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CLINICAL REVIEW                                                                                 For the full versions of these articles see bmj.com




                                   Diagnosis and management of
                                   prosthetic joint infection
                                   Philippa C Matthews,1,2,3 Anthony R Berendt,1,2 Martin A McNally,1 Ivor Byren1,2



1
 Bone Infection Unit, Nuffield     Joint replacement is safe, cost effective,1 and widely        presence of any wound complication was significantly
Orthopaedic Centre NHS Trust,      undertaken. Most prosthetic joint replacements are            associated with deep infection.12 In a prospective case-
Headington, Oxford OX3 7LD         hips and knees; more than 130 000 people underwent            control study, persistence of wound drainage for
2
  Department of Infectious         such procedures in England and Wales in the                   longer than five days after surgery and wound haema-
Diseases, Oxford Radcliffe
Hospitals NHS Trust, John          12 months from April 2006.w1 Subsequent prosthetic            toma were associated with prosthetic joint infection
Radcliffe Hospital, Headington,    joint infection is uncommon—the incidence varies              (odds ratios 1.3 and 11.8).w12 These studies highlight
Oxford OX3 9DU                     between 0.6% and 2% per joint per year.2-5 However,           the need for careful scrutiny of all wound complica-
3
  University of Oxford, Peter
                                   this complication is associated with substantial mor-         tions overlying an arthroplasty.
Medawar Building for Pathogen
Research, Oxford OX1 3SY           bidity and economic cost ($30 000 (£20 500; €22 800)             The proportion of prosthetic joints that become
Correspondence to: P C Matthews    to $50 000 per patient).3 4 6 w2 The diagnosis of prosthe-    infected within three months of arthroplasty varies
p.matthews@doctors.org.uk          tic joint infection is difficult,w2 because symptoms,         widely—from 29% to 69% in cohorts from the United
Cite this as: BMJ 2009;338:b1773
                                   signs, and investigations may all be non-specific.7 w3        Kingdom.2 10 Early infection is usually acquired at the
doi:10.1136/bmj.b1773              Defining diagnostic criteria and optimum manage-              time of surgery or as a consequence of wound infec-
                                   ment is complicated by patient heterogeneity and the          tion, whereas later infections arise because of haema-
                                   small numbers in many published studies.w4 However,           togenous spread8 or because the pathogens are of low
                                   prompt recognition and diagnosis of prosthetic joint          virulence and slow to cause symptoms.
                                   infection facilitates timely intervention to salvage
                                   infected joints, preserve joint function, prevent mor-        Which organisms commonly cause prosthetic joint
                                   bidity, and reduce costs.                                     infection?
                                                                                                 Gram positive organisms, especially staphylococci
                                   What are the clinical features of prosthetic joint            (commensal skin organisms), are most common
                                   infection?                                                    (table 1). 2 9 10 15 17 In early infection, pathogens are
                                   Early prosthetic joint infection (box 1) characteristi-       usually more virulent (for example, Staphylococcus aur-
                                   cally presents with wound inflammation, joint effusion,       eus), 18 whereas more indolent organisms predominate
                                   loss of function, and pain,8 9 w5 w6 with or without wound    later on (for example, coagulase negative staphylo-
                                   dehiscence and discharge.8 9 Later disease is more            cocci, Propionibacterium acnes). 10 In a recent UK study,
                                   likely to present with pain or mechanical dysfunc-            however, most early cases were caused by coagulase
                                   tion.w2 Systemic features, such as pyrexia, nausea, and       negative staphylococci. 8 In this cohort, most antibiotic
                                   malaise, are neither sensitive nor specific.w7 The onset
                                   of symptoms may be acute or insidious, with progres-
                                   sive pain or loss of function.7 9                              SOURCES AND SELECTION CRITERIA
                                                                                                  We performed Medline searches between November
                                   Who is at risk of prosthetic joint infection and when          2008 and January 2009 using the search terms
                                   does it present?                                               “prosthetic joint” and “arthroplasty” combined with
                                   Infection rates vary according to the joint replaced,          “infection”, “guidelines”, “septic arthritis”, “infection
                                   indication for arthroplasty, comorbid conditions, and          diagnosis”, “infection epidemiology”, and “infection
                                   prophylactic strategies (box 2).5 15 Obesity and diabetes      revision arthroplasty”. Where possible, we focused on
                                   have been associated with early infection.9 15 w8 No           articles published in the past five years and restricted our
                                   increase in prosthetic joint infection has been reported       search to literature published in English. We also drew
                                   in small cohorts of patients with kidney transplantsw9 or      from the experience of, and articles and documents
                                   HIV infection,w10 w11 but as arthroplasty is increasingly      published by, our multidisciplinary bone infection unit in
                                                                                                  the United Kingdom (www.noc.nhs.uk), which manages
                                   performed the number at risk may increase.
                                                                                                  around 40 secondary and tertiary referral cases of
                                      In publications from the Mayo Clinic, 25% of wound
                                                                                                  prosthetic joint infection a year.
                                   infections were associated with joint infection,6 and the

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                                          resistant and polymicrobial infections presented
                                          within three months of arthroplasty. 10 Infection with                       Box 1 Definitions of prosthetic joint infection
                                          antibiotic resistant organisms poses an increasing chal-                     No uniform case definitions exist for prosthetic joint
                                          lenge, with meticillin resistant S aureus (MRSA) being                       infection, but widely accepted definitions include any of the
                                          more common than meticillin sensitive S aureus                               following6 7 9-12 w6 w14:
                                          (MSSA) in some series. 9 15                                                       Purulence around a prosthesis at arthrotomy or
                                                                                                                             arthroscopy
                                          Which laboratory investigations are needed?                                       Presence of one or more sinus tract communicating with
                                          Figure 1 summarises key steps in the diagnostic pro-                               the joint
                                          cess. UK guidelines recommend baseline blood tests                                Histological features of infection
                                          for inflammatory markers (C reactive protein, erythro-                            Isolation of an indistinguishable organism from at least
                                          cyte sedimentation rate, leucocyte count) for any case                             two deep culture samples (“indistinguishable” refers to
                                          of septic arthritis.w5 However, these parameters are                               widely performed laboratory characterisation of an
                                          raised for up to two weeks after orthopaedic surgery                               organism; in most cases this will be identification of the
                                          so are non-specific for early infection. 8 Serial measure-                         genus and species, plus antibiotic susceptibilities13).
                                          ments can be useful, 22 because persistently or progres-                           Isolation of a virulent organism, such as Staphylococcus
                                          sively high inflammatory markers may help to                                       aureus, Escherichia coli, or Candida spp, in one deep
                                          distinguish joint infection from an uncomplicated                                  tissue sample is regarded by some as sufficient to
                                          postoperative course. Normal results do not exclude                                confirm the diagnosis.7
                                          joint infection, 7 14 particularly infection with indolent                   Early prosthetic joint infection
                                          organisms.                                                                   Early prosthetic joint infection is most widely defined as
                                             Blood for culture should be taken before patients                         deep infection of an arthroplasty occurring within three
                                          with suspected acute infection are started on anti-                          months of joint replacement. Subsequent presentation is
                                          biotics, although cultures are usually negative.3 9                          divided into delayed (3-12 months after index surgery) or
                                          Early empirical treatment reduces the diagnostic                             late (12 months).8 9 11 14
                                          yield from cultures: more than half of culture negative
                                          cases from the Mayo Clinic had received previous anti
                                          biotics.21 The resulting failure to identify the causative
                                                                                                                      patients with systemic sepsis or rapidly evolving local
                                          pathogen(s) and the antimicrobial sensitivity profile
                                          may jeopardise outcomes. However, it may be impos-                          infection.
                                          sible to take deep cultures before starting antibiotics in                     Superficial swabs reflect colonising flora only, and
                                                                                                                      results must therefore be interpreted with caution.
                                                                                                                      Occasionally, swab results may help to inform empiri-
                                                                                                                      cal antibiotic choicesw13—for example, by identifying
                                             Hot, red swollen joint                                                   carriage of resistant organisms. However, deep sam-
                                         Restricted range of movement
                                                 Pain from joint                                                      ples of synovial fluid and tissue taken at arthrotomy,
                                       Wound discharge or sinus formation                                             arthroscopy, or by aspiration are needed for definitive
  Patient clinically unstable                                                             Patient clinically stable
                                                                                                                      diagnosis. Such cultures were positive in 85% of 297
    or local signs of rapidly                        Refer patient                        and no local signs of       patients undergoing revision arthroplasty who had
        advancing infection                        to orthopaedics                        progressive infection       prosthetic joint infection.13 In this study, the identifica-
           Instigate resuscitative measures                      Baseline bloods for inflammatory markers             tion of indistinguishable organisms from at least three
        Start urgent empirical broad spectrum                                 Blood cultures
        antibiotics* after taking blood cultures                 Radiography to assess joint for loosening
                                                                                                                      culture samples was highly predictive of infection; to
                                                                                                                      optimise diagnostic sensitivity and specificity, the
              Rule out other foci of sepsis                                                                           authors therefore recommended that five or six sam-
                                                                  Joint aspiration under aseptic conditions
    Consider urgent arthrotomy and debridement                         (consider radiological guidance)               ples are sent for culture.13
                                                                               Send samples for:
                                                                                 • microbiology
                                                                                                                         Histopathology can be a crucial adjunct to micro-
                                                                          • cell count and differential               biology in the diagnosis of infection.7 13 This test has
           Organisms seen                                                                 No organisms seen
                                                                                                                      94-98% sensitivity and adds significantly to the number
             on Gram stain                                                                on Gram stain               of cases diagnosed by cultures alone.7w14 Multicentre
   Instigate appropriate first line antibiotics on the          Consider arthroscopy or arthrotomy with               analysis suggests that a white cell count and neutrophil
     basis of the clinical scenario and Gram stain*           sampling for microbiology and histopathology            differential of the synovial fluid are also sensitive
                                                                                                                      markers.23
      Take further samples for microbiology and                        Instigate empirical antibiotics
        histopathology at formal debridement                            pending results of cultures*
                                                                                                                      Which imaging modalities are useful?
                                                                                                                      Plain radiography is often non-specific in early infec-
                                Plan definitive surgical strategy and modify antibiotic                               tion but may be useful to monitor serial changes. Loos-
                                regimen* on the basis of the results of investigations                                ening or bone loss around a previously well fixed
  * Liaise with infectious diseases/microbiology teams                                                                implant is associated with chronic prosthetic joint
                                                                                                                      infection (fig 2). 3 7 8 w14 Ultrasound is useful to confirm
Fig 1 | Algorithm outlining diagnostic and therapeutic interventions in the management of early                       effusion and to facilitate aseptic aspiration. One series
prosthetic joint infection                                                                                            reported abnormalities on 99Tc labelled scintigraphy in

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                                           patients with early prosthetic infections, 9 but the study
                                           did not discuss the low specificity of this test. 8 w2 Com-                    Box 2 Common risk factors for prosthetic joint infection
                                           puted tomography and magnetic resonance imaging                                Patient factors
                                           may be useful in the evaluation of complex cases, but                          Systemic
                                           metal inserts interfere with these tests,w15 and abnor-                        Advanced age9
                                           malities may be non-specific. 14 w15                                           Obesity5 9 15 w8
                                                                                                                          Diabetes mellitus9 15
                                           What management challenges does prosthetic joint
                                           infection pose?                                                                Steroids9
                                           Management of infection in arthroplasty poses the dual                         Malignancy6
                                           challenge of eradicating infection while preserving                            Rheumatoid arthritis5
                                           mechanical joint function. Biofilm is almost univer-
                                                                                                                          Local
                                           sally associated with infection of prosthetic material                         Previous arthroplasty on the same joint 5 9 w38
                                           (table 2), particularly in chronic cases, and this
                                                                                                                          Arthroplasty undertaken to treat a fracture5
                                           underpins the need for thorough debridement
                                           and prolonged treatment with a combination of                                  Type of joint replaced (for example, risk is greater for the
                                                                                                                          knee than the hip)2
                                           antibiotics. 3 11 w16 w17
                                                                                                                          Perioperative wound complications,9 including superficial
                                                                                                                          wound infection,6 w12 haematoma, or persistent wound
                                                                                                                          drainage16
Table 1 | Organisms that commonly cause prosthetic joint infection
                                                                                                                          Operative factors
                              Frequency of         Suggested intravenous                                                  A score ≥36 on the American Society of Anesthesiologists
Infecting organism              pathogen                antibiotic*                     Suggested oral antibiotic*
                                                                                                                          scorew39
Gram positive
                                                                                                                          Duration of operation 75th centile for the procedure or
Coagulase negative            13-37%2 7 10     Glycopeptide9 10 w27                  Rifampicin plus another agent,
staphylococci              15 17 19 w2 w28                                                                                longer than three hours6 w39
                                                                                     such as ciprofloxacin, fusidic
Meticillin sensitive          20-62%7 9 10     Flucloxacillin orceftriaxone8 10 12   acid, trimethoprim, or               Wound classed as contaminated or dirty6 w39
Staphylococcus aureus         17-19 w2 w28                                           doxycycline, according to
                                                                                     sensitivities8 9 15 18 20 w4         No systemic antibiotic prophylaxis
Meticillin resistant       2-49%   4 7 9 10
                                               Glycopeptide  9 10 w27
                                                                                     Rifampicin combinations as           No antibiotic cement5
S aureus                                                                             above, according to sensitivities
                                                                                                                          Patients with the first three operative factors are at greatest risk of developing
                                                                                     Linezolidw36 w37†                    infection at the surgical site
                                   4 7 10 17                            8 10 w19                            10 19 w19
Streptococcus spp          4-27%               Penicillin or ceftriaxone             Amoxicillin or cefalexin
                                  w2


Enterococcus spp           6-13%7 9 10 w3 Penicillin or glycopeptide with or Amoxicillin8 10 or linezolidw36
                                          without an aminoglycoside10 w40 w37†                                              As with all iatrogenic complications after an elective
Diphtheroids                   6-20%7 10       Glycopeptide10                        Rifampicin combinations as          intervention, a diagnosis of prosthetic joint infection
(Corynebacteria spp,                                                                 above, or ampicillin10              can be difficult to accept, for both patients and clinical
Propionibacteria spp)
                                                                                                                         teams. Management often necessitates prolonged inpa-
Gram negative
                                                                                                                         tient stays, repeated surgical procedures, and long term
Enteric Gram negative      2-15%4 7 10 17 Ceftriaxone10; carbapenem with             Ciprofloxacin8 10
bacilli                                   or without aminoglycoside10                                                    antibiotics, all of which may be associated with further
Pseudomonas spp                1-4%7 12        Ceftazidime,8 10 carbapenem, or Ciprofloxacin8 10                         morbidity, pain, and anxiety.w6 Although these aspects
                                               ticarcillin with or without                                               of prosthetic joint infection have not been formally stu-
                                               aminoglycoside                                                            died, it is important to provide a multidisciplinary
Others                                                                                                                   environment in which patients are supported and
Anaerobes                      1-8%10 17       Carbapenem10                          Clindamycin8 or metronidazole10     informed throughout their management.
                                       14 w7
Mycobacteria                  1%-6%           A combination of agents (usually including rifampicin) on the basis
                                               of the antimicrobial susceptibility profile of the organism; seek
                                               microbiology advice                                                       What are the principles of management?
Fungi                            1% 10
                                               Common approaches include        Common approaches include                Long term outcomes are significantly better when
                                               amphotericin or fluconazole, but fluconazole or itraconazole, but         management adheres to guidelines.10 24 Major consid-
                                               seek microbiology advice         seek microbiology advice
                                                                                                                         erations are whether the implant should be retained,
Polymicrobial infections
                                                                                                                         what surgical strategy should be used, and which anti-
≥2 organisms               4-56%9 10 17 w2 Consider co-amoxiclav8; select treatment on the basis of the
                               w25
                                           combination of pathogens and sensitivitiesw25                                 microbial treatment to choose. The decision is influ-
Culture negative infections                                                                                              enced by disease duration, causative pathogen(s),
No pathogen identified        11-26%8 9 18     Glycopeptide with or without  Consider standard combination,              extent of bone and soft tissue involvement, comorbid
                                  w2
                                               carbapenem or cephalosporin21 such as rifampicin plus                     conditions, technical abilities of the surgical team, and
                                                                             ciprofloxacin                               the wishes of the patient (table 3).
*All suggested regimens should be tailored according to sensitivities obtained from the microbiology laboratory
and should be prescribed after consideration of comorbidities (such as renal or hepatic dysfunction), potential
hypersensitivity or side effects (such as rash, nausea, nephrotoxicity), and drug interactions (such as rifampicin       What surgical options are available?
and warfarin). Oral therapy generally requires combination regimens; rifampicin should never be used as
monotherapy, owing to a high rate of selection for resistance.
                                                                                                                         Initial surgical aims are to drain abscesses and remove
†Patients receiving linezolid should be monitored with regular full blood counts and advised about the risk of           dead tissue, to confirm the diagnosis with multiple tissue
peripheral or optic neuropathy.                                                                                          samples,13 and to achieve primary soft tissue closure

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  AREAS FOR FUTURE RESEARCH
      Further development and wider availability of molecular diagnostic techniques may
       help improve microbiological diagnosis in culture negative cases
      Large multicentre randomised trials are needed to establish optimum management
       strategies (in particular, to identify who would benefit from a “debride and retain”
       approach); to evaluate antibiotic regimens; and to stratify the duration of antibiotic
       treatment. This will allow delivery of the most cost effective care


                                       over drains. Management options can thereafter be
                                       divided into three broad categories (table 3)5 8 w2:
                                         Debridement and retention of a well fixed
                                          prosthesis12 18 20 w18 w19
                                         Removal of the prosthesis, then immediate
                                          reimplantation of a new prosthesis (one stage
                                          revision)14 24 or delayed reimplantation, typically
                                          six to eight weeks later (two stage revision)21 24 w20
                                         Palliative strategies are needed in a minority of
                                          cases, usually in patients with severe comorbid
                                          disease.

                                       Debridement, antibiotics, and implant retention
                                       This approach incorporates thorough debridement of
                                       infected tissue around the joint, exchange of replace-
                                       able parts of the prosthesis, soft tissue closure, and
                                       treatment with antibiotics.18-20 w18 w21 In a recent study,                    Fig 2 | Plain radiograph of a chronically infected left total hip
                                       open arthrotomy was superior to arthroscopic                                   replacement, showing loosening (arrows), cortical bone loss,
                                       washout.w18 Certain pathogens, such as penicillin                              and femoral migration of the prosthesis
                                       susceptible streptococci, are associated with good
                                       outcomes.w19                                                                   and it offers the option of local delivery of antibiotics via
                                          This management approach can eradicate infection                            antibiotic eluting cement spacers.5 w20 However, this
                                       while preserving joint function, and it is a particularly                      approach is expensive, time consuming, and may result
                                       attractive option in early infection.8 18 24 w19                               in further tissue damage. In our experience, many
                                                                                                                      patients also find it difficult to cope with restricted
                                       Revision arthroplasty                                                          mobility before reimplantation.
                                       Removal of an infected prosthesis together with the                               Although one stage revision is less common,17 it is
                                       affected bone, soft tissues, and all cement is a demand-                       standard in some centres and can be successful.14 Out-
                                       ing procedure that needs considerable surgical exper-                          come is probably related to the thoroughness of surgi-
                                       tise. Preoperatively, patients need counselling and                            cal resection, regardless of whether one or two stage
                                       optimisation of their general health.                                          reconstruction is used.w22 w23
                                          Two stage revision is the most common approach to                              Serious soft tissue defects can be caused by aggres-
                                       chronic prosthetic joint infection in many centres,7 17 21 w2                  sive local infection or can be secondary to surgical deb-
                                                                                                                      ridement. Around the knee in particular, plastic
Table 2 | Characteristics of biofilms relevant to prosthetic joint infection                                          surgery may be needed to provide soft tissue cover
                                                                                                                      for exposed bone or prosthesis.w24
                     Relevance to
Characteristic       pathophysiology             Clinical correlates
                                                                                                                      What is the best antimicrobial strategy?
Genetic diversity:   Subpopulations of           Organisms may look atypical in vitro, so can confound
small colony         organisms exist as slow     laboratory diagnosis
                                                                                                                      The choice of antibiotics should be based on culture
variantsw17          growing phenotypic          Slow growth increases the risk of antibiotic failure and justifies   results; antibiotics should achieve high concentrations
                     variants                    the use of prolonged treatment11                                     in the tissue and be active against slow growing organ-
Polysaccharide       Extracellular slime;        Microenvironment favours persistence of organisms and may            isms and biofilms.12 w4 w16 Liaison with microbiology
matrix               distributes nutrients and   inhibit bacterial killing and phagocytosis; justifies use of
                     facilitates                 prolonged antibiotic regimens incorporating rifampicin12 20
                                                                                                                      services is advisable.17 w4 We present an overview of
                     communication between                                                                            commonly selected agents (table 1), but the choice of
                     cells                                                                                            agent, route of administration, and duration of treat-
Adherence to         Whole population of       Can significantly reduce yield from bacterial culture of synovial      ment varies greatly.
surfaces             infecting organisms may fluid; therefore, periprosthetic and tissue samples are also
                     be adherent to prosthetic needed to confirm diagnosis7 w14
                     material                                                                                         Empirical antibiotics
Quorum               Genetic interactions        Antibiotic resistance is conferred by sharing of genetic             Empirical antibiotics may be needed while culture
sensingw16           between populations of      resistance determinants; this characteristic is one reason for       results are awaited and for the duration of treatment
                     cells                       using combined oral antibiotic regimens8                             for culture negative infection. Local policies based on

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Table 3 | Characteristics of patients appropriate for different management approaches to                         half life, such as teicoplanin or ceftriaxone, is
prosthetic joint infection                                                                                       optimum.9 w27
Surgical strategy           Patient characteristics
                                                                                                                 Oral treatment
Debridement, antibiotics,   No loosening of prosthesis; adequately functioning joint10 12 w19
and implant retention                                                                                            Oral antibiotics can prolong safe affordable treatment.
                            Healthy soft tissue envelope8 19 w18
                                                                                                                 Rifampicin has excellent biofilm activity but selects
                            Short duration of symptoms8 19 24 w19 (although recent studies also support this
                            approach in some patients with more chronic disease)w18
                                                                                                                 rapidly for resistance if used as monotherapy. The
                            Clearly characterised bacteriology, and highly antibiotic-susceptible organism(s),
                                                                                                                 most robust evidence comes from a randomised con-
                            such as penicillin susceptible Streptococcus sppw19                                  trolled trial of rifampicin plus a fluoroquinolone versus
One stage revision          Unstable implant but intact soft tissue8                                             fluoroquinolone alone12; the success of this regimen is
arthroplasty                Organism susceptible to antibiotics8 w19                                             confirmed by other studies of staphylococcal
                            More complex surgery contraindicated because of comorbidity                          infection.9 12 15 18 Rifampicin and fusidic acid is an alter-
Two stage revision          Unstable implant8                                                                    native combination for treating fluoroquinolone resis-
arthroplasty                Considerable damage to soft tissue8 19
                                                                                                                 tant organisms.20 In a study of 40 episodes of prosthetic
                            Resistant or difficult to treat organism,8 22 such as meticillin resistant
                                                                                                                 knee infection, any rifampicin containing regimen was
                            Staphylococcus aureus, vancomycin resistant enterococci, and fungi                   more than 95% successful.24
                            Long established infection
                            Failure of previous attempt at debridement and retention3                            Duration of antibiotic treatment
                            Serious comorbidity                                                                  The duration of antibiotic treatment varies according
Removal of prosthesis or
arthrodesis                 Repeat surgery unacceptable to the patient or deemed unsafe8                         to surgical management. If an infected prosthesis is
Amputation                  Last resort in the context of uncontrolled symptoms from the joint, including        retained, many clinicians favour up to six weeks’ par-
                            intractable pain or profuse discharge from sinuses that does not respond to          enteral treatment.9 17 If joint revision is undertaken
                            antibiotic suppression                                                               some centres reduce the duration of intravenous anti-
                            Uncontrolled systemic sepsis                                                         biotics to two to four weeks.17 18 Robust data are lacking
                            Mechanical joint failure not amenable to salvage,w41 or severe soft tissue damage    and clinical practice varies. Oral antibiotics are
                            not amenable to reconstruction
                                                                                                                 generally prescribed for a minimum of three to
                            Other options declined by the patient
                                                                                                                 six months for a retained prosthesis and six weeks for
                                                                                                                 revision arthroplasty, without prolonged parenteral
                                      the prevalence of resistant organisms guide the choice                     treatment.11
                                      of agent. If prescribing parenteral treatment, a glyco-                       In the minority of patients in whom surgery is pre-
                                      peptide is often included to cover MRSA.3 10 22 Gram                       cluded or declined, indefinite long term oral antibiotics
                                      negative cover may be added by using an intravenous                        (≥1 year) may be given, with the aim of suppressing but
                                      cephalosporin or carbapenem,10 especially if poly-                         not curing the infection.17 w21 Despite these general
                                      microbial infection is likely.w25 An aminoglycoside is                     recommendations, antibiotic prescribing varies
                                      an alternative choice if concerns exist about Clostridium                  considerably.3 9 17 18 20 22 w2 w28 An American study
                                      difficile diarrhoea.22                                                     found no relation between the duration of parenteral
                                                                                                                 treatment and the risk of relapse,22 and recent UK data
                                      Intravenous treatment                                                      suggest that oral treatment beyond six months does not
                                      Selected patients can continue intravenous antibiotics                     increases the cure rate.w18
                                      in the community under the supervision of an outpati-
                                      ent parenteral antibiotic therapy programme.25 w26 A                       What preventive strategies exist?
                                      once daily antibiotic regimen using agents with a long                     The incidence of prosthetic joint infection has been
                                                                                                                 progressively reduced by improvements in ultraclean
                                                                                                                 air, preoperative preparation, surgical technique, thea-
                                                                                                                 tre design, prophylactic antibiotics, wound care, and
  TIPS FOR NON-SPECIALISTS                                                                                       hand hygiene.w2 Ring fencing of beds for elective
   
                                                                                                                 orthopaedic patients reduced the rate of MRSA infec-
       Patients with arthroplasty who present with wound discharge or erythema over the
       joint, or who report swelling, pain, or restriction of joint movement, should be promptly
                                                                                                                 tion by 70% in one UK centre.w29 Decolonising patients
       investigated for prosthetic joint infection8 11                                                           who are colonised with MRSA before elective surgery
   
                                                                                                                 reduced the risk of implant infection in some cen-
       Refer such patients immediately to an orthopaedic team. In hospital, take baseline
       bloods (for inflammatory markers and cultures)w5 and have the joint imaged and
                                                                                                                 tres,w30 w31 but local guidelines vary. Many orthopaedic
       aspirated. Plain radiographs may be normal, but loosening of the prosthesis raises                        surgeons advocate the use of antibiotic prophylaxis for
       suspicion of infection                                                                                    patients with arthoplasties who are undergoing inva-
   
                                                                                                                 sive dental procedures,w32 although this practice is not
       Collaborate with a microbiologist or infectious diseases doctor early in the course of
       management17                                                                                              supported by clear evidence. Rigorous protocols
                                                                                                                 (including surgical site infection care bundles)w33 are
      Avoid giving empirical antibiotics until samples have been taken for culture unless the
                                                                                                                 essential if infection rates are to be reduced.
       patient is systemically unwell or has local signs of rapidly advancing infection21
      If an attempt is made to retain the prosthesis, surgical debridement of infected soft
                                                                                                                 What are the current developments in this field?
       tissues around the joint plus 3-6 months of antibiotics, using rifampicin based
                                                                                                                 Further multicentre collaborations and randomised
       regimens for staphylococcal infection is recommended9 12 15 18 20
                                                                                                                 trials are needed to answer key questions about

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 SUMMARY POINTS                                                                                                     related quality of life in total hip and total knee arthroplasty. A
                                                                                                                    qualitative and systematic review of the literature. J Bone Joint Surg
 Early diagnosis of prosthetic joint infection reduces morbidity and improves outcomes                              Am 2004;86-A:963-74.
                                                                                                               2    Phillips JE, Crane TP, Noy M, Elliott TS, Grimer RJ. The incidence of
 Infection is eradicated and joint function is preserved in most patients who receive                               deep prosthetic infections in a specialist orthopaedic hospital: a 15-
 appropriate combined surgical and medical treatment                                                                year prospective survey. J Bone Joint Surg Br 2006;88:943-8.
                                                                                                               3    Darouiche RO. Treatment of infections associated with surgical
 A multidisciplinary team is often needed for optimal diagnosis, treatment, and rehabilitation;                     implants. N Engl J Med 2004;350:1422-9.
 specialist referral may be required.                                                                          4    Edwards C, Counsell A, Boulton C, Moran CG. Early infection after hip
                                                                                                                    fracture surgery: risk factors, costs and outcome. J Bone Joint Surg Br
 Well fixed implants can be salvaged by aggressive debridement, antibiotics, and implant                            2008;90:770-7.
 retention                                                                                                     5    Jamsen E, Huhtala H, Puolakka T, Moilanen T. Risk factors for
                                                                                                                    infection after knee arthroplasty. A register-based analysis of 43 149
 Antibiotics are usually needed for three to six months if the prosthesis is retained, or for up to                 cases. J Bone Joint Surg Am 2009;91:38-47.
                                                                                                               6    Berbari EF, Hanssen AD, Duffy MC, Steckelberg JM, Ilstrup DM,
 six weeks after revision arthroplasty                                                                              Harmsen WS, et al. Risk factors for prosthetic joint infection: case-
                                                                                                                    control study. Clin Infect Dis 1998;27:1247-54.
                                                                                                               7    Muller M, Morawietz L, Hasart O, Strube P, Perka C, Tohtz S.
                                                                                                                    Diagnosis of periprosthetic infection following total hip arthroplasty
                                   optimum diagnosis and management of these challen-                               —evaluation of the diagnostic values of pre- and intraoperative
                                   ging infections. For now, attention to sound surgical                            parameters and the associated strategy to preoperatively select
                                                                                                                    patients with a high probability of joint infection. J Orthop Surg
                                   and antimicrobial principles in the context of a coordi-                         2008;3:31.
                                   nated multidisciplinary team offer the best treatment                       8    Zimmerli W, Trampuz A, Ochsner PE. Prosthetic-joint infections. N
                                                                                                                    Engl J Med 2004;351:1645-54.
                                   options.                                                                    9    Pavoni GL, Giannella M, Falcone M, Scorzolini L, Liberatore M,
                                                                                                                    Carlesimo B, et al. Conservative medical therapy of prosthetic joint
                                   Contributors: PCM searched the literature and wrote the original article.
                                                                                                                    infections: retrospective analysis of an 8-year experience. Clin
                                   ARB, MAMcN, and IB added references, contributed data for the                    Microbiol Infect 2004;10:831-7.
                                   algorithms and tables, and provided editorial input and advice. IB is the   10   Moran E, Masters S, Berendt AR, McLardy-Smith P, Byren I, Atkins BL.
                                   guarantor.                                                                       Guiding empirical antibiotic therapy in orthopaedics: the
                                   Competing interests: IB has received consultancy fees from Pfizer. ARB           microbiology of prosthetic joint infection managed by debridement,
                                   has received consultancy or speaker fees from Merck and Pfizer. PM is a          irrigation and prosthesis retention. J Infect 2007;55:1-7.
                                                                                                               11   Trampuz A, Zimmerli W. Prosthetic joint infections: update in
                                   Medical Research Council (UK) clinical research training fellow.                 diagnosis and treatment. Swiss Med Wkly 2005;135:243-51.
                                   Provenance and peer review: Commissioned; externally peer reviewed.         12   Zimmerli W, Widmer AF, Blatter M, Frei R, Ochsner PE. Role of rifampin
                                                                                                                    for treatment of orthopedic implant-related staphylococcal
                                                                                                                    infections: a randomized controlled trial. Foreign-Body Infection (FBI)
                                                                                                                    Study Group. JAMA 1998;279:1537-41.
                                     ADDITIONAL EDUCATIONAL RESOURCES                                          13   Atkins BL, Athanasou N, Deeks JJ, Crook DW, Simpson H, Peto TE,
                                                                                                                    et al. Prospective evaluation of criteria for microbiological diagnosis
                                     For healthcare professionals                                                   of prosthetic-joint infection at revision arthroplasty. The OSIRIS
                                       UpToDate (www.uptodate.com)— This evidence                                  Collaborative Study Group. J Clin Microbiol 1998;36:2932-9.
                                                                                                               14   Ince A, Seemann K, Frommelt L, Katzer A, Loehr JF. One-stage
                                         based, peer reviewed resource for clinicians includes                      exchange shoulder arthroplasty for peri-prosthetic infection. J Bone
                                         information on prevention, diagnosis, and                                  Joint Surg Br 2005;87:814-8.
                                                                                                               15   Choong PF, Dowsey MM, Carr D, Daffy J, Stanley P. Risk factors
                                         management of prosthetic joint infection. Follow the                       associated with acute hip prosthetic joint infections and outcome of
                                         link to infectious diseases then contents, then see the                    treatment with a rifampin based regimen. Acta Orthop
                                         section on skin, soft tissue, and bone infection                           2007;78:755-65.
                                                                                                               16   Saleh K, Olson M, Resig S, Bershadsky B, Kuskowski M, Gioe T, et al.
                                         Infectious Diseases Society of America (www.                              Predictors of wound infection in hip and knee joint replacement:
                                          idsociety.org)—Guidelines on the diagnosis and                            results from a 20 year surveillance program. J Orthop Res
                                                                                                                    2002;20:506-15.
                                          management of prosthetic joint infection will be                     17   Betsch BY, Eggli S, Siebenrock KA, Tauber MG, Muhlemann K.
                                          available online later this year                                          Treatment of joint prosthesis infection in accordance with current
                                                                                                                    recommendations improves outcome. Clin Infect Dis
                                         For guidelines, drug regimens, and management                             2008;46:1221-6.
                                          algorithms, see Zimmerli et al8 and Trampuz and                      18   Berdal JE, Skramm I, Mowinckel P, Gulbrandsen P, Bjornholt JV. Use
                                          Zimmerli11                                                                of rifampicin and ciprofloxacin combination therapy after surgical
                                                                                                                    debridement in the treatment of early manifestation prosthetic joint
                                         Coakley G, Mathews C, Field M, Jones A, Kingsley G,                       infections. Clin Microbiol Infect 2005;11:843-5.
                                          Walker D, et al. BSR  BHPR, BOA, RCGP and BSAC                      19   Marculescu CE, Berbari EF, Hanssen AD, Steckelberg JM,
                                                                                                                    Harmsen SW, Mandrekar JN, et al. Outcome of prosthetic joint
                                          guidelines for management of the hot swollen joint in                     infections treated with debridement and retention of components.
                                          adults. Rheumatology (Oxford) 2006;45:1039-41                             Clin Infect Dis 2006;42:471-8.
                                                                                                               20   Aboltins CA, Page MA, Buising KL, Jenney AW, Daffy JR, Choong PF,
                                         UK Guidelines are currently being drafted for the                         et al. Treatment of staphylococcal prosthetic joint infections with
                                          British Orthopaedic Association, British Infection                        debridement, prosthesis retention and oral rifampicin and fusidic
                                          Society, and Association of Medical Microbiologists                       acid. Clin Microbiol Infect 2007;13:586-91.
                                                                                                               21   Berbari EF, Marculescu C, Sia I, Lahr BD, Hanssen AD, Steckelberg JM,
                                          (projected date of publication is late 2009)                              et al. Culture-negative prosthetic joint infection. Clin Infect Dis
                                                                                                                    2007;45:1113-9.
                                     For patients                                                              22   Mittal Y, Fehring TK, Hanssen A, Marculescu C, Odum SM, Osmon D.
                                       Oxford Bone Infection Unit (www.noc.nhs.uk/                                 Two-stage reimplantation for periprosthetic knee infection involving
                                                                                                                    resistant organisms. J Bone Joint Surg Am 2007;89:1227-31.
                                         ourservices/bone_infection.aspx)—Patient
                                                                                                               23   Parvizi J, Ghanem E, Sharkey P, Aggarwal A, Burnett RS, Barrack RL.
                                         information leaflets on prosthetic joint infection, use                    Diagnosis of infected total knee: findings of a multicenter database.
                                         of antibiotics in bone and joint infection, and central                    Clin Orthop Relat Res 2008;466:2628-33.
                                                                                                               24   Laffer RR, Graber P, Ochsner PE, Zimmerli W. Outcome of prosthetic
                                         venous access devices for parenteral treatment at                          knee-associated infection: evaluation of 40 consecutive episodes at
                                         home                                                                       a single centre. Clin Microbiol Infect 2006;12:433-9.
                                                                                                              25   Matthews PC, Conlon CP, Berendt AR, Kayley J, Jefferies L, Atkins BL,
                                          Uptodate for Patients (www.uptodate.com/patients)                         et al. Outpatient parenteral antimicrobial therapy (OPAT): is it safe for
                                          —Additional information can be found using the                            selected patients to self-administer at home? A retrospective
                                          search term “prosthetic joint infection”                                  analysis of a large cohort over 13 years. J Antimicrob Chemother
                                                                                                                    2007;60:356-62.


BMJ | 6 JUNE 2009 | VOLUME 338                                                                                                                                                         1383

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Prosthetic Joint Infection

  • 1. CLINICAL REVIEW For the full versions of these articles see bmj.com Diagnosis and management of prosthetic joint infection Philippa C Matthews,1,2,3 Anthony R Berendt,1,2 Martin A McNally,1 Ivor Byren1,2 1 Bone Infection Unit, Nuffield Joint replacement is safe, cost effective,1 and widely presence of any wound complication was significantly Orthopaedic Centre NHS Trust, undertaken. Most prosthetic joint replacements are associated with deep infection.12 In a prospective case- Headington, Oxford OX3 7LD hips and knees; more than 130 000 people underwent control study, persistence of wound drainage for 2 Department of Infectious such procedures in England and Wales in the longer than five days after surgery and wound haema- Diseases, Oxford Radcliffe Hospitals NHS Trust, John 12 months from April 2006.w1 Subsequent prosthetic toma were associated with prosthetic joint infection Radcliffe Hospital, Headington, joint infection is uncommon—the incidence varies (odds ratios 1.3 and 11.8).w12 These studies highlight Oxford OX3 9DU between 0.6% and 2% per joint per year.2-5 However, the need for careful scrutiny of all wound complica- 3 University of Oxford, Peter this complication is associated with substantial mor- tions overlying an arthroplasty. Medawar Building for Pathogen Research, Oxford OX1 3SY bidity and economic cost ($30 000 (£20 500; €22 800) The proportion of prosthetic joints that become Correspondence to: P C Matthews to $50 000 per patient).3 4 6 w2 The diagnosis of prosthe- infected within three months of arthroplasty varies p.matthews@doctors.org.uk tic joint infection is difficult,w2 because symptoms, widely—from 29% to 69% in cohorts from the United Cite this as: BMJ 2009;338:b1773 signs, and investigations may all be non-specific.7 w3 Kingdom.2 10 Early infection is usually acquired at the doi:10.1136/bmj.b1773 Defining diagnostic criteria and optimum manage- time of surgery or as a consequence of wound infec- ment is complicated by patient heterogeneity and the tion, whereas later infections arise because of haema- small numbers in many published studies.w4 However, togenous spread8 or because the pathogens are of low prompt recognition and diagnosis of prosthetic joint virulence and slow to cause symptoms. infection facilitates timely intervention to salvage infected joints, preserve joint function, prevent mor- Which organisms commonly cause prosthetic joint bidity, and reduce costs. infection? Gram positive organisms, especially staphylococci What are the clinical features of prosthetic joint (commensal skin organisms), are most common infection? (table 1). 2 9 10 15 17 In early infection, pathogens are Early prosthetic joint infection (box 1) characteristi- usually more virulent (for example, Staphylococcus aur- cally presents with wound inflammation, joint effusion, eus), 18 whereas more indolent organisms predominate loss of function, and pain,8 9 w5 w6 with or without wound later on (for example, coagulase negative staphylo- dehiscence and discharge.8 9 Later disease is more cocci, Propionibacterium acnes). 10 In a recent UK study, likely to present with pain or mechanical dysfunc- however, most early cases were caused by coagulase tion.w2 Systemic features, such as pyrexia, nausea, and negative staphylococci. 8 In this cohort, most antibiotic malaise, are neither sensitive nor specific.w7 The onset of symptoms may be acute or insidious, with progres- sive pain or loss of function.7 9 SOURCES AND SELECTION CRITERIA We performed Medline searches between November Who is at risk of prosthetic joint infection and when 2008 and January 2009 using the search terms does it present? “prosthetic joint” and “arthroplasty” combined with Infection rates vary according to the joint replaced, “infection”, “guidelines”, “septic arthritis”, “infection indication for arthroplasty, comorbid conditions, and diagnosis”, “infection epidemiology”, and “infection prophylactic strategies (box 2).5 15 Obesity and diabetes revision arthroplasty”. Where possible, we focused on have been associated with early infection.9 15 w8 No articles published in the past five years and restricted our increase in prosthetic joint infection has been reported search to literature published in English. We also drew in small cohorts of patients with kidney transplantsw9 or from the experience of, and articles and documents HIV infection,w10 w11 but as arthroplasty is increasingly published by, our multidisciplinary bone infection unit in the United Kingdom (www.noc.nhs.uk), which manages performed the number at risk may increase. around 40 secondary and tertiary referral cases of In publications from the Mayo Clinic, 25% of wound prosthetic joint infection a year. infections were associated with joint infection,6 and the 1378 BMJ | 6 JUNE 2009 | VOLUME 338
  • 2. CLINICAL REVIEW resistant and polymicrobial infections presented within three months of arthroplasty. 10 Infection with Box 1 Definitions of prosthetic joint infection antibiotic resistant organisms poses an increasing chal- No uniform case definitions exist for prosthetic joint lenge, with meticillin resistant S aureus (MRSA) being infection, but widely accepted definitions include any of the more common than meticillin sensitive S aureus following6 7 9-12 w6 w14: (MSSA) in some series. 9 15 Purulence around a prosthesis at arthrotomy or arthroscopy Which laboratory investigations are needed? Presence of one or more sinus tract communicating with Figure 1 summarises key steps in the diagnostic pro- the joint cess. UK guidelines recommend baseline blood tests Histological features of infection for inflammatory markers (C reactive protein, erythro- Isolation of an indistinguishable organism from at least cyte sedimentation rate, leucocyte count) for any case two deep culture samples (“indistinguishable” refers to of septic arthritis.w5 However, these parameters are widely performed laboratory characterisation of an raised for up to two weeks after orthopaedic surgery organism; in most cases this will be identification of the so are non-specific for early infection. 8 Serial measure- genus and species, plus antibiotic susceptibilities13). ments can be useful, 22 because persistently or progres- Isolation of a virulent organism, such as Staphylococcus sively high inflammatory markers may help to aureus, Escherichia coli, or Candida spp, in one deep distinguish joint infection from an uncomplicated tissue sample is regarded by some as sufficient to postoperative course. Normal results do not exclude confirm the diagnosis.7 joint infection, 7 14 particularly infection with indolent Early prosthetic joint infection organisms. Early prosthetic joint infection is most widely defined as Blood for culture should be taken before patients deep infection of an arthroplasty occurring within three with suspected acute infection are started on anti- months of joint replacement. Subsequent presentation is biotics, although cultures are usually negative.3 9 divided into delayed (3-12 months after index surgery) or Early empirical treatment reduces the diagnostic late (12 months).8 9 11 14 yield from cultures: more than half of culture negative cases from the Mayo Clinic had received previous anti biotics.21 The resulting failure to identify the causative patients with systemic sepsis or rapidly evolving local pathogen(s) and the antimicrobial sensitivity profile may jeopardise outcomes. However, it may be impos- infection. sible to take deep cultures before starting antibiotics in Superficial swabs reflect colonising flora only, and results must therefore be interpreted with caution. Occasionally, swab results may help to inform empiri- cal antibiotic choicesw13—for example, by identifying Hot, red swollen joint carriage of resistant organisms. However, deep sam- Restricted range of movement Pain from joint ples of synovial fluid and tissue taken at arthrotomy, Wound discharge or sinus formation arthroscopy, or by aspiration are needed for definitive Patient clinically unstable Patient clinically stable diagnosis. Such cultures were positive in 85% of 297 or local signs of rapidly Refer patient and no local signs of patients undergoing revision arthroplasty who had advancing infection to orthopaedics progressive infection prosthetic joint infection.13 In this study, the identifica- Instigate resuscitative measures Baseline bloods for inflammatory markers tion of indistinguishable organisms from at least three Start urgent empirical broad spectrum Blood cultures antibiotics* after taking blood cultures Radiography to assess joint for loosening culture samples was highly predictive of infection; to optimise diagnostic sensitivity and specificity, the Rule out other foci of sepsis authors therefore recommended that five or six sam- Joint aspiration under aseptic conditions Consider urgent arthrotomy and debridement (consider radiological guidance) ples are sent for culture.13 Send samples for: • microbiology Histopathology can be a crucial adjunct to micro- • cell count and differential biology in the diagnosis of infection.7 13 This test has Organisms seen No organisms seen 94-98% sensitivity and adds significantly to the number on Gram stain on Gram stain of cases diagnosed by cultures alone.7w14 Multicentre Instigate appropriate first line antibiotics on the Consider arthroscopy or arthrotomy with analysis suggests that a white cell count and neutrophil basis of the clinical scenario and Gram stain* sampling for microbiology and histopathology differential of the synovial fluid are also sensitive markers.23 Take further samples for microbiology and Instigate empirical antibiotics histopathology at formal debridement pending results of cultures* Which imaging modalities are useful? Plain radiography is often non-specific in early infec- Plan definitive surgical strategy and modify antibiotic tion but may be useful to monitor serial changes. Loos- regimen* on the basis of the results of investigations ening or bone loss around a previously well fixed * Liaise with infectious diseases/microbiology teams implant is associated with chronic prosthetic joint infection (fig 2). 3 7 8 w14 Ultrasound is useful to confirm Fig 1 | Algorithm outlining diagnostic and therapeutic interventions in the management of early effusion and to facilitate aseptic aspiration. One series prosthetic joint infection reported abnormalities on 99Tc labelled scintigraphy in BMJ | 6 JUNE 2009 | VOLUME 338 1379
  • 3. CLINICAL REVIEW patients with early prosthetic infections, 9 but the study did not discuss the low specificity of this test. 8 w2 Com- Box 2 Common risk factors for prosthetic joint infection puted tomography and magnetic resonance imaging Patient factors may be useful in the evaluation of complex cases, but Systemic metal inserts interfere with these tests,w15 and abnor- Advanced age9 malities may be non-specific. 14 w15 Obesity5 9 15 w8 Diabetes mellitus9 15 What management challenges does prosthetic joint infection pose? Steroids9 Management of infection in arthroplasty poses the dual Malignancy6 challenge of eradicating infection while preserving Rheumatoid arthritis5 mechanical joint function. Biofilm is almost univer- Local sally associated with infection of prosthetic material Previous arthroplasty on the same joint 5 9 w38 (table 2), particularly in chronic cases, and this Arthroplasty undertaken to treat a fracture5 underpins the need for thorough debridement and prolonged treatment with a combination of Type of joint replaced (for example, risk is greater for the knee than the hip)2 antibiotics. 3 11 w16 w17 Perioperative wound complications,9 including superficial wound infection,6 w12 haematoma, or persistent wound drainage16 Table 1 | Organisms that commonly cause prosthetic joint infection Operative factors Frequency of Suggested intravenous A score ≥36 on the American Society of Anesthesiologists Infecting organism pathogen antibiotic* Suggested oral antibiotic* scorew39 Gram positive Duration of operation 75th centile for the procedure or Coagulase negative 13-37%2 7 10 Glycopeptide9 10 w27 Rifampicin plus another agent, staphylococci 15 17 19 w2 w28 longer than three hours6 w39 such as ciprofloxacin, fusidic Meticillin sensitive 20-62%7 9 10 Flucloxacillin orceftriaxone8 10 12 acid, trimethoprim, or Wound classed as contaminated or dirty6 w39 Staphylococcus aureus 17-19 w2 w28 doxycycline, according to sensitivities8 9 15 18 20 w4 No systemic antibiotic prophylaxis Meticillin resistant 2-49% 4 7 9 10 Glycopeptide 9 10 w27 Rifampicin combinations as No antibiotic cement5 S aureus above, according to sensitivities Patients with the first three operative factors are at greatest risk of developing Linezolidw36 w37† infection at the surgical site 4 7 10 17 8 10 w19 10 19 w19 Streptococcus spp 4-27% Penicillin or ceftriaxone Amoxicillin or cefalexin w2 Enterococcus spp 6-13%7 9 10 w3 Penicillin or glycopeptide with or Amoxicillin8 10 or linezolidw36 without an aminoglycoside10 w40 w37† As with all iatrogenic complications after an elective Diphtheroids 6-20%7 10 Glycopeptide10 Rifampicin combinations as intervention, a diagnosis of prosthetic joint infection (Corynebacteria spp, above, or ampicillin10 can be difficult to accept, for both patients and clinical Propionibacteria spp) teams. Management often necessitates prolonged inpa- Gram negative tient stays, repeated surgical procedures, and long term Enteric Gram negative 2-15%4 7 10 17 Ceftriaxone10; carbapenem with Ciprofloxacin8 10 bacilli or without aminoglycoside10 antibiotics, all of which may be associated with further Pseudomonas spp 1-4%7 12 Ceftazidime,8 10 carbapenem, or Ciprofloxacin8 10 morbidity, pain, and anxiety.w6 Although these aspects ticarcillin with or without of prosthetic joint infection have not been formally stu- aminoglycoside died, it is important to provide a multidisciplinary Others environment in which patients are supported and Anaerobes 1-8%10 17 Carbapenem10 Clindamycin8 or metronidazole10 informed throughout their management. 14 w7 Mycobacteria 1%-6% A combination of agents (usually including rifampicin) on the basis of the antimicrobial susceptibility profile of the organism; seek microbiology advice What are the principles of management? Fungi 1% 10 Common approaches include Common approaches include Long term outcomes are significantly better when amphotericin or fluconazole, but fluconazole or itraconazole, but management adheres to guidelines.10 24 Major consid- seek microbiology advice seek microbiology advice erations are whether the implant should be retained, Polymicrobial infections what surgical strategy should be used, and which anti- ≥2 organisms 4-56%9 10 17 w2 Consider co-amoxiclav8; select treatment on the basis of the w25 combination of pathogens and sensitivitiesw25 microbial treatment to choose. The decision is influ- Culture negative infections enced by disease duration, causative pathogen(s), No pathogen identified 11-26%8 9 18 Glycopeptide with or without Consider standard combination, extent of bone and soft tissue involvement, comorbid w2 carbapenem or cephalosporin21 such as rifampicin plus conditions, technical abilities of the surgical team, and ciprofloxacin the wishes of the patient (table 3). *All suggested regimens should be tailored according to sensitivities obtained from the microbiology laboratory and should be prescribed after consideration of comorbidities (such as renal or hepatic dysfunction), potential hypersensitivity or side effects (such as rash, nausea, nephrotoxicity), and drug interactions (such as rifampicin What surgical options are available? and warfarin). Oral therapy generally requires combination regimens; rifampicin should never be used as monotherapy, owing to a high rate of selection for resistance. Initial surgical aims are to drain abscesses and remove †Patients receiving linezolid should be monitored with regular full blood counts and advised about the risk of dead tissue, to confirm the diagnosis with multiple tissue peripheral or optic neuropathy. samples,13 and to achieve primary soft tissue closure 1380 BMJ | 6 JUNE 2009 | VOLUME 338
  • 4. CLINICAL REVIEW AREAS FOR FUTURE RESEARCH Further development and wider availability of molecular diagnostic techniques may help improve microbiological diagnosis in culture negative cases Large multicentre randomised trials are needed to establish optimum management strategies (in particular, to identify who would benefit from a “debride and retain” approach); to evaluate antibiotic regimens; and to stratify the duration of antibiotic treatment. This will allow delivery of the most cost effective care over drains. Management options can thereafter be divided into three broad categories (table 3)5 8 w2: Debridement and retention of a well fixed prosthesis12 18 20 w18 w19 Removal of the prosthesis, then immediate reimplantation of a new prosthesis (one stage revision)14 24 or delayed reimplantation, typically six to eight weeks later (two stage revision)21 24 w20 Palliative strategies are needed in a minority of cases, usually in patients with severe comorbid disease. Debridement, antibiotics, and implant retention This approach incorporates thorough debridement of infected tissue around the joint, exchange of replace- able parts of the prosthesis, soft tissue closure, and treatment with antibiotics.18-20 w18 w21 In a recent study, Fig 2 | Plain radiograph of a chronically infected left total hip open arthrotomy was superior to arthroscopic replacement, showing loosening (arrows), cortical bone loss, washout.w18 Certain pathogens, such as penicillin and femoral migration of the prosthesis susceptible streptococci, are associated with good outcomes.w19 and it offers the option of local delivery of antibiotics via This management approach can eradicate infection antibiotic eluting cement spacers.5 w20 However, this while preserving joint function, and it is a particularly approach is expensive, time consuming, and may result attractive option in early infection.8 18 24 w19 in further tissue damage. In our experience, many patients also find it difficult to cope with restricted Revision arthroplasty mobility before reimplantation. Removal of an infected prosthesis together with the Although one stage revision is less common,17 it is affected bone, soft tissues, and all cement is a demand- standard in some centres and can be successful.14 Out- ing procedure that needs considerable surgical exper- come is probably related to the thoroughness of surgi- tise. Preoperatively, patients need counselling and cal resection, regardless of whether one or two stage optimisation of their general health. reconstruction is used.w22 w23 Two stage revision is the most common approach to Serious soft tissue defects can be caused by aggres- chronic prosthetic joint infection in many centres,7 17 21 w2 sive local infection or can be secondary to surgical deb- ridement. Around the knee in particular, plastic Table 2 | Characteristics of biofilms relevant to prosthetic joint infection surgery may be needed to provide soft tissue cover for exposed bone or prosthesis.w24 Relevance to Characteristic pathophysiology Clinical correlates What is the best antimicrobial strategy? Genetic diversity: Subpopulations of Organisms may look atypical in vitro, so can confound small colony organisms exist as slow laboratory diagnosis The choice of antibiotics should be based on culture variantsw17 growing phenotypic Slow growth increases the risk of antibiotic failure and justifies results; antibiotics should achieve high concentrations variants the use of prolonged treatment11 in the tissue and be active against slow growing organ- Polysaccharide Extracellular slime; Microenvironment favours persistence of organisms and may isms and biofilms.12 w4 w16 Liaison with microbiology matrix distributes nutrients and inhibit bacterial killing and phagocytosis; justifies use of facilitates prolonged antibiotic regimens incorporating rifampicin12 20 services is advisable.17 w4 We present an overview of communication between commonly selected agents (table 1), but the choice of cells agent, route of administration, and duration of treat- Adherence to Whole population of Can significantly reduce yield from bacterial culture of synovial ment varies greatly. surfaces infecting organisms may fluid; therefore, periprosthetic and tissue samples are also be adherent to prosthetic needed to confirm diagnosis7 w14 material Empirical antibiotics Quorum Genetic interactions Antibiotic resistance is conferred by sharing of genetic Empirical antibiotics may be needed while culture sensingw16 between populations of resistance determinants; this characteristic is one reason for results are awaited and for the duration of treatment cells using combined oral antibiotic regimens8 for culture negative infection. Local policies based on BMJ | 6 JUNE 2009 | VOLUME 338 1381
  • 5. CLINICAL REVIEW Table 3 | Characteristics of patients appropriate for different management approaches to half life, such as teicoplanin or ceftriaxone, is prosthetic joint infection optimum.9 w27 Surgical strategy Patient characteristics Oral treatment Debridement, antibiotics, No loosening of prosthesis; adequately functioning joint10 12 w19 and implant retention Oral antibiotics can prolong safe affordable treatment. Healthy soft tissue envelope8 19 w18 Rifampicin has excellent biofilm activity but selects Short duration of symptoms8 19 24 w19 (although recent studies also support this approach in some patients with more chronic disease)w18 rapidly for resistance if used as monotherapy. The Clearly characterised bacteriology, and highly antibiotic-susceptible organism(s), most robust evidence comes from a randomised con- such as penicillin susceptible Streptococcus sppw19 trolled trial of rifampicin plus a fluoroquinolone versus One stage revision Unstable implant but intact soft tissue8 fluoroquinolone alone12; the success of this regimen is arthroplasty Organism susceptible to antibiotics8 w19 confirmed by other studies of staphylococcal More complex surgery contraindicated because of comorbidity infection.9 12 15 18 Rifampicin and fusidic acid is an alter- Two stage revision Unstable implant8 native combination for treating fluoroquinolone resis- arthroplasty Considerable damage to soft tissue8 19 tant organisms.20 In a study of 40 episodes of prosthetic Resistant or difficult to treat organism,8 22 such as meticillin resistant knee infection, any rifampicin containing regimen was Staphylococcus aureus, vancomycin resistant enterococci, and fungi more than 95% successful.24 Long established infection Failure of previous attempt at debridement and retention3 Duration of antibiotic treatment Serious comorbidity The duration of antibiotic treatment varies according Removal of prosthesis or arthrodesis Repeat surgery unacceptable to the patient or deemed unsafe8 to surgical management. If an infected prosthesis is Amputation Last resort in the context of uncontrolled symptoms from the joint, including retained, many clinicians favour up to six weeks’ par- intractable pain or profuse discharge from sinuses that does not respond to enteral treatment.9 17 If joint revision is undertaken antibiotic suppression some centres reduce the duration of intravenous anti- Uncontrolled systemic sepsis biotics to two to four weeks.17 18 Robust data are lacking Mechanical joint failure not amenable to salvage,w41 or severe soft tissue damage and clinical practice varies. Oral antibiotics are not amenable to reconstruction generally prescribed for a minimum of three to Other options declined by the patient six months for a retained prosthesis and six weeks for revision arthroplasty, without prolonged parenteral the prevalence of resistant organisms guide the choice treatment.11 of agent. If prescribing parenteral treatment, a glyco- In the minority of patients in whom surgery is pre- peptide is often included to cover MRSA.3 10 22 Gram cluded or declined, indefinite long term oral antibiotics negative cover may be added by using an intravenous (≥1 year) may be given, with the aim of suppressing but cephalosporin or carbapenem,10 especially if poly- not curing the infection.17 w21 Despite these general microbial infection is likely.w25 An aminoglycoside is recommendations, antibiotic prescribing varies an alternative choice if concerns exist about Clostridium considerably.3 9 17 18 20 22 w2 w28 An American study difficile diarrhoea.22 found no relation between the duration of parenteral treatment and the risk of relapse,22 and recent UK data Intravenous treatment suggest that oral treatment beyond six months does not Selected patients can continue intravenous antibiotics increases the cure rate.w18 in the community under the supervision of an outpati- ent parenteral antibiotic therapy programme.25 w26 A What preventive strategies exist? once daily antibiotic regimen using agents with a long The incidence of prosthetic joint infection has been progressively reduced by improvements in ultraclean air, preoperative preparation, surgical technique, thea- tre design, prophylactic antibiotics, wound care, and TIPS FOR NON-SPECIALISTS hand hygiene.w2 Ring fencing of beds for elective orthopaedic patients reduced the rate of MRSA infec- Patients with arthroplasty who present with wound discharge or erythema over the joint, or who report swelling, pain, or restriction of joint movement, should be promptly tion by 70% in one UK centre.w29 Decolonising patients investigated for prosthetic joint infection8 11 who are colonised with MRSA before elective surgery reduced the risk of implant infection in some cen- Refer such patients immediately to an orthopaedic team. In hospital, take baseline bloods (for inflammatory markers and cultures)w5 and have the joint imaged and tres,w30 w31 but local guidelines vary. Many orthopaedic aspirated. Plain radiographs may be normal, but loosening of the prosthesis raises surgeons advocate the use of antibiotic prophylaxis for suspicion of infection patients with arthoplasties who are undergoing inva- sive dental procedures,w32 although this practice is not Collaborate with a microbiologist or infectious diseases doctor early in the course of management17 supported by clear evidence. Rigorous protocols (including surgical site infection care bundles)w33 are Avoid giving empirical antibiotics until samples have been taken for culture unless the essential if infection rates are to be reduced. patient is systemically unwell or has local signs of rapidly advancing infection21 If an attempt is made to retain the prosthesis, surgical debridement of infected soft What are the current developments in this field? tissues around the joint plus 3-6 months of antibiotics, using rifampicin based Further multicentre collaborations and randomised regimens for staphylococcal infection is recommended9 12 15 18 20 trials are needed to answer key questions about 1382 BMJ | 6 JUNE 2009 | VOLUME 338
  • 6. CLINICAL REVIEW 1 Ethgen O, Bruyere O, Richy F, Dardennes C, Reginster JY. Health- SUMMARY POINTS related quality of life in total hip and total knee arthroplasty. A qualitative and systematic review of the literature. J Bone Joint Surg Early diagnosis of prosthetic joint infection reduces morbidity and improves outcomes Am 2004;86-A:963-74. 2 Phillips JE, Crane TP, Noy M, Elliott TS, Grimer RJ. The incidence of Infection is eradicated and joint function is preserved in most patients who receive deep prosthetic infections in a specialist orthopaedic hospital: a 15- appropriate combined surgical and medical treatment year prospective survey. J Bone Joint Surg Br 2006;88:943-8. 3 Darouiche RO. Treatment of infections associated with surgical A multidisciplinary team is often needed for optimal diagnosis, treatment, and rehabilitation; implants. N Engl J Med 2004;350:1422-9. specialist referral may be required. 4 Edwards C, Counsell A, Boulton C, Moran CG. Early infection after hip fracture surgery: risk factors, costs and outcome. J Bone Joint Surg Br Well fixed implants can be salvaged by aggressive debridement, antibiotics, and implant 2008;90:770-7. retention 5 Jamsen E, Huhtala H, Puolakka T, Moilanen T. Risk factors for infection after knee arthroplasty. A register-based analysis of 43 149 Antibiotics are usually needed for three to six months if the prosthesis is retained, or for up to cases. J Bone Joint Surg Am 2009;91:38-47. 6 Berbari EF, Hanssen AD, Duffy MC, Steckelberg JM, Ilstrup DM, six weeks after revision arthroplasty Harmsen WS, et al. Risk factors for prosthetic joint infection: case- control study. Clin Infect Dis 1998;27:1247-54. 7 Muller M, Morawietz L, Hasart O, Strube P, Perka C, Tohtz S. Diagnosis of periprosthetic infection following total hip arthroplasty optimum diagnosis and management of these challen- —evaluation of the diagnostic values of pre- and intraoperative ging infections. For now, attention to sound surgical parameters and the associated strategy to preoperatively select patients with a high probability of joint infection. J Orthop Surg and antimicrobial principles in the context of a coordi- 2008;3:31. nated multidisciplinary team offer the best treatment 8 Zimmerli W, Trampuz A, Ochsner PE. Prosthetic-joint infections. N Engl J Med 2004;351:1645-54. options. 9 Pavoni GL, Giannella M, Falcone M, Scorzolini L, Liberatore M, Carlesimo B, et al. Conservative medical therapy of prosthetic joint Contributors: PCM searched the literature and wrote the original article. infections: retrospective analysis of an 8-year experience. Clin ARB, MAMcN, and IB added references, contributed data for the Microbiol Infect 2004;10:831-7. algorithms and tables, and provided editorial input and advice. IB is the 10 Moran E, Masters S, Berendt AR, McLardy-Smith P, Byren I, Atkins BL. guarantor. Guiding empirical antibiotic therapy in orthopaedics: the Competing interests: IB has received consultancy fees from Pfizer. ARB microbiology of prosthetic joint infection managed by debridement, has received consultancy or speaker fees from Merck and Pfizer. PM is a irrigation and prosthesis retention. J Infect 2007;55:1-7. 11 Trampuz A, Zimmerli W. Prosthetic joint infections: update in Medical Research Council (UK) clinical research training fellow. diagnosis and treatment. Swiss Med Wkly 2005;135:243-51. Provenance and peer review: Commissioned; externally peer reviewed. 12 Zimmerli W, Widmer AF, Blatter M, Frei R, Ochsner PE. Role of rifampin for treatment of orthopedic implant-related staphylococcal infections: a randomized controlled trial. Foreign-Body Infection (FBI) Study Group. JAMA 1998;279:1537-41. ADDITIONAL EDUCATIONAL RESOURCES 13 Atkins BL, Athanasou N, Deeks JJ, Crook DW, Simpson H, Peto TE, et al. Prospective evaluation of criteria for microbiological diagnosis For healthcare professionals of prosthetic-joint infection at revision arthroplasty. The OSIRIS UpToDate (www.uptodate.com)— This evidence Collaborative Study Group. J Clin Microbiol 1998;36:2932-9. 14 Ince A, Seemann K, Frommelt L, Katzer A, Loehr JF. One-stage based, peer reviewed resource for clinicians includes exchange shoulder arthroplasty for peri-prosthetic infection. J Bone information on prevention, diagnosis, and Joint Surg Br 2005;87:814-8. 15 Choong PF, Dowsey MM, Carr D, Daffy J, Stanley P. Risk factors management of prosthetic joint infection. Follow the associated with acute hip prosthetic joint infections and outcome of link to infectious diseases then contents, then see the treatment with a rifampin based regimen. Acta Orthop section on skin, soft tissue, and bone infection 2007;78:755-65. 16 Saleh K, Olson M, Resig S, Bershadsky B, Kuskowski M, Gioe T, et al. Infectious Diseases Society of America (www. Predictors of wound infection in hip and knee joint replacement: idsociety.org)—Guidelines on the diagnosis and results from a 20 year surveillance program. J Orthop Res 2002;20:506-15. management of prosthetic joint infection will be 17 Betsch BY, Eggli S, Siebenrock KA, Tauber MG, Muhlemann K. available online later this year Treatment of joint prosthesis infection in accordance with current recommendations improves outcome. Clin Infect Dis For guidelines, drug regimens, and management 2008;46:1221-6. algorithms, see Zimmerli et al8 and Trampuz and 18 Berdal JE, Skramm I, Mowinckel P, Gulbrandsen P, Bjornholt JV. Use Zimmerli11 of rifampicin and ciprofloxacin combination therapy after surgical debridement in the treatment of early manifestation prosthetic joint Coakley G, Mathews C, Field M, Jones A, Kingsley G, infections. Clin Microbiol Infect 2005;11:843-5. Walker D, et al. BSR BHPR, BOA, RCGP and BSAC 19 Marculescu CE, Berbari EF, Hanssen AD, Steckelberg JM, Harmsen SW, Mandrekar JN, et al. Outcome of prosthetic joint guidelines for management of the hot swollen joint in infections treated with debridement and retention of components. adults. Rheumatology (Oxford) 2006;45:1039-41 Clin Infect Dis 2006;42:471-8. 20 Aboltins CA, Page MA, Buising KL, Jenney AW, Daffy JR, Choong PF, UK Guidelines are currently being drafted for the et al. Treatment of staphylococcal prosthetic joint infections with British Orthopaedic Association, British Infection debridement, prosthesis retention and oral rifampicin and fusidic Society, and Association of Medical Microbiologists acid. Clin Microbiol Infect 2007;13:586-91. 21 Berbari EF, Marculescu C, Sia I, Lahr BD, Hanssen AD, Steckelberg JM, (projected date of publication is late 2009) et al. Culture-negative prosthetic joint infection. Clin Infect Dis 2007;45:1113-9. For patients 22 Mittal Y, Fehring TK, Hanssen A, Marculescu C, Odum SM, Osmon D. Oxford Bone Infection Unit (www.noc.nhs.uk/ Two-stage reimplantation for periprosthetic knee infection involving resistant organisms. J Bone Joint Surg Am 2007;89:1227-31. ourservices/bone_infection.aspx)—Patient 23 Parvizi J, Ghanem E, Sharkey P, Aggarwal A, Burnett RS, Barrack RL. information leaflets on prosthetic joint infection, use Diagnosis of infected total knee: findings of a multicenter database. of antibiotics in bone and joint infection, and central Clin Orthop Relat Res 2008;466:2628-33. 24 Laffer RR, Graber P, Ochsner PE, Zimmerli W. Outcome of prosthetic venous access devices for parenteral treatment at knee-associated infection: evaluation of 40 consecutive episodes at home a single centre. Clin Microbiol Infect 2006;12:433-9. 25 Matthews PC, Conlon CP, Berendt AR, Kayley J, Jefferies L, Atkins BL, Uptodate for Patients (www.uptodate.com/patients) et al. Outpatient parenteral antimicrobial therapy (OPAT): is it safe for —Additional information can be found using the selected patients to self-administer at home? A retrospective search term “prosthetic joint infection” analysis of a large cohort over 13 years. J Antimicrob Chemother 2007;60:356-62. BMJ | 6 JUNE 2009 | VOLUME 338 1383