Recommendations for the clinical practice

1. Recommendations for the clinical practice Osteo-articular infections (OAI) on material (prosthesis, implant, osteosynthesis)Pr M Dupon CHU Bordeaux, France Organized by the SPILF (Society of Infectious Pathology of French Language) with the cooperation of the following learned societies : CMIT (College of the Academics of Infectious and tropical Diseases) GPIP (Group of Pediatric Infectious Pathology) SFAR (French Society of Anaesthetics and Intensive Care) SFHH (French Society of Hospital Hygiene) SFM (French Society of Microbiology) SFMN (French Society of Nuclear Medicine) SOFCOT (French Society of Orthopaedic Surgery) SOFMER (French Society of Physical Medicine and Rehabilitation) SFR (French Society of Radiology) SFR (French Society) of Rheumatology)

2. Rédaction V3 complète • Réunions téléphoniques • RPC are medical and professional recommendations which can be used to establish medical references, that is " standards of practice " determining what it is suited and\or inappropriate to make, during the implementation of preventive, diagnostic and\or therapeutic strategies in given clinical situations ". These standards can be used for: • Improve the quality of the professional practices • establish a reference table of a clinical audit • be at the origin of tools of regulation in a conventional frame(executive). • A rigorous and explicit approach must be applied to prepare " medical and professional valid and credible recommendations.

3. Recommandation gradation French High Authority of Health (HAS) gradation This gradation of the recommendations based on the scientific level of proof of the literature does not suppose obligatorily a degree of force of these recommendations. It can exist recommendations of rank C or founded on a professional agreement nevertheless strong in spite of the absence of a scientific support. • OAI : Variable levels of proof, mostly weak • In the absence of precision, the suggested recommendations correspond with • a professional agreement • The expression of a professional agreement must translate a professional consensus obtained by a formalized method (vote, Delphi method…)

4. PLAN How to classify the various osteo-articular infections on material? How to assert the diagnosis of osteo-articular infections on material? What are the modalities of the therapeutic care? What are prerequisites to minimize this type of infections? What medico-legal repair for the consequences of the postoperative ostéo-articular infections on material?

5. Question 1 How to classify the various osteo-articular infections on material?

6. Determining factors of a classification Definition of the type of material Material of osteosynthesis Material (affixed to the bone: plate, intramedullary : nail; rachis: inter-somatic stems, screws, grafts, cages, artificial ligaments) External fixing Prostheses Osseous substitutes and allografts Length of infection evolution Ambiguity of acute or chronic infection terms (clinician≠microbiologist≠surgeon) Time of diagnosis after the material implantation : early infection: <1 mois delayed infection: 2 to 6 months late infection: > 6 months No universal classification

7. Determining factors of a classification • To take account of 7 fundamental points • Mode of contamination(direct, hematogen, by contiguity) • Chronology,allowing to make difference between post-operative infection and hematogenous infection) (symptom-free period, time of contamination,delay before management) • Infectious state(knowledge of microorganisms, repercussion of the infection) • Mechanical state of the infected site(loosened prosthesis or not, consolidated fracture or not, material present or not, explantable or not) • Localization of the infection(peripheral bone, joint, spinal column) • State of skin and soft tissues • State of the patient(functional and general, immune status, underlying ground) Beginning of medical care Infectious signs at prosthesis level Prosthesis implantation Remote infectious site Free interval Delay before manage-ment Time of contamination temps

8. Surgical Site Infection risk factors (1) Opened fractures, significant risks tibial localization severity of the soft tissue lesions evaluated by classification of Gustilo(level 2) Closed fractures of the long bones Diabetes = factor of difficulty of cicatrization after osteosynthesis of ankle or the foot(level 2) Orthopedic Surgery significant increase of the SSI risk age >65 years, existence of another infectious site, preoperative stay exceeding 4 days (level 2) weak increase of the SSI risk obesity, corticosteroid therapy, recent radiotherapy on operational site, healing delay, hematoma occurence (level 2), rheumatoid polyarthritis (opinion of expert) Spine diabetes perioperative plasma glucose level rise (level 3) • Rheumatoid polyarthritis • no stop of the corticosteroid therapy (risk of acute suprarenal incapacity) • Methotrexate continuation does not increase the risk of SSI (level 1) • Anti-TNF (HAS recommendations) • Stop of the anti-TNF 2 -5 half-lives before the intervention and until complete cutaneous healing.

9. Microbial epidemiology Microorganisms Frequency (%) Total Osteosynthesis prosthesis matérial Coagulase <0 Staph. 30 à 4322 Staphylococcus aureus 12 à 2330 Streptococcus sp 9 à 101 Enterococcus sp 3 à 73 Gram négative bacilli 3 à 610 Anaerobic (P acnes)2 à 45 Polymicrobial 10 à 1227 No bacteria 10 à 112 Others: Candida, Corynebacteria, ..

10. Question 2 How to assertdiagnosis of osteo-articular infections on material?

11. Clinical signs Fistula = infection (level 3) In the month following material implantation (level3) Pain of abnormal intensity Purulent discharge Scar disunity or necrosis At a distance of the implementation (rank C) Pain After a long free interval, in front of local signs, look for a hematogenic infection (rank B) Absence of inflammatory sign: do not eliminate an infection (level 2)

12. Biological signs No biological parameter is specific Leucocytose: low VPP or VPN (level 2) A normal value of VS and of CRP does not eliminate an infection (expert opinion) In the month after the implantation (rank C) Interest of CRP follow-up SR: no diagnostic value After 3 months, suspicion of infection if: (rank B) SR > 22 - 30 mm, = 82-93 %, Sp = 84 % CRP > 10-13,5 mg / l, Se = 91-97 %, Sp = 86-92 % if no confusing factors

13. Radiological signs Need for producing a standard plain radio even if normal in 50% of the cases (rank B) Signs to be sought (level 2): Sequestration Bone loosening (border width >2mm during 1 year) Blurred osteolytic lesions Periosteal reaction Presence of intra-articular gas Mobilisation or fracture of the material Se : 14%; Spe : 70%

14. Computed tomography and ultrasonography signs Computed tomography (CT) It is recommended to produce a scanner with injection of contrast product (rank B) Peripheral bone structure osseous, soft tissues ++ Interferences in the vicinity of metal implants Signs to be sought (level 2): Periosteal reactions Blurred osteolytic lesions Soft tissue abnormalities and collections Ultrasonography Signs :(level 2) : Intraarticular fluid accumulation or around the implant Soft tissues thickening • Absence of intra-articular effusion: strong NPV

15. MRI, arthrographic signs Magnetic resonance imaging(MRI) artifacts making interpretation difficult(material, immediate post-operative period)- Injection of Gadolinium ++ Signs: (level 2): Oedema of soft tissues (hypersignal T2) Intra-osseous or soft tissues collection Sinus tract (hypersignal T2) Articular effusion (hypersignal T2) Osseous sequestration (hyposignal) Arthrography(iodine contrast) Sinus tract, para-articular collection, can be used to guide joint aspiration and drainage procedures. (level 2):

16. Nuclear imaging Bone scintigraphy with HDP-Tc99m: abnormal fixation in the 3 phases (level 2): Se: 90-100%; Sp: 30-40%;VPN: 100% Labelled leukocyte scan (or scan with anti-granulocyte antibodies)with late images at 24h (level 2) improved Spe Hybrid imaging single photon emission tomography/ computed tomography (SPET/CT) increased spatial resolution Se: 81-97%; Sp: 89-100% But persistence of increased uptake between 6-12 months after a surgery (perform sulfo-colloids-Tc99m medullar scintigraphy to look for absence of congruence) For the spine, scintigraphy with Gallium 67 (level 2) Positron Emission Tomography/CT imaging with F-18 fluorodeoxyglucose is under evaluation (for chronic infection)

17. Imaging strategy Early (<1 month) or hematogenous infection : restricted contribution puncture of a collection, with surgical asepsis, under control echo or TDM if nonaccessible clinically(rank C) Delayed or late Infection (>1 month) Radio operator standard (simplicity, reproducibility, low cost)(rank B) TDM with injection(rank B) puncture of a collection, with surgical asepsis, under echo or TDM or arthroscanner if clinically non-accessible (rank C) Imaging with radioisotopes (bone scintigraphy associated to scintigraphy with tagged PNM) (rank C) Rachis MRI (early or late infection) Scintigraphy with Ga67 (delayed or late infection)(rank B) • Absence of intra-articular effusion: strong NPV

18. Question 2 2.4 What is the contribution of the microbiology and the anatomo-pathology? How to assertdiagnosis of osteo-articular infections on material?

19. How should diagnostic microbiological sampling be performed?(1) General principles wait a minimum of 15 days after any antibiotherapy before any test, to decrease the rate of false negative samples (except in case of sepsis and after evaluating the risk for disseminated infection)(expertadvice). Pre-operative sampling It is strongly recommended not to sample with a swab on the scar, even if it is not healed. to perform pre-operative sampling with surgical asepsis if diagnosis doubt It is recommended to perform hemocultures and pre-operative sampling (puncture of a joint or of an abscess) to rapidly initiate probabilistic antibiotherapy if general signs of sepsis not to perform sampling from the outlet of a fistula; to carry out hemocultures and a preoperative puncture in order to begin a probabilistic antibiotherapy quickly if sepsis with general signs to carry out a puncture (vpp: 67-100%, vpn: 95%) in case of intra-articular effusion or abscess; if not liquid, tissue biopsy with the true-cut (rank B) to collect part of the liquid in a hermetically closed sterile syringe and to inoculate hémoculture vials for aerobes and anaerobes with the other part

20. Per-operative sampling It is recommended to sample at the beginning of surgery, without any antibiotherapy, and before any antibioprophylaxis. to perform 5 samplings at the level of macroscopically pathological areas (grade B). These samplings may be liquid (pus, articular fluid) or solid (granulomatous tissue, bone tissue, interposition tissue, and any suspicious tissue). to change sampling tools between each sampled site. Post-operative sampling In case of septic surgery, the positivity (with the same bacterium or another) of cultured drain fluids seems to be linked with a higher risk of infection relapse (level 2). In case of infection on external fixator pin, it is recommended to perform sampling along the pin (level 2) How should diagnostic microbiological sampling be performed? (2)

21. Microbiological techniques at the laboratory (1) It is recommended to maintain incubation of culture media for at least 14 days (expert advice). Pre-operative samplings: articular fluid It is recommended to perform a cytological test (count and formula) in the 2 h following sampling. >1,700 leucocytes/mm3 (Se 94%, Spe 88%) and >65% of PMN neutrophils are strongly suggestive of infection on prosthesis in articular fluid (level 2). It is recommended to seed the articular fluid on enriched agars to be incubated in aerobic condition, under 5% of CO2 and in anaerobic condition, and to inoculate hemoculture vials for aerobics and anaerobes.

22. Per-operative sampling It is recommended to crush solid samples to seed on solid and liquid enriched media and eventually on a medium for mycobacteria to perform direct examination to screen for PMN neutrophils and bacteria (Gram staining)(Se : 6%, Spe ~ 100%). to freeze a part of samples (-80°C) for specific screening (fungus, mycobacteria) and eventually for molecular biological techniques. It is recommended to identify all the different colonies, especially staphylococci slow culture(« small colony variants ») to perform an antibiogram on the various types of colonies isolated. It is necessary to asses glycopeptide MICs on staphylococci and to check, if possible, the susceptibility to oxacillin by screening for the mecA gene. It is necessary to assessMICs of beta-lactams on the non-groupable streptococci. New methods under evaluation : sonication, broad-range PCR (16S RNA) Microbiological techniques at the laboratory (2)

23. How to assertdiagnosis of osteo-articular infections on material? Question 2 2.5 What are the arguments in favour of the diagnosis? Definite infection and probably excluded or not detectable infection

24. What data suggests the diagnosis (proved infection, and non detectable or no infection)? • The working group, with an exploratory objective, has judged useful to propose a binary classification (proved infection /infection probably excluded or not detectable) by considering that between the two, there are several situations of possible infection for which specific criteria cannot be defined • Consider that the initial clinical, biological, and/or imaging approach, has allowed to suspect infection. • Consider that 5 samplings at least were performed

25. What data suggests the diagnosis (proved infection, and non detectable or no infection)? ou or or or ou

26. What are the modalities of therapeutic management? Question 3 What are the specificities of surgical treatment?

27. What is the rational for the  therapeutic strategy?Biofilm and biomaterials The oxides contained in the material are responsible for a secondary binding interaction surface for bacteria. This process begins by a phenomenon of attraction-adhesion during which bacteria are reversibly adsorbed on the material. Then, the bacteria irreversibly colonize the material. Bacteria develop a survival strategy within a dynamic entity defined as the biofilm, made of a polysaccharidic substance secreted by bacteria called « slime » which permits the definitive adherence of bacteria on the material. The bacteria in the biofilm are organized in micro-colonies (« small colony variant ») under the influence of inter-cellular communications leading to a stationary growth phase due to the absence of ATP production. This has for consequence: to limit the activity of some antibiotics which diffuse badly in the biofilm, the prolonged persistence of S. aureus in osteoblasts, escaping the immune defense mechanism. This biofilm spreads to all the material surface in a few days explaining why a late surgical lavage is inefficient beyond 15 days the need to remove the prosthetic material, most of the time

28. Conservation of the prosthesis It is recommended to use synovectomy and lavage («debridement») with implant retention in the case of very recent infection (post-operative until D15, recent secondary infection without loosening) (grade C). It is not recommended to perform arthroscopic synovectomy at the knee level but open arthrotomy (grade C) . It is recommended to initiate antibiotherapy as soon as bacteriological samplings have been made, first in a probabilistic way, then adapted to documentation. The recommended course length is 6 weeks.It is useless to prolong beyond this.

29. Removal of implants Hip: Use the previous surgical approach provided it can be extended Femoral implants can be extracted by endo-femoral route or by femorotomy. It is recommended to perform femorotomy with large vascularized bone fragment to improve the removal of cement, to carefully close the femorotomy, and to osteosynthesize it with strong cerclage. In case of intra-pelvic implant dislocation, of protrusion without bone barrier, or intra-pelvic foreign bodies, it is strongly recommended to asses cases with vascular risk(expert advice) Knee and other joints: Same principle Removal of infected implants does not present any specific problem.

30. One or two stage surgical revision ? The majority of the authors recommends revision with 2 separate procedures even if the analysis of the litterature does not objectively define indications for 1 or 2 stages. What can be the choice criteria? The certitude to have identified the bacterium : choose a single procedure The bacterial profile Bacteria for which antibiotherapy is limited (multi-resistant bacterium, Pseudomonas aeruginosa), a mycobacterium, a fungus are indications for surgery with two procedures. Knowledge of the terrain  it seems that a patient with a long history of prosthesis infection is not a good candidate for surgery in one procedure. Problems with anesthesia  If the patient cannot undergo 2 procedures, a single surgery should be chosen after discussion with the anesthesiologist, the surgeon, and the patient (or his family). antibiotherapy [6/8 w-6 m[ Follow-up t One -stageexplantation+ réimplantation

31. Modalities surgery in the two procedures What is the ideal delay for replacement? There is no answer in the literature. In case of 2 short steps, the recommended delay is between 4 and 6 weeks during which antibiotherapy is given without interruption. If bacteriological samplings are negative after 15 d of culture, treatment may be interrupted. antibiotherapy  6/8 w suivi t reimplantation explantation

32. Modalities surgery in the two procedures What is the ideal delay for replacement? In case of 2 long steps, the delay range from 3 to 6 months knowing that after 3 months the functionnal result will be less good. The antibiotherapy must be interrupted for 15 days before replacement. The usefulness of performing a puncture before reimplantation is not confirmed. The antibiotherapy will be resumed post-operatively and stopped if the culture is negative (after 15 days).(expert advice) Using a spacer :recommended with an essentially mechanical aim so as to facilitate replacement of the prosthesis reimplantation Antibiotic window culture Follow-up antibiotherapy t explantation Additionnal histological and microbiological samplings puncture

33. Question 3 What are the specificities of anti-infectious treatment? What are the modalities of therapeutic management?

34. What is the contribution of local antibiotherapy? • Strong doses of antibiotics may need to be used for therapy. • These types of cement is prepared by the surgeon extemporaneously in the operating room (high-loaded) and are only recommended temporarily in 2 presentations: • cement beads used to fill a cavity. • spacer with cement impregnated with antibiotics, with the objective on one hand to maintain the space after removing the implant and, on the other hand, to obtain local antibiotherapy • The kinetics of antibiotic release includes two phases: an immediate phase during 7 days, with a high concentration and a secondary phase, for the years with much weaker doses (sub-inhibiting doses). • The antibiotics used in cement are currently aminosides, vancomycin, and clindamycin.and need to be active against identified bacterium • These cements must in no case dispense from a prescription of general antibiotherapy and differ from the licensed antibiotic cement used for prosthesis (re)implantation prophylaxis.

35. General principles for sytemic antibiotherapy (1) Rules for optimal antibiotherapy (grade C) : based on culture results (in case of sepsis, probabilistic antibiotherapy must be initiated after microbiological sampling), antibiotherapy initiated as a combination; achieving adequate plasmatic concentrations; using molecules with a good bone distribution in order to achieve high concentration in the tissue; in case of infection due to staphylococci, never use monotherapy with rifampicin, fusidic acid, fluoroquinolones, and fosfomycin: linezolid, daptomycin, tigecyclin do not have marketing authorisation for medicinal products in 2009, for the treatment of bone and joint infections

36. General principles for sytemic antibiotherapy (2) • Mode of administration : • It is recommended to administer the treatment initially intravenously. No study has validated the duration of parenteral antibiotherapy. It is usually 10 to 15 days long (expert advice). • After this, it is recommended to switch to per os administration if antibiotics : • have a good bioavailability and a good bone distribution, • have a good digestive tolerance • have no negative interaction • and if observance is good . • If switching to oral treatment is impossible, it is mandatory to maintain parenteral antibiotherapy as long as necessary, either in hospital or in ambulatory treatment (grade C). • In this case, it is recommended to insert a central catheter which may be changed if the planned duration of antibiotherapy <6 weeks, or atotally implantedcentralvenous access device(TICVAD) if the planned duration of antibiotherapy >6 weeks

37. General principles for sytemic antibiotherapy (4) • Duration of antibiotic treatment: (expert advice) • minimum of 6 weeks. • usual length reported in litterature : 6 to 12 weeks. • maintaining antibiotherapy >12 weeks should be discussed • variation according to surgical management • Surveillance of antibiotherapy: • effectiveness assessed first on clinical data then on biological parameters (CRP). It is recommended to dose antibiotics with high inter-individual variations of blood concentrations. It is recommended to dose aminosides (peak) and glycopeptides. If rifampicin used, check that the antibiotic to which it is combined is not under dosed. • tolerance assessed on clinical and on biological parameters (CBC/platelets, hepatic parameters, renal function). It is also necessary to measure blood concentrations of some antibiotics such as aminosides (trough level).

38. 3.3.2.2. Choosing antibiotic: meticillin resistant staphylococci

39. doses and ways of administration of antibiotics(for a normal renal and hepatic function)

40. Empirical antibiotherapy • Antibiotic scheme before obtaining per operative bacteriological results when there is no reliable documentation in the patient’s history, when there are general signs indicating the emergency of treatment (sepsis), or for culture negative infection. • suggested associations by order of preference, must be adapted according to the microbial ecology of each institution (expert advice): • ureidopenicillin/ beta-lactamase inhibitor + vancomycin • 3rd generation cephalosporin + vancomycin • carbapenem (except ertapenem) + vancomycin • 3rd generation cephalosporin + fosfomycin.

41. Suppressive antibiotherapy (grade C) • indefinite long term oral antibiotics (≥1 year), • palliative but not curing the infection, • only with well-tolerated molecules and easy administration (per os) • in the minority of patients in whom surgery is precluded or declined, • available bacterial target

42. Follow-up of patients: organization and structures optimal management requires : an accurate clinical evaluation a microbiological diagnosis requiring validated techniques both for sampling and for identification of micro-organisms a therapeutic strategy defined during multidisciplinary staff meetings implementing specific treatments especially for surgical and anti-infectious goals in the short term a global continuous and clear management until coming back home, with a healthcare file including all the detail care continuous information of the patient interregional reference centers for the management of complex bone and joint infections Is cure possible?  the infectious and functional criteria should be taken into account. there is no criterion defining infection cure. It is recommended to follow-up patient between 1-2 years after the end of antibiotherapy the functional result is obtained by assessing mobility, pain, strength, balance, and walking (specific score for joints).

43. Question 4 What are the pre-requisites to pour minimize these types of infection?

44. What are the standards in terms of healthcare environment control?  Hygiene  procedures? Environmental surveillance? No formal proof of so-called “septic” units effectiveness on the prevention of SSI The procedures to be applied are the same that those described during the non-septic surgery They concern: Management of potential portals of entry during care giving Air treatment efficiency, (expert recommendations by the French Society for Hospital Hygiène Société Française d’Hygiène Hospitalière –SFHH- 2004, Healthcare personnel discipline, Effectiveness of professional wear and operative sheets, Managing surgical instruments, Cleaning surfaces,  Surgical block architecture, Environmental  surveillance.

45. .What measures should be undertaken for the preparation of the patient before surgery ? (1) These measures concern preparation for an orthopedic intervention as in a non-infected patient. (grade C) Specific risk factors a priori accessible to corrective treatment: Length of pre-operative  hospitalization >4 days Tobacoo, diabetes, obesity, denutrition Rheumatoid polyarthritis treatments No systematical screen for nasal carriage of S. aureus • When Staphylococcus aureus SSI rates remain unusually high (>2%), it is recommended to perform nasal swabs of caregivers and patients. • Nasal screening for methicillin resistant S aureus is recommended in patients who must undergo planned cardiac or orthopedic surgery, transferred from ICU, long and median stay structure, or in case of chronic cutaneous lesions. • It is not recommended to use mupirocin systematically pour to prevent the onset of SSI in MRSA carriers.

46. What measures should be undertaken for the preparation of the patient before surgery ?(2) Global prevention measures against infection in orthopedic and trauma surgery: 1. Recommendations for skin care and preparation were specified in the french consensus conference «pre-operative management of infectious risk» (SFHH). 2. Systemic route antibioprophylaxis was codified by the 1992 french consensus conference «antibioprophylaxis in surgical settings in the adult», and updated in 1999 (SFAR). 3. Per-operative normothermia is applicable to orthopedic and traumatological surgery. 4. Peri-operativehyperoxygenation could be used for orthopedic and traumatological surgery. 5. It is recommended to use local antibiotherapy for prophylaxis such as antibiotic impregnated cements for 1st intention arthroplasty 6. it is not necessary to carry out antibioprophylaxis in a septic patient in order to avoid false negativity of the microbiology sample

47. What measures are undertaken to fight the risk of cross transmission when managing a patient infected in an orthopedic surgical block?? Should there be a chronological order for surgery? There is no need to impose a specific order of passage if hygiene precautions are observed (grade C). What precautions should be taken in the surgical block after operating a septic patient? It is recommended to perform the usual cleaning program and to respect the time needed for particle decontamination of the operating room between two interventions In case of Multi Resistant Bacteria, there are no supplementary precautions to take for the cleaning of the rooms but complementary precautions of the «contact» type must be respected (grade C). No «septic» operating room is necessary if cleaning procedures between two interventions with various contamination are observed and if rooms are equipped with efficient ventilation systems (grade C) There is no need to have separate post surgery surveillance rooms for patients having undergone different surgeries,

48. Thanks RPC are available at www. infectiologie.com and will be published in Médecine et Maladies Infectieuses (Elsevier)

49. RPC are available at www. infectiologie.com and will be published in Médecine et Maladies Infectieuses (Elsevier)