joint infections:using the oxacillin minimum inhibitory con-centration to guide appropriate ceftriaxoneuse. Clin Infect Dis 2013; 57:161–2.5. Osmon DR, Berbari EF, Berendt AR, et al.Diagnosis and management of prostheticjoint infection: clinical practice guidelines bythe Infectious Diseases Society of America.Clin Infect Dis 2013; 56:e1–25.6. Zimmerli W, Widmer AF, Blatter M, et al.Role of rifampin for treatment of orthopedicimplant-related staphylococcal infections: arandomized controlled trial. Foreign-BodyInfection (FBI) Study Group. JAMA 1998;279:1537–41.7. Acocella G. Pharmacokinetics and metabo-lism of rifampin in humans. Rev Infect Dis1983; 5(S3):S428–32.8. Thornsberry C, Hill BC, Swenson JM,McDougal LK. Rifampin: Spectrum of anti-bacterial activity. Rev Infect Dis 1983; 5(S3):S412–7.9. Liu C, Bayer A, Cosgrove SE, et al. Clinicalpractice guidelines by the Infectious DiseasesSociety of America for the treatment ofmethicillin-resistant Staphylococcus aureusinfections in adults and children. Clin InfectDis 2011; 52:e18–55.10. Jenny JY, Barbe B, Gaudias J, Boeri C, Argen-son JN. High infection control rate and func-tion after routine one-stage exchange forchronically infected TKA. Clin Orthop RelatRes 2013; 471:238–43.11. Singer J, Merz A, Frommelt L, Fink B. Highrate of infection control with one-stage revi-sion of septic knee prostheses excludingMRSA and MRSE. Clin Orthop Relat Res2012; 470:1461–71.12. Bejon P, Berendt A, Atkins BL, et al. Two-stage revision for prosthetic joint infection:predictors of outcome and the role of reim-plantation microbiology. J Antimicrob Che-mother 2010; 65:569–75.13. Byren I, Bejon P, Atkins BL, et al. Onehundred and twelve infected arthroplastiestreated with “DAIR” (debridement, antibiot-ics and implant retention): antibiotic dura-tion and outcome. J Antimicrob Chemother2009; 63:1264–71. Erratum in J AntimicrobChemother 2011; 66:1203.Correspondence: Douglas R. Osmon, MD, Division of Infec-tious Diseases, Department of Internal Medicine, Mayo ClinicCollege of Medicine, 200 First St SW, Marian Hall 5, Roches-ter, MN 55905 (osmon.douglas@mayo.edu).Clinical Infectious Diseases 2013;57(1):162–4© The Author 2013. Published by Oxford University Presson behalf of the Infectious Diseases Society of America. Allrights reserved. For Permissions, please e-mail: journals.permissions@oup.com.DOI: 10.1093/cid/cit189164 • CID 2013:57 (1 July) • CORRESPONDENCE

Reply to Eisen and Denholm, Dauchy et al, Fierer, and Nguyen and Jones

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