Sendi, Parham

Zimmerli, Werner

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EDITORIAL COMMENTARY • CID 2010:50 (1 January) • 17E D I T O R I A L C O M M E N T A R YAntibiotics for Prevention of Periprosthetic Joint InfectionFollowing Dentistry: Time to Focus on DataWerner Zimmerli1 and Parham Sendi1,21Unit of Infectious Diseases, Basel University Medical Clinic, Liestal, and 2University Clinic for Infectious Diseases, University Hospital Bern and University of Bern,Switzerland(See the article by Berbari et al, on pages 8–16.)The population of individuals with arti-ficial joints is steadily increasing, becausemore devices are implanted, and the lifespan of people with implants is longer.During a 10-year period, the total numberof knee replacements increased from270,000 to 550,000 per year, and the totalnumber of total hip replacements in-creased from 120,000 to 200,000 per yearin the United States [1]. Prosthetic joint–associated infection (PJI) is a devastatingcomplication that occurs in 0.3%–1% ofthose patients who undergo total hip ar-throplasty and in 1%–2% of patients aftertotal knee arthroplasty [2]. Of these epi-sodes, 35%–40% occur by the hematog-enous route [3]. Most of these episodesare sequelae of Staphylococcus aureus sep-sis, skin infection, or urosepsis [4–6].It is conceivable that a small portion ofthese PJI episodes are caused by transi-tional bacteremia during dental work.However, clinical experience does not fa-vour this hypothesis, and to date, only fewindirect data were available for discussion.Received 2 September 2009; accepted 2 September 2009;electronically published 1 December 2009.Reprints and correspondence: Dr. Werner Zimmerli, Unit ofInfectious Diseases, Basel University Medical Clinic, Rheinstrasse26, CH-4410 Liestal, Switzerland (werner.zimmerli@unibas.ch).Clinical Infectious Diseases 2010; 50:17–9 2009 by the Infectious Diseases Society of America. Allrights reserved. For permission to reuse, please contactjournalpermissions@press.uchicago.edu.1058-4838/2010/5001-0003$15.00DOI: 10.1086/648677The potential origin of !10% of the mi-croorganisms isolated from individualswith PJI is oral or dental [7]. In a studyof 189 episodes of late infection that oc-curred after total joint replacement, only4 (2.1%) of the episodes were due to vir-idans streptococci [8]. Moreover, a poten-tial oral or dental origin is less likely to belinked to a dental procedure than to poordental hygiene. Bartzokas et al [9] re-ported 4 cases in which the infecting or-ganism in the prosthesis was indistin-guishable from isolates of the same speciesobtained from the oral flora on cell wallpolypeptide electrophoresis. Examinationof the patients’ mouths revealed perio-dontal disease and caries in all patients. Incontrast, and to the best of our knowledge,the molecular proof of hematogenouslycaused PJI as a direct sequel of previousdental treatment is still lacking. Neverthe-less, it cannot be excluded that a smallminority of hematogenous PJIs are causedby bacteremia directly triggered by dentalmanipulation. The rate of PJI attributableto bacteremia after dental procedures hasbeen estimated from 0 of 112 cases [6] to7 (0.2%) of 3490 cases [10].This low number of cases can be alsoexplained by the bacterial density and theduration of bacteremia during or afterdental manipulation. These 2 factors arecrucial for successful seeding on extravas-cular devices [11]. In an experimentalmodel, the presence of a foreign body de-creased the minimal abscess-forming dose1100,000 fold [12]. This is attributable toa locally acquired granulocyte defect [12].Therefore, implants may be endangeredduring episodes of bacteremia that are in-duced by dental manipulation. However,the density and duration of bacteremia ismuch lower during dental work than it isduring overt sepsis. After dental extractionin children, it ranges from 1 through 28colony-forming units (CFU) per milliliterof blood and does not exceed 15 min [13,14]. In a guinea pig model, the criticalbacterial density in the bloodstream re-sulting in permanent infection associatedwith extravascular foreign bodies was atleast 100 CFU S. aureus per mL blood [11].Similarly, in a rabbit prosthetic knee jointmodel, 3 intravascular injections of highdoses (1109 CFU) of S. aureus were re-quired to cause PJI [15]. This indicatesthat hematogenous PJI does not generallyoccur during transient low-inoculum bac-teremia but, rather, occurs during clini-cally overt sepsis.In view of the devastating consequencesof PJI, many experts have published theiropinion regarding the possible benefit ofantibiotic prophylaxis before dental workin patients with joint replacements. Noneof these publications was based on an ap-propriate clinical trial. Therefore, it doesnot astonish that some of the experts ar-18 • CID 2010:50 (1 January) • EDITORIAL COMMENTARYgued in favor of and others against pro-phylaxis [16, 17]. In this confusing situ-ation, the American Academy of Ortho-pedic Surgeons (AAOS) and the AmericanDental Association published a statementreflecting the panel opinion on this topic[18]. Interestingly, the original statementof an expert panel of dentists, orthopedicsurgeons, and infectious disease specialistsconcluded that “antibiotic prophylaxis isnot indicated for most dental patients withtotal joint replacements” [18]. In themeantime, a new statement by the AAOSinforms: “ … the AAOS recommends thatclinicians consider antibiotic prophylaxisfor all total joint replacement patientsprior to any invasive procedure that maycause bacteremia” [19]. This discrepancyis hard to understand. Because physiciansand dentists will follow the most recentlypublished AAOS information statement,this has several unfavorable consequences:First, general prophylaxis increases the(unjustified) use of antibiotics; second, therisk of adverse effects (eg, toxicity and al-lergy) may not be counterbalanced by pre-vention of PJI; and third, the dentist maybe sued for not giving antibiotics accord-ing to the published consensus statement.This unjustified liability problem can onlybe tackled with conclusive data from aclinical study.In this issue of Clinical Infectious Dis-eases, Berbari et al [20] present a case-control study to examine the associationbetween dental procedures—with or with-out antibiotic prophylaxis—and PJI. Therationale for this study was the discrep-ancy between the multitude of expertopinions and the lack of evidence regard-ing the benefit of antibiotic prophylaxisbefore dental procedures. The authorsfound no increased risk of PJI after dentalprocedures. In addition, antibiotic pro-phylaxis was not associated with riskreduction.Infectious diseases specialists envy thesample sizes in clinical studies performedby investigators who have access to verylarge numbers of patients (eg, cardiologystudies), in which small differences in out-comes can be thoroughly tested for theirstatistical significance. However, PJI is arare event that occurs in ∼1% of all pri-mary arthroplasties. The estimated pro-portion of these cases attributed to dentalprocedures is small (∼10%, or ∼0.1% ofall primary arthroplasties) [6, 10]. There-fore, even when antibiotic prophylaxiscould prevent 80% of all potential he-matogenous PJIs after dental procedure,the absolute risk reduction would be only∼0.08%. These figures indicate that at least1250 individuals must be treated with pro-phylactic antibiotics during dental pro-cedures to prevent a single PJI. In otherwords, proof of superiority of antibioticprophylaxis with a power of 80% in a pla-cebo-controlled trial would require severalhundred thousands persons with joint re-placements to undergo dental work, witha follow-up of at least 2 years. Therefore,a case-control study, as performed by Ber-bari et al [20], is the only feasible option.As with every case-control study, thereis an increased susceptibility to samplingand differential measurement bias. Berbariet al [20] elegantly minimized these po-tential biases by sampling the case patientsand control subjects in the same way, byusing data (ie, dental charts) recorded be-fore the outcome (PJI) occurred, and byblinding the reviewer of the dental recordsto the case or control status of the patient.However, matching was not performed onany variable. Yet, given the prospectivesurveillance of this study and the highnumber of variables reported to be asso-ciated with an increased risk for PJI, it isimpossible to find a sufficient number ofcontrol subjects with the same value ofpotential confounding variables. Taken to-gether, the study performed by Berbari etal [20] is methodologically well conductedand provides data on the topic of anti-biotics for prevention of PJI during dentalprocedures.In 35 of the 339 episodes, PJI was po-tentially caused by a microorganism fromthe oral or dental flora. This number isdifficult to interpret, because the body siteof the bacteria’s origin was not examined,and the PJI population includes both he-matogenously and intraoperatively ac-quired infections. However, antibioticprophylaxis could not lower the risk of PJI.Although it is conceivable that hematog-enous seeding from the oral flora to theprosthetic joint does occur, these eventsseem not to be directly associated withdental procedures.Good dental hygiene may, therefore, bemuch more relevant than antibiotic pro-phylaxis before dental manipulation. Ber-bari et al [20] showed that more controlsubjects than patients with PJI had mul-tiple dental hygiene visits [63% vs 54%]and that there was a trend for a lower riskfor developing a PJI if a patient had atleast 1 dental hygiene visit (odds ratio, 0.7;95% confidence interval, 0.5–1.03; Pp). This observation is important, be-.07cause the fear of bacteremia may preventpeople with joint replacement from con-sulting the dentist or undergoing dentalhygiene.In conclusion, the study by Berbari etal [20] has the potential to reassure theresponsible physicians and dentists thatantibiotic prophylaxis is not needed for allpatients with total joint replacement priorto any dental procedure and to convinceindividuals with joint replacement thatmeticulous dental hygiene is important.AcknowledgmentsPotential conflicts of interest. W.Z. has re-ceived recent research funding from Novartis(Switzerland) and Pfizer (Switzerland) and is aconsultant for Pfizer (Switzerland). P.S.: noconflicts.References1. Del Pozo JL, Patel R. Clinical practice: infec-tion associated with prosthetic joints. N EnglJ Med 2009; 361:787–94.2. Zimmerli W, Trampuz A, Ochsner PE. Pros-thetic-joint infections. N Engl J Med 2004;351:1645–54.3. Laffer RR, Graber P, Ochsner PE, Zimmer-li W. Outcome of prosthetic knee-associatedinfection: evaluation of 40 consecutive epi-sodes at a single centre. Clin Microbiol In-fect 2006; 12:433–9.4. Murdoch DR, Roberts SA, Fowler VG Jr, etal. Infection of orthopedic prostheses afterEDITORIAL COMMENTARY • CID 2010:50 (1 January) • 19Staphylococcus aureus bacteremia. Clin InfectDis 2001; 32:647–9.5. Maderazo EG, Judson S, Pasternak H. Lateinfections of total joint prostheses: a reviewand recommendations for prevention. ClinOrthop 1988; 229:131–42.6. Ainscow DA, Denham RA. The risk of hae-matogenous infection in total joint replace-ments. J Bone Joint Surg Br 1984; 66:580–2.7. Steckelberg JM, Osmon DR. Prosthetic jointinfections. In: Waldvogel FA, Bisno AL, edsInfections associated with indwelling medicaldevices. 3rd ed. Washington DC: AmericanSociety for Microbiology, 2000:173–209.8. Deacon JM, Pagliaro AJ, Zelicof SB, HorowitzHW. Prophylactic use of antibiotics for pro-cedures after total joint replacement. J BoneJoint Surg Am 1996; 78:1755–70.9. Bartzokas CA, Johnson R, Jane M, Martin MV,Pearce PK, Saw Y. Relation between mouthand haematogenous infection in total joint re-placements. BMJ 1994; 309:506–8.10. Waldman BJ, Mont MA, Hungerford DS. To-tal knee arthroplasty infections associated withdental procedures. Clin Orthop 1997; 343:164–72.11. Zimmerli W, Zak O, Vosbeck K. Experimentalhematogenous infection of subcutaneouslyimplanted foreign bodies. Scand J Infect Dis1985; 17:303–10.12. Zimmerli W, Waldvogel FA, Vaudaux P, Ny-degger UE. Pathogenesis of foreign body in-fection: description and characteristics of ananimal model. J Infect Dis 1982; 146:487–97.13. Coulter WA, Coffey A, Saunders ID, Emmer-son AM. Bacteremia in children followingdental extraction. J Dent Res 1990; 69:1691–5.14. Lucas VS, Lytra V, Hassan T, Tatham H, Wil-son M, Roberts GJ. Comparison of lysis fil-tration and an automated blood culture sys-tem (BACTEC) for detection, quantification,and identification of odontogenic bactere-mia in children. J Clin Microbiol 2002; 40:3416–20.15. Blomgren G, Lindgren U. Late hematogenousinfection in total joint replacement: studies ofgentamicin and bone cement in the rabbit.Clin Orthop 1981; 155:244–8.16. Uckay I, Pittet D, Bernard L, Lew D, PerrierA, Peter R. Antibiotic prophylaxis before in-vasive dental procedures in patients with ar-throplasties of the hip and knee. J Bone JointSurg Br 2008; 90:833–8.17. Kingston R, Kiely P, McElwain JP. Antibioticprophylaxis for dental or urological proce-dures following hip or knee replacement. JInfect 2002; 45:243–5.18. American Dental Association and AmericanAcademy of Orthopaedic Surgeons. Antibioticprophylaxis for dental patients with total jointreplacements. J Am Dent Assoc 2003; 134:895–8.19. American Academy of Orthopaedic Surgeons.Antibiotic prophylaxis for bacteremia in pa-tients with joint replacements. Available at:http://www.aaos.org/about/papers/advistmt/1033.asp. Accessed 9 November 2009.20. Berbari EF, Osmon DR, Carr A, et al. Dentalprocedures as risk factors for prosthetic hip orknee infection: a hospital-based prospectivecase-control study. Clin Infect Dis 2010; 50:8–16 (in this issue).

Antibiotics for Prevention of Periprosthetic Joint Infection Following Dentistry: Time to Focus on Data

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