Marion Couderc

Géraldine Bart

Dr Guillaume Coiffier
email: guillaume.coiffier@chu-rennes.fr

Sophie Godot

Raphaele Seror

Jean-Marc Ziza

Pascal Coquerelle

Christelle Darrieutort-Laffite

Couderc Marion

Bart Géraldine

Coiffier Guillaume

Godot Sophie

Seror Raphaele

Ziza Jean-Marc

Coquerelle Pascal

Darrieutort-Laffite Christelle

Lormeau Christian

Salliot Carine

Veillard Eric

Bernard Louis

Baldeyrou Marion

Bauer Thomas

Hyem Beate

Touitou Robert

Fouquet Bernard

Mulleman Denis

Flipo René-Marc

Guggenbuhl Pascal

recommendations on the management of septic arthritis in an adult native joint

Keywords: Recommendation, Septic arthritis, Bone and joint infection Antibiotic therapy prior to aspiration? Acute arthritis Yes

ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Septic arthritis (SA) is defined as the presence of a culturable microorganism in the synovium and the joint cavity responsible for an inflammatory reaction in the joint. Although rare, this is the primary diagnostic concern for the clinician when faced with a patient with acute arthritis due to the morbidity and mortality and the functional risks involved. The latest French recommendations available are from 1991 (1) and needed to be updated.

The recommendations proposed relate to the diagnosis and treatment of peripheral SA in adults in a native joint involving a pyogenic bacterial infection. These recommendations do not cover mycobacterial infectious arthritis, Lyme arthritis, viral, parasitic and fungal arthritis, diabetic foot infection, Whipple's disease or reactive arthritis.

Methodology used to compile the recommendations

The methodology was inspired by the HAS recommendations [START_REF]Élaboration de recommandations de bonne pratique : méthode « Recommandations pour la pratique clinique[END_REF]. The working group was made up of 14 rheumatologists, 2 infectious disease specialists, 1 orthopaedic surgeon, 1 physiatrist, 1 general practitioner and 1 microbiologist.

The group devised several pragmatic questions for the diagnosis and treatment of SA. A critical analysis of the literature was carried out to provide answers to these questions. Three general principles and 16 specific recommendations were formulated and then graded according to the level of scientific evidence [Appendix A, Table S1; See the supplementary material associated with this article online].

The recommendations were first reviewed by the review group made up of 30 rheumatologists [START_REF] Stirling | False-negative rate of gram-stain microscopy for diagnosis of septic arthritis: suggestions for improvement[END_REF] working in hospitals and 9 in private practice) proposed by the French Rheumatology Society (SFR), 7 infectious disease specialists proposed by the French Language Infectious Diseases Society (SPILF) and 5 orthopaedic surgeons proposed by the French Orthopaedic and Trauma Surgery Society (SOFCOT).

After an initial review, 8 recommendations proposed did not obtain the consensus defined as an average of ≥8.0 and/or ≥80% of reviewers with a score ≥8. These recommendations were therefore adapted to the review group's proposals while still conforming with the data in the literature and then resubmitted to the review group for validation. The antibiotic therapies proposed by the working group were validated by the SPILF recommendations group.

General principles and recommendations

Table 1 summarizes all of the recommendations with their level of evidence and their level of consensus.

General principles

Principle A-Septic arthritis is a diagnostic emergency due to the morbidity and mortality and the functional risk related to structural damage.

SA is a serious disease with a mortality rate of around 7% at 3 months, which increases with age [START_REF] Abram | Mortality and adverse joint outcomes following septic arthritis of the native knee: a longitudinal cohort study of patients receiving arthroscopic washout[END_REF]. It is often associated with osteochondral complications responsible for a secondary functional disability [START_REF] Mcbride | Epidemiology, Management, and Outcomes of Large and Small Native Joint Septic Arthritis in Adults[END_REF][START_REF] Carpenter | Evidence-based diagnostics: adult septic arthritis[END_REF][START_REF] Wu | Septic arthritis significantly increased the long-term mortality in geriatric patients[END_REF].

In animal models, this irreversible anatomical damage appears after 7 to 15 days [START_REF] Bremell | Histopathological and serological progression of experimental Staphylococcus aureus arthritis[END_REF][START_REF] Riegels-Nielson | Rabbit model of septic arthritis[END_REF] and a human study demonstrated better outcomes when antibiotic therapy was initiated within 10 days [START_REF] Broy | A comparison of medical drainage (needle aspiration) and surgical drainage (arthrotomy or arthroscopy) in the initial treatment of infected joints[END_REF].

Principle B-Efforts should be made to provide microbiological documentation (blood cultures and joint aspiration) of the septic arthritis before starting antibiotic treatment.

Treatment of SA is based on antibiotic therapy adapted to the bacterial microorganism in question and then bacterial sensitivity tests (Recommendation 9). The bacterial microorganism is identified by synovial fluid (SF) analyses and/or blood cultures, which must be performed systematically (Recommendations 3 and 5).

The bacteria involved in SA are, in order of frequency, staphylococci, streptococci and gram-negative rods [START_REF] Mcbride | Epidemiology, Management, and Outcomes of Large and Small Native Joint Septic Arthritis in Adults[END_REF][START_REF] Carpenter | Evidence-based diagnostics: adult septic arthritis[END_REF][START_REF] Riegels-Nielson | Rabbit model of septic arthritis[END_REF][START_REF] Broy | A comparison of medical drainage (needle aspiration) and surgical drainage (arthrotomy or arthroscopy) in the initial treatment of infected joints[END_REF][START_REF] Couderc | Predictive value of the usual clinical signs and laboratory tests in the diagnosis of septic arthritis[END_REF][START_REF] Murillo | The changing epidemiology of bacteraemic osteoarticular infections in the early 21st century[END_REF][START_REF] Dubost | Three-decade trends in the distribution of organisms causing septic arthritis in native joints: single-center study of 374 cases[END_REF][START_REF] Newman | Septic arthritis due to gram negative bacilli: older patients with good outcome[END_REF]. In France, SA involving gonococci and methicillin-resistant Staphylococcus aureus (MRSA) is rare [START_REF] Dubost | Three-decade trends in the distribution of organisms causing septic arthritis in native joints: single-center study of 374 cases[END_REF].

Almost 20% of cases of arthritis that clinicians consider septic and treat with antibiotics have no microbiological documentation, especially in cases of prior antibiotic therapy [START_REF] Clerc | Adult native septic arthritis: a review of 10 years of experience and lessons for empirical antibiotic therapy[END_REF]. SA is therefore diagnosed even in the absence of documentation.

Principle C-Septic arthritis must be managed from the start by a medical and surgical team that has experience with this condition.

Except in special cases (SA in a small, non-weight-bearing joint with sensitive bacteria, without any comorbidity), hospitalization is usually necessary to optimize the initial diagnostic and therapeutic management of SA and to help manage the patient's comorbidities.

A large number of risk factors for a poor outcome (antibiotic failure, joint sequelae or mortality) have been reported (Appendix A, Table S2).

SA can be considered as a complex bone and joint infection in certain cases, depending on: the patient's disposition (allergy, pregnancy, kidney or liver failure), the microorganism identified (polymicrobial, suspected contaminant), local septic complications (fistulization, abscess, osteitis, joint destruction) or general complications (endocarditis) or treatment (antibiotic resistance, drug intolerance, recurrence).

The management of complex SA requires discussion between rheumatologists, orthopaedists, microbiologists and infectious disease specialists.

Specific recommendations

Recommendation 1-Septic arthritis should be considered in all cases of acute monoarthritis whether the patient is febrile or not. Oligo-or polyarthritis does not rule out the diagnosis.

SA must be systematically considered in cases of acute monoarthritis (characterized by painful swelling with joint stiffness) that has generally been active for less than 2 weeks. However, symptoms can vary hugely (5,10) (Appendix A, Table S3). Several differential diagnoses are possible in cases of acute arthritis (Table 2). The absence of a fever does not rule out the diagnosis of SA as it is only observed in around half of the cases [START_REF] Carpenter | Evidence-based diagnostics: adult septic arthritis[END_REF][START_REF] Couderc | Predictive value of the usual clinical signs and laboratory tests in the diagnosis of septic arthritis[END_REF][START_REF] Ferrand | Morbimortality in adult patients with septic arthritis: a three-year hospital-based study[END_REF][START_REF] Nolla | Pyogenic arthritis of native joints in non-intravenous drug users: A detailed analysis of 268 cases attended in a tertiary hospital over a 22-year period[END_REF]. Polyarticular involvement can be encountered (10-17%). It is often accompanied by sepsis or septic shock, and is a factor for poor prognosis [START_REF] Couderc | Predictive value of the usual clinical signs and laboratory tests in the diagnosis of septic arthritis[END_REF][START_REF] Lieber | Clinical characteristics and outcomes in polyarticular septic arthritis[END_REF].

Recommendation 2-Suspected septic arthritis justifies looking for signs of immediate severity (quick SOFA ≥2).

One third of patients with SA have initial sepsis [START_REF] Ferrand | Morbimortality in adult patients with septic arthritis: a three-year hospital-based study[END_REF][START_REF] Nolla | Pyogenic arthritis of native joints in non-intravenous drug users: A detailed analysis of 268 cases attended in a tertiary hospital over a 22-year period[END_REF][START_REF] Maneiro | Predictors of treatment failure and mortality in native septic arthritis[END_REF]. Sepsis is defined as an inappropriate host response to an infection that causes organ dysfunction [START_REF] Maneiro | Predictors of treatment failure and mortality in native septic arthritis[END_REF].

In the presence of at least 2 of the following signs: respiratory rate >22/min, impaired alertness and/or SBP <100 mmHg (quick SOFA ≥2), the SOFA (Sepsis-related Organ Failure Assessment) immediate severity score must be assessed [START_REF] Singer | The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)[END_REF] (Table 3). If the SOFA score is ≥2, probabilistic antibiotic therapy and close monitoring are necessary and possibly transfer to a specialized unit (intensive care or critical care) (Figure 1).

Recommendation 3-It is essential to perform joint aspiration before administering antibiotics for a cytobacteriological analysis of the synovial fluid. The additional inoculation of the synovial fluid in blood culture bottles is recommended, in particular in cases of prior antibiotic therapy or long waiting times.

Prior antibiotic therapy decreases the detection sensitivity for a microorganism in the SF [START_REF] Hindle | Septic arthritis of the knee: the use and effect of antibiotics prior to diagnostic aspiration[END_REF]. Purulent SF is suggestive of SA, but not specific, as it may be encountered during metabolic or reactive arthritis [START_REF] Couderc | Predictive value of the usual clinical signs and laboratory tests in the diagnosis of septic arthritis[END_REF].

SF must be injected into an EDTA or heparinized tube (to avoid SF coagulation a dry tube should not be used), shipped quickly (in under 2 hours) to the laboratory for cytological analysis and in a dry tube for the microbiological analysis (Gram staining direct examination (DE), culture) and microcrystal detection [START_REF] Stirling | False-negative rate of gram-stain microscopy for diagnosis of septic arthritis: suggestions for improvement[END_REF].

Inoculating the SF in a blood culture bottle in the laboratory or at the patient's bed is thought to increase microbiological identification capabilities by 20%, especially in the case of prior antibiotic therapy [START_REF] Hughes | Culture with BACTEC Peds Plus/F bottle compared with conventional methods for detection of bacteria in synovial fluid[END_REF].

After Gram staining, the DE is only positive in about 1/3 of SA cases [START_REF] Carpenter | Evidence-based diagnostics: adult septic arthritis[END_REF][START_REF] Couderc | Predictive value of the usual clinical signs and laboratory tests in the diagnosis of septic arthritis[END_REF][START_REF] Newman | Septic arthritis due to gram negative bacilli: older patients with good outcome[END_REF][START_REF] Stirling | False-negative rate of gram-stain microscopy for diagnosis of septic arthritis: suggestions for improvement[END_REF]. A negative DE therefore does not rule out SA.

In case of prior antibiotic therapy, there is no recommended antibiotic window before performing a joint aspiration. If the first aspiration is negative, it can be repeated (after 48 hours of culture for example).

Synovial needle biopsies are not thought to improve bacteriological identification compared to SF [START_REF] Coiffier | Ultrasound-guided synovial biopsy improves diagnosis of septic arthritis in acute arthritis without enough analyzable synovial fluid: a retrospective analysis of 176 arthritis from a French rheumatology department[END_REF].

They should be considered in second place, in particular when the SF cannot be aspirated (synovitis) [START_REF] Coiffier | Ultrasound-guided synovial biopsy improves diagnosis of septic arthritis in acute arthritis without enough analyzable synovial fluid: a retrospective analysis of 176 arthritis from a French rheumatology department[END_REF].

Recommendation 4-Based on the analysis of synovial fluid, microcrystal detection must be carried out in addition to the cytobacteriological analysis but their presence does not rule out the diagnosis of septic arthritis.

The main differential diagnosis of SA is metabolic arthritis (gout, chondrocalcinosis), the diagnosis of which is based on the detection of crystals in the SF. However, metabolic and septic arthritis can coexist [START_REF] Shah | Does the presence of crystal arthritis rule out septic arthritis?[END_REF]. The presence of crystals in the SF should therefore not rule out the diagnosis of SA at the outset and in such cases the SF should always be sent to the laboratory for microbiological analysis.

The white cell count and differential of the SF can guide the diagnosis of acute arthritis but no threshold is discriminating (Appendix A, Table S4). The higher the SF white cell count, the more likely it is to be septic [START_REF] Carpenter | Evidence-based diagnostics: adult septic arthritis[END_REF]. This is all the more true in the absence of crystals in the synovial fluid [START_REF] Ferreyra | Combining cytology and microcrystal detection in nonpurulent joint fluid benefits the diagnosis of septic arthritis[END_REF].

No biochemical SF marker (lactate, glucose, etc.) is currently sufficiently effective for diagnosing SA to be recommended systematically (Appendix A, Table S5).

Broad-range 16S rDNA PCR on SF has been disappointing when it comes to diagnosing SA. The only study conducted on native joints reported that 16S rDNA PCR was less effective than direct examination, blood cultures or SF culture, with a very low sensitivity (26) (Appendix A, Table S6). Therefore a negative 16S rDNA PCR on SF does not rule out SA.

Recommendation 5-At least 2 sets of blood cultures should be performed before proposing antibiotic therapy, even in the absence of fever.

Blood cultures are positive in 9 to 36% of SA cases and are sometimes the only test to identify the bacteria [START_REF] Clerc | Adult native septic arthritis: a review of 10 years of experience and lessons for empirical antibiotic therapy[END_REF][START_REF] Stirling | False-negative rate of gram-stain microscopy for diagnosis of septic arthritis: suggestions for improvement[END_REF]. At least 2 pairs of aerobic and anaerobic bottles are necessary, and if possible the blood should be drawn before antibiotic therapy [START_REF] Habib | ESC Guidelines for the management of infective endocarditis: The Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC)[END_REF][START_REF] Baddour | Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications: A Scientific Statement for Healthcare Professionals From the American Heart Association[END_REF]. There is no rationale for preferring blood cultures in the event of a spike in fever [START_REF] Habib | ESC Guidelines for the management of infective endocarditis: The Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC)[END_REF]. Blood culture bottles should be full enough (≥8 mL/bottle) to reduce the risk of false negatives.

As for the other biological blood parameters, none are sufficiently effective to be recommended for diagnostic purposes. An elevated white cell count and an inflammatory syndrome are common but not specific [START_REF] Mcbride | Epidemiology, Management, and Outcomes of Large and Small Native Joint Septic Arthritis in Adults[END_REF][START_REF] Carpenter | Evidence-based diagnostics: adult septic arthritis[END_REF][START_REF] Couderc | Predictive value of the usual clinical signs and laboratory tests in the diagnosis of septic arthritis[END_REF][START_REF] Shaikh | Is serum procalcitonin measurement a useful addition to a rheumatologist's repertoire? A review of its diagnostic role in systemic inflammatory diseases and joint infections[END_REF]. A procalcitonin level <0.5 ng/mL does not rule out SA therefore this test is not recommended [START_REF] Baddour | Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications: A Scientific Statement for Healthcare Professionals From the American Heart Association[END_REF][START_REF] Shaikh | Is serum procalcitonin measurement a useful addition to a rheumatologist's repertoire? A review of its diagnostic role in systemic inflammatory diseases and joint infections[END_REF][START_REF] Zhao | Serum procalcitonin levels as a diagnostic marker for septic arthritis: A meta-analysis[END_REF].

Recommendation 6-An X-ray is useful for diagnosing a pre-existing arthropathy and for structural monitoring, but

should not delay joint aspiration. No further imaging is required to make a positive diagnosis of septic arthritis.

X-ray is not particularly effective for diagnosing SA as signs are not usually visible on an X-ray for at least ten days [START_REF] Couderc | Predictive value of the usual clinical signs and laboratory tests in the diagnosis of septic arthritis[END_REF]. However, this imaging enables an anatomical analysis of the joint which may offer a differential diagnosis and serve as a reference for monitoring [START_REF] Beaman | ACR Appropriateness Criteria® Suspected Osteomyelitis, Septic Arthritis, or Soft Tissue Infection (Excluding Spine and Diabetic Foot)[END_REF].

MRI can reveal soft tissue abscesses, oedema and bone erosions during SA [START_REF] Karchevsky | MRI findings of septic arthritis and associated osteomyelitis in adults[END_REF][START_REF] Bierry | MRI findings of treated bacterial septic arthritis[END_REF]. However, limited access to this examination makes its use inappropriate for the diagnosis of SA in an emergency. MRI is the preferred imaging method for certain specific sites such as septic arthritis of the sacroiliac joints and pubic symphysis. Data on an 18 FDG PET/CT for SA in a native joint is very limited and its accessibility makes it as unsuitable for SA as an MRI (34).

Recommendation 7-There is no indication for the systematic use of a joint ultrasound. Joint ultrasound is nevertheless useful to confirm the presence of intra-articular effusion in case of clinical uncertainty and can be used to guide aspiration.

In cases of SA, ultrasound can reveal joint effusion and/or synovitis, which can be useful for a deep joint [START_REF] Gaigneux | Ultrasound abnormalities in septic arthritis are associated with functional outcomes[END_REF]. With an ultrasound it is not possible to distinguish between SA and other types of arthritis, although it can provide indirect information suggesting metabolic arthritis (tophus, double contour sign, 'snowstorm' appearance) [START_REF] Filippucci | Ultrasound in crystal-related arthritis[END_REF].

It can be used to distinguish between arthritis and a periarticular disorder (bursitis or tenosynovitis), which can be hard to tell apart upon clinical examination (Appendix A, Table S7). Lastly, ultrasound can help guide joint aspiration in a difficult-to-access joint.

Recommendation 8-A cardiac ultrasound should be used to screen for infective endocarditis in cases of septic arthritis caused by Staphylococcus aureus, non-groupable oral streptococci, Streptococcus gallolyticus or Enterococcus faecalis.

Infective endocarditis (IE) should be considered in the event of a heart valve insufficiency murmur with positive blood cultures. However, even when a blood culture is negative, certain bacterial species such as Streptococcus sp. call for screening for IE [START_REF] García-País | Streptococcus bovis septic arthritis and osteomyelitis: A report of 21 cases and a literature review[END_REF]. The frequency of peripheral SA associated with IE (around 5%) is lower than that of spondylodiscitis. The most frequent clinical presentation is acute monoarthritis predominant in the large joints of the lower limbs [START_REF] González-Juanatey | Rheumatic manifestations of infective endocarditis in non-addicts. A 12-year study[END_REF]. They are often the source of Staphylococcus aureus IE complications [START_REF] Nolla | Pyogenic arthritis of native joints in non-intravenous drug users: A detailed analysis of 268 cases attended in a tertiary hospital over a 22-year period[END_REF]. Although rare, acute Staphylococcus aureus oligoarthritis associated with IE is particularly serious [START_REF] Lieber | Clinical characteristics and outcomes in polyarticular septic arthritis[END_REF][START_REF] Habib | ESC Guidelines for the management of infective endocarditis: The Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC)[END_REF].

Recommendation 9-Except where there are signs of immediate severity (sepsis with SOFA ≥2), antibiotic therapy should not be prescribed before joint aspiration is performed to analyze the synovial fluid. Antibiotic therapy will be initiated upon receipt of positive microbiological results (direct examination, synovial fluid culture or blood culture). Probabilistic antibiotic therapy can also be considered in the case of clearly purulent synovial fluid without crystals.

The clinical situations calling for antibiotic therapy are presented in the algorithm (Figure 1). Given the small number of clinical trials published, the main scientific evidence comes from retrospective series [START_REF] Nolla | Pyogenic arthritis of native joints in non-intravenous drug users: A detailed analysis of 268 cases attended in a tertiary hospital over a 22-year period[END_REF][START_REF] Stengel | Systematic review and meta-analysis of antibiotic therapy for bone and joint infections[END_REF][START_REF] Norden | Evaluation of new anti-infective drugs for the treatment of infectious arthritis in adults. Infectious Diseases Society of America and the Food and Drug Administration[END_REF] or prosthetic joint infections [START_REF] Spilf | Recommendations for bone and joint prosthetic device infections in clinical practice (prosthesis, implants, osteosynthesis)[END_REF][START_REF] Osmon | Diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America[END_REF].

Initially, a bactericidal antibiotic (β-lactam) is needed, especially when there is concomitant bacteraemia, but dual therapy is not indicated from the outset (except for Pseudomonas aeruginosa). In the absence of septic shock, there is no indication to add an aminoglycoside (except for infections with Enterococcus sp. or

Pseudomonas aeruginosa) [START_REF] Coiffier | Do aminoglycosides still have a role in acute osteoarticular infections in adults in 2012?[END_REF][START_REF] Safdar | Does combination antimicrobial therapy reduce mortality in Gram-negative bacteraemia? A meta-analysis[END_REF].

First-line antibiotics according to the main microorganisms encountered are recapped in Table 4 (Appendix

A, boxes text S1, S2 and S3).

If the patient is allergic to penicillin, a cephalosporin can be considered as there is little risk of a crossallergy between penicillins and cephalosporins [START_REF] Apter | Is there cross-reactivity between penicillins and cephalosporins?[END_REF].

If it is necessary to start probabilistic antibiotic therapy before the microbiology results are available (signs of immediate severity with SOFA ≥2), it is advisable to prescribe an injectable 1st generation cephalosporin (1GC) (cefazolin) for patients under the age of 70 (to cover at least Staphylococcus aureus and Streptococcus sp.), and prioritize an injectable third generation cephalosporin (3GC) (ceftriaxone or cefotaxime) for patients over 70 because of the higher likelihood of GNR arthritis (46) (Figure 1).

In cases of SA without bacteriological documentation despite repeating microbiological testing, switching to oral therapy is not possible and the IV β-lactam initially prescribed must be continued for the entire duration of treatment.

Table 5 summarizes the practical methods for using the proposed antibiotics to treat SA and their potential side effects.

Recommendation 10-The total duration of antibiotic therapy (IV then oral) should be 4 to 6 weeks for pyogenic bacterial septic arthritis. A total duration of 7 days is sufficient in cases of Neisseria gonorrhoeae arthritis.

The duration of antibiotic therapy currently accepted to treat SA in a native joint is between 4 and 6 weeks. This duration depends on the speed of diagnosis and antibiotic treatment initiation, the clinical response to antibiotic therapy, and the bacterial species isolated [START_REF] Carpenter | Evidence-based diagnostics: adult septic arthritis[END_REF][START_REF] Mathews | Bacterial septic arthritis in adults[END_REF][START_REF] Coakley | British Society for Rheumatology Standards, Guidelines and Audit Working Group. BSR & BHPR, BOA, RCGP and BSAC guidelines for management of the hot swollen joint in adults[END_REF]. A treatment duration of 4 weeks has been suggested in cases of streptococcal SA, and 6 weeks for Staphylococcus [START_REF] Coiffier | Broad-range 16 s rDNA PCR in synovial fluid does not improve the diagnostic performance of septic arthritis in native joints in adults: cross-sectional singlecenter study in 95 patients[END_REF]. There are currently no well-conducted randomized studies to answer this question, but a French clinical trial is in progress (SHASAR study). One randomized study has shown the non-inferiority of a duration of 6 vs 12 weeks of antibiotic therapy in infectious pyogenic spondylodiscitis [START_REF] Bernard | Antibiotic treatment for 6 weeks versus 12 weeks in patients with pyogenic vertebral osteomyelitis: an open-label, non-inferiority, randomised, controlled trial[END_REF].

Shorter antibiotic therapy could be considered in cases of SA in small joints (fingers, wrist) together with articular lavage/synovectomy surgery. One open-label randomized study has demonstrated the noninferiority of 2 versus 4 weeks of antibiotic treatment in this particular context [START_REF] Gjika | Two weeks versus four weeks of antibiotic therapy after surgical drainage for native joint bacterial arthritis: a prospective, randomised, non-inferiority trial[END_REF]. However, this study did not treat haematogenous SA, but mainly SA in small joints (fingers or toes), involving sensitive bacteria (S. aureus in only 1/3 of cases), after direct inoculation (bite or wound), with bacteraemia in only 4%. Therefore these results cannot be transposed in practice to the management of haematogenous SA in native joints. One study has reported a significantly higher rate of infection relapse with 14 days of antibiotic therapy compared to 3 to 6 weeks of treatment for large native joint SA (4).

Seven days of antibiotic therapy is sufficient for infections with Neisseria gonorrhoeae and by extrapolation, other Neisseria sp. like Neisseria meningitidis, which can be responsible for SA [START_REF] Bardin | Gonococcal arthritis[END_REF].

In cases of concomitant bacteraemia without IE, antibiotic treatment should be administered for SA for at least 5 days intravenously, and at least 7 days for S. aureus SA [START_REF] Nolla | Pyogenic arthritis of native joints in non-intravenous drug users: A detailed analysis of 268 cases attended in a tertiary hospital over a 22-year period[END_REF]. In the absence of signs of sepsis (SOFA ≥2), of sustained S. aureus bacteraemia, IE or multi-resistant bacteria (MRSA, P. aeruginosa, etc.), a randomized study recently confirmed the non-inferiority of an early switch to oral therapy (after 7 days) in the treatment of a bone and joint infection [START_REF] Li | Oral versus Intravenous Antibiotics for Bone and Joint Infection[END_REF].

Recommendation 11-The joint should be drained for as long as there is abundant effusion. Repeat joint aspiration drainage and surgical lavage (if possible arthroscopic) are equally recommended, based on the hospital's resources.

During SA, 2 phases can be distinguished: the initial congestive phase with fluid that can be aspirated from the joint cavity, associated with weak to moderate hypervascularized tissue synovitis, and the synovial phase with significant, more or less vascularized synovial tissue hypertrophy, without fluid that can be aspirated [START_REF] Riegels-Nielson | Rabbit model of septic arthritis[END_REF].

In the congestive phase, the main purpose of drainage is to decrease the intra-cavity bacterial inoculum to enhance the effect of antibiotic therapy and limit cartilage damage. Incomplete joint drainage has been identified as an independent risk factor for treatment failure [START_REF] Maneiro | Predictors of treatment failure and mortality in native septic arthritis[END_REF]. No negative impact on mortality has been observed if surgical drainage is performed at least 48 hours after initiating treatment compared to earlier treatment [START_REF] Kodumuri | Time delay between diagnosis and arthroscopic lavage in septic arthritis. Does it matter?[END_REF]. No functional benefits of early surgical lavage/synovectomy have been demonstrated [START_REF] Lauper | Native septic arthritis is not an immediate surgical emergency[END_REF]. No longitudinal study has demonstrated the superiority of early surgery over needle aspiration drainage in the treatment of SA in a native joint [START_REF] Broy | A comparison of medical drainage (needle aspiration) and surgical drainage (arthrotomy or arthroscopy) in the initial treatment of infected joints[END_REF][START_REF] Ravindran | Medical vs surgical treatment for the native joint in septic arthritis: a 6-year, single UK academic centre experience[END_REF][START_REF] Harada | Native Joint Septic Arthritis: Comparison of Outcomes with Medical and Surgical Management[END_REF][START_REF] Flores-Robles | Medical Versus Surgical Approach to Initial Treatment in Septic Arthritis: A Single Spanish Center's 8-Year Experience[END_REF]. In fact, surgical joint drainage (open surgery or arthroscopy) has been associated with a worse functional prognosis and higher mortality (58), while percutaneous drainage has been associated with better functional recovery [START_REF] Broy | A comparison of medical drainage (needle aspiration) and surgical drainage (arthrotomy or arthroscopy) in the initial treatment of infected joints[END_REF][START_REF] Maneiro | Predictors of treatment failure and mortality in native septic arthritis[END_REF].

British guidelines in 2006 recommended repeat SF drainage until the joint dries "as often as necessary", with no preference given between repeat aspiration and arthroscopic lavage [START_REF] Coakley | British Society for Rheumatology Standards, Guidelines and Audit Working Group. BSR & BHPR, BOA, RCGP and BSAC guidelines for management of the hot swollen joint in adults[END_REF].

For large joints, arthroscopic lavage is recommended if the response to repeat percutaneous needle aspiration is insufficient [START_REF] Coakley | British Society for Rheumatology Standards, Guidelines and Audit Working Group. BSR & BHPR, BOA, RCGP and BSAC guidelines for management of the hot swollen joint in adults[END_REF], in particular with persistently positive cultures despite suitable antibiotic therapy.

Recommendation 12-An additional surgical procedure (joint lavage and/or synovectomy) should be considered if the infection is not controlled systemically or locally despite appropriate antibiotic therapy and repeat joint aspiration drainage.

Synovectomy surgery is not relevant for first-line treatment of SA in a native joint, especially in the congestive phase. This procedure has a stiffening effect that delays short-term functional recovery and does not improve the functional prognosis in the medium term [START_REF] Nolla | Pyogenic arthritis of native joints in non-intravenous drug users: A detailed analysis of 268 cases attended in a tertiary hospital over a 22-year period[END_REF][START_REF] Coakley | British Society for Rheumatology Standards, Guidelines and Audit Working Group. BSR & BHPR, BOA, RCGP and BSAC guidelines for management of the hot swollen joint in adults[END_REF].

However, it should be considered in cases of persistent synovial hypertrophy with poor infection control despite appropriate antibiotic therapy, and after ruling out a differential diagnosis. Synovectomy can be performed by arthrotomy or arthroscopy depending on the hospital's technical resources.

The efficacy of the two techniques seems to be equivalent, but functional recovery in the medium term is inferior with arthrotomy and there are more complications (58-60). Arthroscopy should be preferred for the shoulder or knee, while open synovectomy should be considered when arthroscopic access poses technical difficulties.

As an indication, arthroscopic lavage should be considered in case of persistent purulent fluid and/or a positive culture after 5 to 7 days of suitable antibiotic therapy and synovectomy can be considered in cases of persistent inflammatory synovial hypertrophy after 15 days of appropriate antibiotic therapy and after ruling out a differential diagnosis (other coexisting inflammatory rheumatism, especially metabolic).

Recommendation 13-Early physical therapy adapted to the patient's pain level is essential to maintain then improve passive joint range. Immobilization can be offered for pain relief for as short a time as possible.

The absolute priority as far as physical therapy is concerned is recovering or maintaining joint range, initially by passive mobilization adapted to the patient's pain level, then active mobilization. Muscle therapy is secondary and can be started later.

There are no comparative studies evaluating the different methods of physical therapy during or after SA, but certain surgical trials have reported the importance of starting the day after surgery, under the supervision of the physical therapy team (60). No studies have evaluated the relevance of systematic joint immobilization.

Recommendation 14-In cases involving a weight-bearing joint, partial weight-bearing with 2 canes (normal gait simulation) is possible as soon as the pain allows and the infection is in check.

The recommended period to avoid weight-bearing for a weight-bearing joint (hip, knee or ankle) is not specified in the literature. No studies have shown the effectiveness of non-weight-bearing for preventing chondrolysis or epiphyseal osteonecrosis during SA.

Walking should be progressively encouraged based on pain levels during hospitalization (non-weightbearing using 2 canes), gradually recovering weight-bearing over 4 to 6 weeks (60).

Recommendation 15-Septic arthritis must be monitored both clinically and by lab tests (CRP). The purpose of monitoring is to keep track of the infection, find and eradicate the portal of entry (if identified), and assess functional sequelae. An X-ray is necessary at the end of antibiotic treatment to assess any structural damage.

There is no data in the literature on the frequency or duration of SA monitoring. At least 6 months of follow-up is suggested.

The clinical information to consider is fever, pain, joint range, joint swelling, muscle atrophy and functional repercussions.

A poor functional outcome is not synonymous with a relapse or treatment failure. Structural joint damage is frequently observed after SA (almost 50%), even when healed. A type 1 complex regional pain syndrome (formerly known as reflex sympathetic dystrophy) can complicate and modify functional recovery, especially in wrist and ankle SA.

The standard weight-bearing X-ray makes it possible to assess the osteochondral structural damage.

It is useful to monitor complete blood count, kidney function and transaminases with lab tests to assess tolerance to antibiotic therapy.

It can be useful to monitor changes in CRP, although a persistent inflammatory syndrome does not mean that the infection has not healed. It is important to be able to look for other causes of inflammatory syndrome in this context (thrombophlebitis, lymphangitis due to an IV catheter, non-eradication of a persistent portal of entry (bedsore, cancer, etc.), concomitant IE, or non-infectious synovitis in the infected or another joint (metabolic, chronic progressive inflammatory rheumatism, post-infectious reactive synovitis, etc.).

The portal of entry responsible for haematogenous SA must always be sought and eradicated based on bacteriological documentation (Appendix A, Box text S4).

Recommendation 16-In cases of joint destruction responsible for painful and debilitating functional disability, a prosthetic joint or arthrodesis (depending on the joint site) should be considered and discussed in a multidisciplinary meeting.

There are few studies analyzing post-SA arthroplasty in native joints. This possibility can be considered as soon as the infection subsides, particularly in a hip, which is especially vulnerable, carries a high risk of sequelae (rapid chondrolysis, osteonecrosis) and is difficult to access for surgical lavage/synovectomy.

One prospective study has described certain cases of hip arthroplasty immediately following SA with a good functional prognosis (61).

The timeline and methods of perioperative care must be discussed on a case-by-case basis in a local multidisciplinary meeting. In a complex context (comorbidities, bacterial resistance or surgical difficulties), it is best to refer the patient to a reference centre for complex bone and joint infections.

Table 1 :

 1 58. Johns BP, Loewenthal MR, Dewar DC. Open Compared with Arthroscopic Treatment of Acute Septic Arthritis of the Native Knee. J Bone Joint Surg Am. 2017;99(6):499-505 59. Böhler C, Pock A, Waldstein W, Staats K, Puchner SE, Holinka J, Windhager R. Surgical treatment of shoulder infections: a comparison between arthroscopy and arthrotomy. J Shoulder Elbow Surg. 2017;26(11):1915-1921. 60. Peres LR, Marchitto RO, Pereira GS, et al. Arthrotomy versus arthroscopy in the treatment of septic arthritis of the knee in adults: a randomized clinical trial. Knee Surg Sports Traumatol Arthrosc. 2016;24(10):3155-3162. 61. Gupta MN, Sturrock RD, Field M. A prospective 2-year study of 75 patients with adult-onset septic arthritis. Rheumatology General principles and recommendations for the management of septic arthritis in an adult native joint.It is essential to perform joint aspiration before administering antibiotics for a cytobacteriological analysis of the synovial fluid (except where there are immediate severity signs of sepsis with a SOFA ≥2). The additional inoculation of the synovial fluid in blood culture bottles is recommended, in particular in cases of prior antibiotic therapy or long waiting times.Based on the analysis of the synovial fluid, microcrystal detection must be carried out in addition to the cytobacteriological analysis but their presence does not rule out the diagnosis of septic arthritis.Except where there are signs of immediate severity (sepsis with SOFA ≥2), antibiotic therapy should not be prescribed before joint aspiration is performed to analyze the synovial fluid. Antibiotic therapy will be initiated upon receipt of positive microbiological results (direct examination, synovial fluid culture or blood culture). Probabilistic antibiotic therapy can also be considered in the case of clearly purulent synovial fluid without crystals.

		Oxford. 2001;40(1):24-30.
			Level of		Level of agreement
			evidence	*	Average	≥8/10
	General principles
	A	Septic arthritis is a diagnostic emergency due to the morbidity and mortality and the functional risk related to structural damage.	3a -C	R1	9.50 ±1.4	95.0%
	B	Efforts should be made to provide microbiological documentation (blood cultures and joint aspiration) of the septic arthritis before starting antibiotic treatment.	2b -C	R1	9.43 ±1.5	90.0%
	C	Septic arthritis must be managed from the start by a medical and surgical team that has experience with this condition.	5 -D	R2	8.91 ±1.5	90.6%
	Specific recommendations
	1	Septic arthritis should be considered in all cases of acute monoarthritis whether the patient is febrile or not. Oligo-or polyarticular involvement does not rule out the diagnosis.	2a -B	R1	9.30 ±1.4	87.5%
	2	Suspected septic arthritis justifies looking for signs of immediate severity (quick SOFA ≥2).	3b -C	R2	9.09 ±1.5	87.5%
	3		2a -B 4 -C	R1	9.13 ±1.8	80.0%
	4		2a -B 3b -C	R1	8.93 ±1.3	80.0%
	5	At least 2 sets of blood cultures should be performed before proposing antibiotic therapy, even in the absence of a fever.	2a -B	R2	9.53 ±0.8	96.9%
		An X-ray is useful for diagnosing a pre-existing arthropathy and for structural monitoring, but
	6	should not delay the joint aspiration. No further imaging is required to make a positive diagnosis	3b -C	R1	9.15 ±1.4	87.5%
		of septic arthritis.
		There is no indication for the systematic performance of a joint ultrasound. Joint ultrasound is
	7	nevertheless useful to confirm the presence of intra-articular effusion in case of clinical	2b -B	R1	9.53 ±0.8	95.0%
		uncertainty and can be useful to guide aspiration.
		A cardiac ultrasound should be used to screen for infective endocarditis in cases of septic
	8	arthritis caused by Staphylococcus aureus, non-groupable oral streptococci, Streptococcus gallolyticus or	3b -C	R2	8.97 ±1.6	90.6%
		Enterococcus faecalis.
	9		3b -C	R2	8.50 ±2.2	81.5%
		The total duration of antibiotic therapy (IV then oral) should be 4 to 6 weeks for pyogenic
	10	bacterial septic arthritis. A total duration of 7 days is sufficient in cases of Neisseria gonorrhoeae	3b -C	R1	8.85 ±1.6	82.5%
		arthritis.
		The joint should be drained for as long as there is abundant effusion. Surgical lavage (if possible
	11	arthroscopic) and repeat joint aspiration drainage are equally recommended, based on the	3b -C	R2	9.06 ±1.3	93.8%
		hospital's resources.
		An additional surgical procedure (joint lavage and/or synovectomy) should be considered if the
	12	infection is not controlled systemically or locally despite appropriate antibiotic therapy and repeat	3b -C	R2	9.19 ±1.5	90.6%
		joint aspiration drainage.
	13	Early physical therapy adapted to the patient's pain level is essential to maintain then improve passive joint range. Immobilization can be offered for pain relief for as short a time as possible.	4 -D	R1	8.75 ±2.2	85.0%
	14	In cases involving a weight-bearing joint, partial weight-bearing with 2 canes (normal gait simulation) is possible as soon as the pain allows and the infection is in check.	5 -D	R1	8.90 ±1.9	90.0%
		Septic arthritis must be monitored both clinically and by lab tests (CRP). The purpose of
	15	monitoring is to keep track of the infection, find and eradicate the portal of entry (if identified), and assess functional sequelae. An X-ray is necessary at the end of antibiotic treatment to assess	5 -D	R2	9.44 ±1.0	96.9%
		any structural damage.
		In cases of joint destruction responsible for painful and debilitating functional disability, a
	16	prosthetic joint or arthrodesis (depending on the joint site) should be considered and discussed in	4 -D	R1	8.75 ±1.3	82.5%
		a multidisciplinary meeting.

Table 2 :

 2 Main differential diagnoses of septic arthritis in cases of acute febrile mono-or oligoarthritis. Adult onset Still's disease. b FMF: Familial Mediterranean Fever (recurrent illness), c CAPS: Cryopyrin-Associated Periodic Syndrome.

	Soft tissue inflammation and infections	Bursitis (septic or microcrystalline)
		Acute resorption of apatite calcification
		Infectious dermohypodermitis (erysipelas)
	Microcrystalline and metabolic arthropathies	Acute arthritis with monosodium urate deposits (gout)
		Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease
		(chondrocalcinosis)
		Acute resorption of apatite calcification
	Inflammatory rheumatic disorders	Peripheral spondyloarthritis including psoriatic arthritis
		Rheumatoid arthritis
		Auto-inflammatory diseases (AOSD a , FMF b , CAPS c etc.)
		Vasculitis (Henoch Schönlein Purpura, Behçet's disease)
		Systemic autoimmune diseases
	Infectious or post-infectious arthropathies	Post-venereal or post-dysenteric reactive arthritis
		Post-streptococcal arthritis or rheumatic fever
		Fungal or parasitic arthritis
		Viral arthritis (hepatitis A, B C, rubella, parvovirus B19, HIV, arbovirus)
	Other arthropathies	Episodic attacks of synovitis (intermittent hydarthrosis)
		Haemarthrosis
	a AOSD:

Table 3 :

 3 SOFA (Sequential Organ Failure Assessment) immediate severity score. Should be calculated if quick-SOFA ≥2 (confusion or respiratory rate >22/min, or SBP <100 mmHg)

		0	1	2	3	4
	PaO2/FiO2, mmHg (kPa) a	≥400 (53.3)	<400/53.3	<300 (40)	<200 (26.7)	<100 (13.3)
		SaO2 ≥95%	SaO2 90-94%	SaO2 <90%	with ventilatory assistance	with ventilatory
						assistance
	Platelets (G/L)	≥150	<150	<100	<50	<20
	Bilirubin (µmol/L)	<20	20-32	33-101	102-204	>204
	Cardiovascular	MAP ≥70 mmHg	MAP <70 mmHg	Dopamine <5	Dopamine 5.1-15	Dopamine >15
				or Dobutamine	or Adrenaline ≤0.1	or Adrenaline >0.1
				(any dosage)	or Noradrenaline ≤0.1	or Noradrenaline >0.1
	Glasgow score	15	13-14	10-12	6-9	<6
	Creatinine (µmol/L)	<110	110-170	171-299	300-440	>440
		≥500	≥500	≥500	<500	<200
	Urine output (mL/24h)
	a Adapted to the patient's assessment excluding critical care (SaO2 added)
	Definition of sepsis if SOFA ≥2 and of septic shock if sepsis + filling and vasopressor + lactates >2 mmol/L

Table 4 .

 4 Antibiotic therapies proposed for the treatment of septic arthritis in an adult native joint based on the main bacterial species isolated.

	Bacterial species	First-line IV antibiotic	Switch to oral antibiotic (according to bacterial sensitivity test)	Antibiotic if contraindication
	Methicillin-sensitive Staphylococcus aureus	cloxacillin, oxacillin or cefazolin	Rifampicin c + FQ d or FQ d + Clindamycin e	Infectious disease consult Choice between
	Methicillin-resistant Staphylococcus aureus	Vancomycin or Teicoplanin	Rifampicin c + FQ d or FQ d + Clindamycin e	Daptomycin, Rifampicin + others (cotrimoxazole, cyclins, linezolid)
	Streptococci	Amoxicillin	Amoxicillin	Clindamycin or anti-streptococcal FQ d
	Enterococci	Amoxicillin + Gentamicin f or Amoxicillin + Ceftriaxone	Amoxicillin	Infectious disease consult
		(Infectious disease consult)
	Group 1 and 2 Enterobacteriaceae	Cefotaxime or Ceftriaxone	FQ d (if strain sensitive to nalidixic acid)	Infectious disease consult
	Group 3 Enterobacteriaceae a	Cefepime	Infectious disease consult according to bacterial sensitivity test	Infectious disease consult
	Pseudomonas aeruginosa	Ceftazidime + Ciprofloxacin b	Infectious disease consult according to bacterial sensitivity test	Infectious disease consult
	Anaerobes	Amoxicillin if sensitive or Metronidazole	Clindamycin or Amoxicillin	Infectious disease consult
	Neisseria gonorrheae	Ceftriaxone or Cefotaxime	FQ d	Infectious disease consult

a Group 3 Enterobacteriaceae (Enterobacter sp., Citrobacter freundii, Serratia sp., Morganella sp., Providencia sp.) should not be treated using a 3GC antibody (cephalosporinase is induced, making the antibiotic inactive), but with a 4th generation cephalosporin such as cefepime. b A dual therapy comprised of Ceftazidime + amikacin can be used for the first 48 hours (decrease in bacterial inoculum) pending the final bacterial sensitivity test (sensitivity to ciprofloxacin) c Rifampicin should not be used as a monotherapy. d FQ: the following fluroquinolones can be used in the treatment of septic arthritis: ofloxacin, levofloxacin, ciprofloxacin and moxifloxacin. All of these FQs are effective against staphylococci, Enterobacteriaceae and gonococci. Levofloxacin and moxifloxacin are effective against streptococci. Ciprofloxacin and levofloxacin are effective against Pseudomonas aeruginosa. Moxifloxacin should be used with caution due to its cardiac toxicity (heart rhythm disorders) and potential liver toxicity. e Clindamycin monotherapy can be proposed as an alternative (second-line treatment), according to US recommendations, in staph infections sensitive to erythromycin and clindamycin, in particular if resistant to FQ and/or rifampicin. f Gentamicin is offered for a period of 3 to 5 days in the absence of concomitant endocarditis.

Table 5 .

 5 Practical methods for using the main antibiotics for the treatment of septic arthritis in adult native joints: dosages (in the absence of renal impairment), route of administration and main adverse reactions to look for.IV: 75 to 100 mg/kg/day a IV: 75 to 100 mg/kg/day a Flash IV 2 g every 12 (if total dose 4 g) or every 24 h (if total dose 2 g) IV to divide into 6 infusions/day or continuous infusion after a loading dose of 2 g over 1 hour then syringe pump b IV to divide into 3 infusions/day or continuous infusion after a loading dose of 2 g over 1 hour then syringe pump b IV to divide into 3 infusions/day or continuous infusion after a loading dose of 2 g over 1 hour then syringe pump b

	Antibiotic	Dosage (CKD-EPI >60 ml/min)	Route of administration	Monitoring
	Cloxacillin	IV: 150 mg/kg/day a	IV to divide into 4 to 6 infusions/day	Drug eruption
	Oxacillin	without exceeding 16 g/day	or continuous infusion after a loading dose of	Acute tubulopathy (drug-induced crystalluria)
			2 g over 1 hour then syringe pump b	GI disorders
				Acute cytolytic hepatitis
	Amoxicillin	IV: 150 to 200 mg/kg/day a	IV to divide into 6 infusions/day	Drug eruption
		without exceeding 16 g/day	or continuous infusion (daily dose divided into	GI disorders
			three 8-hour infusions) after a loading dose of	Encephalitis (confusion/epilepsy)
		Oral: 4.5 to 6 g/day in 3 doses	2 g over 1 hour then syringe pump b	Acute interstitial nephritis
				Acute tubulopathy (drug-induced crystalluria)
	Cefazolin	IV 80 to 100 mg/kg/day a	IV to divide into 4 to 6 infusions/day	Cytopenia
			or continuous infusion (daily dose divided into	Acute cytolytic hepatitis
			two 12-hour infusions) after a loading dose of
			2 g over 1 hour then syringe pump b
	Ceftriaxone	IV: 2 to 4 g/day		Cytopenia
				Acute cytolytic hepatitis
				GI disorders (risk of PMC)
	Cefotaxime	IV: 150 to 200 mg/kg/day a
	Ceftazidime
	Cefepime
	Vancomycin	IV: 40 mg/kg/day a ,	Loading dose of 1 g over 1 h then syringe pump,	For vancomycin:
		to adapt to assays	to be adapted to assays b	'Red man' syndrome if infused too fast.
				Vascular toxicity: requires central line or
				adapted dilutions by peripheral line.
	Teicoplanin	IV: 10 mg/kg a with loading and then maintenance dose	Loading dose 10 mg/kg/12 h the first 3 days then 1 slow IV injection of 10 mg/kg/day over 30 min b	For all glycopeptides: Ototoxicity and nephrotoxicity Drug eruption
		to adapt to assays	IM route possible (same doses)
	Rifampicin	10 to 15 mg/kg/day a	Taken orally on an empty stomach,	Enzyme induction: many combinations
		600 mg once daily (<45 kg)	once a day if total dose <900 mg,	contraindicated (anticoagulants, antiretrovirals,
		900 mg once daily (45 to 60 kg)	in 2 doses if total dose >900 mg	calcineurin inhibitors, etc.)
		600 mg twice daily (>60 kg)		GI disorders
				Acute cytolytic hepatitis
				Orange coloration of secretions
				Never as a monotherapy
	Ofloxacin	200 mg twice daily (monotherapy)	Always oral	Neutropenia (combination with rifampicin)
		200 mg twice daily (combination with		Tendinopathy (risk of rupture)
		rifampicin)		Photosensitization
	Levofloxacin			Risk of QT prolongation (moxifloxacin)
		500 mg once daily (<60 kg)		GI disorders (risk of PMC)
		750 mg once daily (>60 kg)
	Ciprofloxacin
		500 mg twice daily (<60 kg)
		750 mg twice daily (>60 kg)
	Moxifloxacin
		400 mg once daily
	Clindamycin	600 mg three times a day (60 to 90 kg)	Oral (or IV)	GI disorders (risk of PMC)
		900 mg three times a day (>90 kg)		Frequent rashes
				Risk of QT prolongation (IV use)
	Gentamicin	6 to 8 mg/kg once daily	IV over 30 minutes, once daily	Nephrotoxicity c
				Ototoxicity
	Amikacin	20 to 30 mg/kg once daily
	a Weight dose calculated using the ideal body weight if BMI >25. Ideal weight using Lorentz formula = height (cm) -100 -(height (cm) -150)/X,
	(where X = 2 if woman and X = 4 if man)

b

The use of a syringe pump for antibiotic therapy requires drug monitoring by assaying the trough level 48 to 72 hours after changing the dosage. Target assay between 20 and 50 µg/mL for β-lactams and between 30 and 50 µg/mL for glycopeptides.

c

No need to determine the trough level of aminoglycosides for short-term treatment (<5 days) for patients without renal impairment (CKD-EPI >60 ml/min). The trough level assay is only recommended if an aminoglycoside is needed in patients with renal impairment and/or for prolonged treatment, such as with concomitant endocarditis. IV: Intravenous, PMC: Pseudomembranous colitis

Acknowledgements

The working group wishes to thank the SFR for its logistical support and all the reviewers who made it possible to compile these recommendations. The working group thanks SPILF and SOFCOT for their contribution to these recommendations.

Conflicts of interest:

The authors declare that they have no conflicts of interest in relation to the content of the recommendations.

Review group:

Rheumatologists (in alphabetical order): Athan Baillet (Grenoble University Hospital), André Basch (private practice, Lyon), Pauline Baudet (Caen University Hospital), Guy Baudens (private practice, Valencienne), Rachel Brault (Poitiers University Hospital), Maurizzio Carteni (private practice, Coutance), Xavier Deprez (Valencienne Hospital), Emmanuelle Dernis (Le Mans Hospital), Vincent Ducoulombier (Lille Catholic Institute Hospitals), Vincent Dielbot (private practice, Bilière), Aline Frazier (APHP Cochin, Paris), Cécile Guilyardi (private practice, Nimes), Franck Grados (Amiens University Hospital), Emmanuel Hoppé (Angers University Hospital), Damien Loeuille (Nancy University Hospital), Thierry Marhadour (Brest University Hospital), Jean-Camille Méric (private practice, Ales), Frédéric Maury (private practice, Beuvry), Hubert Marotte (Saint-Etienne University Hospital), Gaël Mouterde (Montpellier University Hospital), Sébastien Ottaviani (APHP Bichat, Paris), Edouard Pertuisset (Pontoise Hospital), David Perard (private practice, Villeurbanne), Murielle Piperno (Lyon University Hospital), Adeline Ruyssen-Witrand (Toulouse University Hospital), Jean-Hugues Salmon (Reims University Hospital), Thierry Shaeverbecke (Bordeaux University Hospital), Isabelle Valls-Bellec (private practice, Brest).

Infectious disease specialists (in alphabetical order):

Eric Bonnet (Toulouse Hospital), Remy Gauzit (APHP Cochin, Paris), Nahema Issa (Bordeaux University Hospital), David Lebeaux (APHP Pompidou, Paris), Laurence Maulin (Aix-en-Provence Hospital), Delphine Poitrenaud (Ajaccio Hospital), Pierre Tattevin (Rennes University Hospital), Yves Welker (Poissy Hospital).

Orthopaedists (in alphabetical order):

Jean-Yves Jenny (Strasbourg University Hospital), Didier Mainard (Nancy University Hospital), Simon Marmor (Diaconesses Croix-Saint-Simon Hospital Group, Paris), Nicolas Reina (Toulouse University Hospital), Philippe Rosset (Tours University Hospital).

Appendix A. Supplementary data

Supplementary data (Tables S1-S7, boxes text S1-S4) associated with this article can be found in the online version at …


Ph.D Niklas Henke
email: henkeniklas1@googlemail.com

Corporal Implications of Design Practices and Methods

Keywords: Design, Management, Innovation, Marketing, Embodiment

In this paper, I analyze the characteristics of method-guided and nonmethod-guided design practices from the perspective of their corporal implications. To this end, I refer to the most common design methods reported in the literature as compare them to participative observations in the French and German design and innovation sectors over the last five years. While design methods are supposed to frame the project set-up with a high level of rationalization, non-method-guided design practices demonstrate a higher mobilization of intuition, experience, and tacit knowledge. I trace these differences along with their varying corporal implications and highlight their underlying epistemological approaches. In conclusion, I argue for the need to integrate affective and corporal education in design curricula.

Introduction

At present, design practices are being reshaped by two major tendencies. On the one hand, design practices become increasingly influenced by artificial intelligence [START_REF] Mazzone Marian | Art, creativity, and the potential of artificial intelligence[END_REF]. On the other hand, design practices are partly merging with other communication professions [START_REF] Bernard | Les industries culturelles et créatives face à l'ordre de l'information et de la communication[END_REF]Henke & Martin-Juchat, 2021). In this article, I focus on the latter trend and take a closer look at similarities and differences between design practices commonly used by designers and those realized by other communication professionals. My particular focus is on the role of design methods and their link with the participants' human body.

According to Lipovetsky and Serroy (2013), modern progress can be conceptualized as a constant aestheticization of products, services, and brands. This aestheticization promotes the socioeconomic importance of design as a professional discipline for marketing, product development, and brand management [START_REF] Peter | Eine neue Strategie der Unterneh-mensführung [The design value. A new strategy of corporate management[END_REF]Kapferer, 2012;[START_REF] Rieke Nina | Mit dem Leitsystem für wertorientierte Markenführung mehr gesellschaftlichen Impact erzielen [How values make brands strong. Achieving more social impact with the guiding system for value-based brand management[END_REF].

Accordingly, design has the potential of adding value and meaning to communication [START_REF] Heilbrunn Benoît | La marque[END_REF]Michel, 2017), and it is able to do so, in a tacit manner (Henke, 2021b), thus addressing affects and the human body. The growing importance of design for the development of new technologies and services can be traced in the transition from Marketing 1.0 to 5.0. Specifically, as proposed by Kotler et al. (2021), marketing transformed from product-driven (Marketing 1.0) to customer-oriented (Marketing 2.0), human-centric (Marketing 3.0), digital (Marketing 4.0), and, ultimately, to Marketing 5.0: "for the good of humanity" (Ibid.). In this article, I argue that an important task of design is to add such emotional and ethical value to communication. Therefore, integrating design and exploiting creativity in industrial processes is essential to stay competitive (Kogan & Andonova, 2019;Reckwitz, 2019).

Design in an industrial context is frequently realized not by designers, but by other professionals-most notably, those in the communication domain. Different professions show varying approaches of integrating design in industrial processes, which changes the project set-up, the participants' interaction framework, and, consequently, the corresponding design outcomes. For instance, design methods are more frequently applied by communication professions than by designers (Henke, 2021a). Nowadays, we can observe a heterogeneity of design practices. Different agencies, projects, or designers lead to different design practices, methods, and epistemological approaches, which makes it difficult to compare design practices. One of the main differences that sets apart different design practices is the presence or absence of methods. 1 In what follows, I will trace their differences more precisely and discuss the emerging consequences.

Research Questions

In this article, I address the following two main research questions. First, what is the link between the application or non-application of design methods (as well as the gradations between those) and the role of the human body in design projects? Second, which consequences can be identified for the project itself and the involved practitioners?

Hypothesis

My leading research hypothesis is as follows: Method-guided design practices differ from non-method-guided ones by varying corporal implications. Specifically, I predict that non-method-guided practices prioritize intuition, affects and, consequently, the human body. To formulate my prediction even more straightforwardly: I expect that the heterogeneity of design practices can be located along the different gradations attributed to the role of the human body.

Method

To address the aforementioned research questions, I refer to design methods as described in the literature, as well as my professional observations in the French and German design and innovation sectors over the last five years. My active participation in innovation and design projects gave me the possibility to approach my research questions taking the perspective of a "reflective practitioner" [START_REF] Schön | The reflective practitioner. How professionals think in action[END_REF].

While there is extensive literature on design theory, an exhaustive analysis of the application/non-application of design methods in the light of their consequences for the human body is yet to be conducted. This is particularly striking in the context of the recent growing research interest in grounded cognition, embodiment, and affects. Therefore, my approach links the aforementioned questions with my in-field observations as a reflective practitioner grounded in professional experience. The general and re-occurring mechanisms that I can identify, are more important in my approach, then the specific details of the observed design projects.

Theoretical Framework

Design practices show a particular mode of reasoning and follow their proper epistemological and socio-psychological logic [START_REF] Cross | Developments in design methodology[END_REF][START_REF] Cross | Designerly ways of knowing[END_REF]Beyaert-Geslin, 2012). Specifically, Doorst (2017) proposed to consider design abduction as a different mode of reasoning distinct from deduction, induction, and normal abduction. Similarly, Gentes (2017) proposed projective abduction as the principal mode of design reflection. As I will argue later, the mode of reasoning becomes relevant to my research questions when taking an embodiment perspective [START_REF] Niedenthal | Embodying emotion[END_REF]. According to Lévy (2018), design can be understood as both a transformative and a transforming practice, which suggests that, through its impact on citizens' daily life, design possesses its socio-political power. This capacity of design represents an economic potential for socioeconomic actors. Accordingly, design gets more and more finely integrated into industrial processes. By now, design has become an indispensable element in the construction and maintenance of brand communication (Michel, 2017;[START_REF] Peter | Eine neue Strategie der Unterneh-mensführung [The design value. A new strategy of corporate management[END_REF][START_REF] Rieke Nina | Mit dem Leitsystem für wertorientierte Markenführung mehr gesellschaftlichen Impact erzielen [How values make brands strong. Achieving more social impact with the guiding system for value-based brand management[END_REF]. Its capacity to address the affective dimension of communication is particularly important for its economic value. To understand affects, I will follow the anthropological perspective of grounded cognition and embodiment [START_REF] Niedenthal | Embodying emotion[END_REF]. The core idea of this approach is that affects should be understood as grounded in the human body. Accordingly, affective experiences and higher cognitive processes are conceptualized as grounded in the individual's physiological structure. This perspective resonates with the approaches previously proposed by [START_REF] Varela Francisco | The embodied mind. Cognitive science and human experience[END_REF], [START_REF] Fabienne | Penser le corps affectif comme un média dans une perspective d'anthropologie par la communication [Thinking of the affective body as a medium in an anthropological perspective through communication[END_REF], 2020), and [START_REF] Damasio | The strange order of things. Life, feeling, and the making of cultures[END_REF]. In contrast to computational cognition models, the anthropological perspective of grounded cognition and embodiment posits that cognition and creativity are constituted by practitioners' bodies. The essential consequence of this perspective for my research question is that it underlines the physical properties of design projects, including those of practitioners' bodies, the involved materiality, and the chosen places. This line of thought also reflects the perspective of Dourish ( 2001) and [START_REF] Smith Maarten | Scaffolding shared imagination with tangible design[END_REF], showing that the materialities of design tools (e.g. software, post-its) also constitute a design project. Similarly to actor-network theory (ANT), meaning can be understood as constructed through the interaction between practitioners and the involved materialities and places (Hummels et al., 2019, p. 61). The results of these processes frame the interaction with new products and services. Therefore, I aim to specify how the application of design methods influences design projects.

Results

Niklas, HENKE; Design Practice and Method

In this section, I will briefly present the design methods I refer to in this article, without going into detail about their respective mechanisms, particularities, as well as advantages or disadvantages. The presented methods are the most common ones in the observed design and innovation projects. Most of them include Design Thinking [START_REF] Seitz | Design thinking und der neue Geist des Kapitalismus. Soziologische Betrachtungen einer Innovationskultur [Design thinking and the new spirit of capitalism[END_REF][START_REF] Bonnet Fabien | Le Design Thinking -Au coeur d'un discours sur la rationalisation de l'émergence en organisation [Design Thinking -At the heart of a discourse on the rationalisation of emergence in organisations[END_REF], Creative Problem Solving (Marchal, 2012;Vial, 2020Vial, /2015)), the Double Diamond of the British Design Council2 , the Concept-Knowledge (C-K) theory [START_REF] Hatchuel Armand | CK theory: Modelling creative thinking and its impact on research[END_REF], the Kano model [START_REF] Sauerwein Elmar | The kano model: How to delight your customers[END_REF], and the Theory of Inventive Problem Solving (TRIZ) (Livotov, 2009). What is particularly relevant when analyzing these methods is that they share several underlying mechanisms. A dominant parallel is the alternation between phases of divergence and convergence. Another one is the repetition of these phases in iteration cycles (differing according to each project). For each of these methods, it is essential to define input information maximally precisely. Throughout the project, they aim for a high level of transparency and traceability. Each step, idea, and artifact is documented as precisely as possible, which, among other things, helps to track the emergence of ideas. Therefore, project managers are supposed to document project artifacts in a maximally tangible and explicit way. Overall, the design methods are meant to frame the project set-up in a transparent manner. However, the described guidelines represent ideal cases-the reality of each design project adapts itself to the particularities of the specific project context and the flexibility of the involved participants.

When comparing the presented principles of design methods with design practices that I observed during the last five years in the French and German design and innovation sectors, I obtained the following picture. First of all, I observed a nuanced heterogeneity of practices. Most of these practices are guided by intuition, experience, and tacit knowledge. 3 In these cases, conception and perception of designs are guided by the designers' cognitive evaluations and affective reactions. Interestingly, a common quality judgment is when the result feels right to the designer. This kind of affect is blended with the designer's prior knowledge about the project, its sociocultural context, the project owner, and the brand. Thus, what is happening here is that a designer synchronizes the emerging affective reactions with internalized conceptualizations of the target group. The designs are sensibly screened for what do they evoke? Might this work for the target group? During this process of affective screening, the role of the human body remains for most part implicit. I rarely observed that the human body is explicitly considered as a variable that affects the design process. As mentioned previously, the guiding questions are similar to the ones used in user research. At this point, let me recall that we observe different approaches towards user research-for instance, some designers always apply it, some never, and some punctually according to each project. However, the affective reactions and cognitive evaluations of a design are blended with pop-cultural and sociopolitical trends -constantly aiming to evaluate whether a design proposition is suitable for the corresponding market and the respective brand positioning. In that sense, the competence of the designer is to sense the project in the holistic context of the society. This aptly captures daily working practices of successful designers. Using a term coined by Kees Overbeeke, the approach of Bierut (2015)4 can be described as educated intuition (Overbeeke & Hummels, 2014).

In conclusion, for both method-guided and non-method-guided practices, the precise definition of input information is an important feature in order to augment the probability of satisfying outcomes. However, unlike method-guided practices, their non-method-guided counterparts show a higher level of improvisation, spontaneity, and flexibility. The project relies on the affective-and in most cases implicit-screening of design propositions. For method-guided practices, project artifacts and affective evaluations are meant to be made more explicit. In summary, while method-guided practices demonstrate a higher level of rationalization, non-method-guided ones remain more intuitive. Of note, this conclusion should be taken as somewhat schematizing-admittedly, most practices are located inbetween the two extremes and show fine nuances of the described principles, thus illustrating the aforementioned heterogeneity of design practices.

Discussion

In previous sections, I described the common underlying logic of design methods and compared them with observations of design practices. My results revealed that, while method-guided practices imply a higher level of rationalization, non-method guided ones show a higher mobilization of intuition, experience, and tacit knowledge. In non-method-guided practices, a designer evaluates the quality of designs through the affective screening of design proposition, informed by the designer's knowledge about the sociocultural context of the project. In the theoretical framework adopted in this article, affects are assumed to be interwoven with the designer's physiological structure. Accordingly, the described design practices can be understood as following a higher level of corporal implication. The application or non-application of design methods therefore changes the designers' attitude towards the project and the respective design propositions. Said differently, the application of design methods implies different affective and corporal dispositions. These varying corporal implications between method-guided and non-method-guided practices correspond to different epistemological approaches.

Conclusions

In this article, I analyzed design methods as presented in the literature and design practices as observed in the French and German design and innovation sectors over the last five years. The application or nonapplication of structured methods influences the attributed role of the human body and the consideration of affects. I identified varying corporal implications corresponding to different underlying epistemologies. While the indicated design methods aim for a high level of transparency, rationalization, and explicitation, non-methodguided design practices are mostly guided by intuition, experience, and tacit knowledge. In the latter case, the project follows a designer's affective screening of a given design. The grounding of affects in the human body is present in an implicit manner. Therefore, it corresponds to Polanyi's (2009Polanyi's ( /1966) definition of tacit competences. In the process of affective screening, the designer senses whether or not a design feels right, and this evaluation includes a consideration of the respective sociocultural context of the project and the involved brand positioning. In conclusion, while I differentiated method-guided practices from non-method-guided ones, this differentiation should be perceived as somewhat schematizing, as, in fact, each design project is unique and there is a fine gradation between the two aforementioned types practices. Further research will be necessary to precise all the gradations between those extremes. Yet, the results underscore the importance of affective and corporal education in design curricula. Developing concrete concepts and formats for doing so is a promising task for future research projects. In further research, it would also be meaningful to evaluate the respective design quality.

While other variables are for instance, the project context or the designer's education, in this article, I focus on the mentioned one.

https://www.designcouncil.org.uk/news-opinion/what-framework-innovation-designcouncils-evolved-double-diamond

Following the understanding of tacit knowledge as described byPolanyi (2009Polanyi ( /1966)).

For examples, see the website ofPentagram (www.pentagram.com).

Acknowledgments

I acknowledge the valuable feedback of Fabienne Martin-Juchat and Pierre Lévy while I was writing this article.

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