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REVIEW

Prosthetic joint infection: Recent developmentsin diagnosis and management

Maria Adriana Cataldo a, Nicola Petrosillo a, Michela Cipriani b,Roberto Cauda b, Evelina Tacconelli b,*

a 2nd Infectious Diseases Division, National Institute for Infectious Diseases, Lazzaro Spallanzani, Via Portuense, 292 00149

Rome, Italyb Department of Infectious Diseases, Universita Cattolica, Largo F. Vito, 1 00168 Rome, Italy

Accepted 29 September 2010Available online 7 October 2010

KEYWORDSProsthetic joint infec-tion;Diagnosis;Therapy

Summary Over the past years there has been a significant increase in the number of joint

prosthesis replacements worldwide. The most serious complication of joint prosthesis is infec-

tion with an incidence of 1.5e2.5% for primary interventions and up to 20% for revision proce-

dures. The mortality rate ranges between 1% and nearly 3%. The economic cost of this

complication is up to $50,000 per patient and $250,000 million per year. A major issue in

the management of prosthetic joint infection (PJI) is the relative difficulty in making a diagno-

sis so to cause a significant effect on the prognosis. Goals of the treatment are to eradicate

infection, prevent its recurrence and preserve mechanical joint function. In this review we fo-

cus on the value of traditional and newer diagnostic tests and we discuss management and pre-

ventive strategies. European networks are needed to define the best diagnostic and treatment

strategies in order to reduce future challenge posed by PJIs.

2010 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Over the past years there has been a significant increase inthe number of joint prosthesis replacements. In 2006 about

800,000 hip and knee arthroplasties were performed in theUnited States1 and 130,000 in England.2 Kurtz et al. formu-lated projections for the number of primary and revision to-tal hip and knee arthroplasties that will be performed in theUnited States through 2030 and estimated an increase by174%e572,000 for hip per year and by 673%e3.48 million

for knee prosthesis per year.3 The most serious complicationof joint prosthesis is infection with an incidence of 1.5e2.5%

for primary interventions and up to 20% for revision proce-dures.4 The mortality rate ranges between 1% and nearly3%.4 The economic cost of this complication is up to$50,000 per patient and $250,000 million per year.5,6 In rea-son of the increase of life expectancy and of the predictedgrowth of the number of joint replacement procedures,

* Corresponding author. Tel.: 39 06 30154945; fax: 39 06 3054519.E-mail address: etacconelli@rm.unicatt.it (E. Tacconelli).

0163-4453/$36 2010 The British Infection Association. Published by Elsevier Ltd. All rights reserved.doi:10.1016/j.jinf.2010.09.033

www.elsevierhealth.com/journals/jinf

Journal of Infection (2010) 61, 443e448

mailto:etacconelli@rm.unicatt.ithttp://dx.doi.org/10.1016/j.jinf.2010.09.033http://www.elsevierhealth.com/journals/jinfhttp://dx.doi.org/10.1016/j.jinf.2010.09.033http://dx.doi.org/10.1016/j.jinf.2010.09.033http://dx.doi.org/10.1016/j.jinf.2010.09.033http://dx.doi.org/10.1016/j.jinf.2010.09.033http://dx.doi.org/10.1016/j.jinf.2010.09.033http://dx.doi.org/10.1016/j.jinf.2010.09.033http://www.elsevierhealth.com/journals/jinfhttp://dx.doi.org/10.1016/j.jinf.2010.09.033mailto:etacconelli@rm.unicatt.it

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the next few years are likely to register a significant incre-ment in the number of prosthetic joint infections (PJIs)with a strong impact on countries health economic balance.

Epidemiology

A common case definition for PJI has not yet beenestablished, although there are widely accepted diagnostic

criteria.7e9 Infections are usually classified in relation tothe time of onset after surgery as early (first 3 months af-ter surgery), delayed (between 3 months and 2 years af-ter surgery) or late (more than 2 years after surgery).10,11

PJIs occur more frequently in patients with a previous revi-sion arthroplasty and in subjects with diabetes mellitus,rheumatoid arthritis, obesity, neoplasm, and immunosup-pression.7,12 Surgical factors such as sterility, long opera-tive time, use of antibiotic-impregnated cement are alsodeterminant in the risk of infection.13e16 Microorganismsmay reach the prosthesis at the time of implantation orlater by haematogenous spread.7,17 The development of bi-ofilm has a strategic role in the pathogenesis of PJI. Micro-

organisms adhere to the implant and form a biofilm in whichthey are protected from the host immune system and frommost antibiotics.10

The most frequent etiologic agents are staphylococci,accounting for more than 50% of PJIs.10 Staphylococcus au-reus is usually isolated in early infections whereas coagu-lase-negative staphylococci in late infections18 as well asStreptococci (9e10%), enterococci (3e7%) and anaerobes(2e4%).10 Gram-negative bacteria, mostly Pseudomonasaeruginosa, Enterobacter spp., Proteus spp., even toughrelatively uncommon agents, have an important clinical im-pact because of the difficulty in treatment.19,20 Interest-ingly, in a recent study, gram-negative organisms wereinvolved in 15% of the episodes of PJIs.19 Compared to pa-

tients with infections due to gram-positive bacteria, thosewith gram-negative PJIs were older and developed infec-tion earlier.19 Overall, about 20% of PJIs are polymicrobialand 7e11% are culture-negative.21,22 Unusual pathogens,such as Candida spp., Brucella spp. and mycobacteriahave also been reported.23 A main concern in the recentyears, has been the increase in reports of infections dueto antibiotic-resistant bacteria. In a large surveillance onsurgical site infection after orthopaedic interventions,59% of the S. aureus isolates were methicillin-resistant. Sal-gado et al. observed that PJIs due to methicillin-resistant S.aureus (MRSA) have a higher risk of treatment failure thanPJIs due to methicillin-susceptible S. aureus.24

Diagnosis

A major issue in the management of PJI is the relativedifficulty in making a diagnosisso to cause a significant effecton the prognosis of PJI. Indeed, a delay in the antibiotic andsurgical treatment has an important impact on the chance ofsaving the prosthesis and the joint function. The diagnosis ofPJI is based on clinical signs, laboratory and microbiologicaltests, histopathology and imaging studies. Inflammatorymarkers (C reactive protein, erythrocyte sedimentationrate, white blood cells count) determination is recommen-ded but is not specific, particularly for early infection, since

these parameters are high for up to two weeks aftersurgery.25 Recently, the role of procalcitonin in the diagnosisof deep implant infection in patients with a revision totalknee or hip replacement has been evaluated. Procalcitoninlevels (>0.3 ng/ml) were very specific (98%) but had a lowsensitivity (33%).26 Blood cultures should be performed, al-though they are often negative due to the frequent use ofempirical antimicrobial therapy.27 Deep samples of synovial

fluid and periprosthetic tissue cultures are more specific andaccurate for detecting the etiologic agent. Unfortunately,deep cultures are uncommonly taken before starting antibi-otics, thus false-negative cultures are possible. Culture ofa superficial wound could be taken but it often representsbacterial skin colonisation. The use of polymerase-chain-re-action (PCR) assays may be helpful for a rapid and more sen-sitive microbiological diagnosis although ad hoc studiesyielded controversial results.28e33 In a study comparingPCR and conventional culture techniques in the diagnosisof PJIs, significantly higher sensitivity, accuracy and nega-tive predictive values were reported for PCR versus cultures,with 83% concordance between the results of intraoperativeculture and PCR detection of the causative bacteria.29 How-

ever, other studies reported lower PCR sensitivity (54%) anda large number of false positive results.30,32 Synovial fluidwhite cell count and neutrophil differential may be a rapidway for differentiating PJI from aseptic failure.34 Majorlimits of these methods arerelated to the lack of cut-offs ap-plicable to all types of prosthetic joint or to patients with un-derlying inflammatory joint disease. Histopathology couldadd important information helping in the diagnosis of acuteinflammation.9 Recently, a sonication technique, used tosample biofilm bacteria on the surface of removed hip andknee implants placed in solid containers, was clinically vali-dated.35 A prospective trial compared culture of samples ob-tained by sonication of explanted hip and knee prostheses to

dislodge adherent bacteria from the prosthesis with conven-tional culture of periprosthetic tissue for the microbiologicdiagnosis of PJI. The sensitivities of periprosthetic tissueand sonicate-fluid cultures significantly differed (60.8% and78.5%, respectively) while the specificities were of similarvalue (99.2% and 98.8%, respectively). Fourteen cases ofPJIs were detected by sonicate-fluid culture but not by pros-thetic-tissue culture. The sensitivities of periprosthetic tis-sue and sonicate-fluid culture significantly differed also inpatients receiving antimicrobial therapy within 14 days be-fore surgery (45% and 75%, respectively).35 The main limita-tion of this technique is the difficult to identify bacterialspecies because of their variations in phenotypicappearanceand biochemical reaction.36

Plain radiographs have low sensitivity and low specificityfor the detection of PJI especially in early infection. Serialradiographs may be useful in monitoring bone changes.Computed tomography (CT) and magnetic resonance (MR)provide more specific information about normal and ab-normal tissue but are associated with artefacts producedby prostheses. Bone scintigraphy with technetium-99-mlabelled methylene diphosphonate is not specific for in-fection and remains abnormal from more than one yearafter prostheses implantation.37 The addition of gallium-67improves the specificity up to 70e80%. Labelled-leukocyteimaging combined with bone marrow imaging with the useof technetium-99-m labelled sulphur colloid is, at the

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moment, the most accurate imaging test.38 F-fluorodeoxy-glucose positron emission tomography (FDG-PET) has a sen-sitivity ranging from 28% to 91% and specificity from 9% to97% in the diagnosis of PJIs.39 This variability depends onthe different diagnostic criteria used. Recently, the roleof scintigraphy with (99m) TC-labelled anti-granulocyte an-tibodies alone and in conjunction with SPECT/CT for diag-nosing low-grade joint infection was assessed. The addition

of SPECT with and without CT improved the utility of (99m)TC-labelled anti-granulocyte antibodies.40 Other imagingstudies such as scintigraphy with anti-granulocyte mono-clonal antibodies and combined PET and CT imaging are un-der investigation.

Antimicrobial therapy

Goals of the treatment of PJI are to eradicate infection,prevent its recurrence and preserve mechanical jointfunction. Drugs administered for PJIs should have bacteri-cidal activity against slow-growing organisms in biofilm andachieve high concentration into the bone. Among the

oldest antibiotics, cefazolin, rifampicin, minocycline andcotrimoxazole should be considered. Recently, Zeller et al.reported that use of cefazolin by continuous infusion waseffective in treating 93% of patients with bone and jointinfections.41 Bone cefazolin concentrations were also deter-mined in eight patients confirming high levels of penetra-tion. Rifampicin is active against stationary phase bacteriain biofilm present on implants. Its use is recommended forthe treatment of PJIs due to staphylococci in combinationwith another antimicrobial agent active against these bacte-ria to avoid the development of resistance. The associationwith quinolones is the most widely used and its efficacy hasbeen documented in several studies.42,43 A meta-analysis on

clinical efficacy of antibiotic agents for bone and joint infec-tions in adults, showed a trend towards improved, long-last-ing infection control in favour of a rifampicineciprofloxacincombination versus ciprofloxacin monotherapy for the treat-ment of staphylococcal infections related to orthopaedicdevices (absolute risk difference 29%).44 Cotrimoxazole fre-quently retains activity against multidrug-resistant staphylo-cocci, is able to diffuse in bone tissue and is absorbed ifadministered by oral route. Due to these characteristics, itrepresents an attractive choice for the treatment of PJIs.High-dose of trimethoprimesulfamethoxazole has beenused to treat MRSA implant infections with an overall curerate at 6 years of 67%.45 Both cotrimoxazole and minocyclinehave been used in association with rifampicin.45,46

Newer antibiotics such as linezolid, tigecycline, dapto-mycin, although not approved for bone infections, areincreasingly used. Linezolid is a bacteriostatic antibiotic,with excellent bioavailability by oral administration. Thedrug achieves a bone concentration above the MICs of themajority of gram-positive cocci, including multidrug-resis-tant strains, and, according to in vitro studies, is able to killaround half of clinical isolates of MRSA cells within biofilms.Retrospective studies reported a success rate ranging from80%46e100% of PJIs treated with linezolid.47,48 Prolongedoral therapy with the association of rifampicin/linezolid orrifampicin/cotrimoxazole were found to be equally effec-tive in treating patients with bone and joint infection,

including those with infected orthopaedic devices, causedby resistant gram-positive cocci.49 Recently, Galdelmanet al. reported that co-administration of linezolid and ri-fampicin resulted in a decrease in the area under theplasma concentration-time curve over the dosing intervaland maximum concentration values for linezolid.50 The clin-ical significance of this interaction is unknown.

Daptomycin has activity against several gram-positive

bacteria, including MRSA and vancomycin-resistant entero-cocci (VRE) and is able to kill also stationary phase bacteriain biofilm. Its use has been investigated in orthopaedicinfections and showed a cumulative cure rate of 81%.51 Theanalysis of outcomes in 62 patients with osteomyelitis froman ongoing, retrospective database of daptomycin use inthe USA, the Cubicin Outcomes Registry and Experience(CORE), showed a success rate of 89% and of 100% in thesubgroup with orthopaedic devices.52 The optimal dosageof daptomycin for bone and joint infections is still underevaluation, although published data showed a higher failurerate in patients receiving 4 mg/kg/day or less.52 In the USAa trial comparing the efficacy and safety of daptomycin atdifferent dosage (6 mg/kg and 8 mg/kg) is ongoing. A possi-

ble role of tigecycline in treating orthopaedic infections issuggested by animal studies that showed good cure ratesof MRSA osteomyelitis.53 The mean percentage of clinicalisolates of MRSA cells killed in biofilms was 57% after expo-sure to tigecycline.54 Human trials on the use of tigecyclinein bone and joint infection are lacking.

The ideal antimicrobial agents and the best duration oftreatment for PJIs are still not defined and a very fewrandomised controlled trials have compared the efficacy ofdifferent antibiotics. Guidelines for the management of PJIare expected very soon from the Infectious Diseases Societyof America, the British Orthopaedic Association and theBritish Infection Association.

Choice of the antibiotic agent should be dependent onthe type of bacteria and its sensitivity profile, patientscharacteristic and long term goals. Suggested therapy formethicillin-susceptible staphylococci is nafcillin or oxacillinfollowed by rifampicin plus ciprofloxacin per os. Intravenousglycopeptides followed by oral therapy containing rifampi-cin associated with other antibiotics, according to thesusceptibility profile, are recommended for the treatmentof PJIs caused by MRSA. For the treatment of PJIs caused bya gram-negative bacteria, a cephalosporin, like ceftriaxoneor ceftazidime, or a carbapenem eventually combined withan aminoglycoside could be used. For oral treatmentquinolones and cotrimoxazole are good choices. In infec-tions by Enterobacteriaceae the association quinolones plus

rifampicin could also be used.To increase the rate of microorganisms eradication, the

antibiotic treatment should be administered for a long time.In the majority of patients a surgical debridement or pros-thetic joint removal is required. In patients undergoingdebridement with retention of the prosthesis the antibioticis generally prescribed for 3 or 6 months (in hip and kneeprosthesis, respectively), whereas in patients undergoinga two-stage exchange the therapy is often administered for4e6 weeks. In a recent retrospective study, antibiotic therapyappeared to be limited to a 6-week course, with one week ofintravenous administration.55 Interestingly, oral treatmentbeyond six months did not enhance the cure rate.56

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Prevention

Antibiotic prophylaxis before the intervention of implanta-tion of prosthesis has been proven to be effective inreducing the risk of subsequent infection. First or secondgeneration cephalosporins are commonly recommended inorthopaedic surgery. In settings with a high prevalence ofMRSA, glycopeptides are suggested.57

The use of antibiotic prophylaxis in patients with jointprostheses undergoing dental, genitourinary tract andgastrointestinal tract procedures is controversial. In a re-cent study, antibiotic prophylaxis in high-risk or low-riskdental procedures did not decrease the risk of subsequenttotal hip or knee infections.58 The American Association ofOrthopaedic Surgeons recommends to consider the adminis-tration of antibiotic prophylaxis prior to any invasive proce-dure that may cause bacteraemia (dental, urologic andother surgical and medical procedures) in patients with to-tal joint replacement, especially if one or more of the fol-lowing risk factors are present: immunocompromised/immunosuppressed patients, inflammatory arthropathies,

drug-induced immunosuppression, radiation-induced immu-nosuppression, patients with co-morbidities (e.g. diabetes,obesity, smoking), previous prosthetic joint infections, mal-nourishment, haemophilia, HIV infection, insulin-depen-dent diabetes, malignancy.59

Decolonisation with mupirocin of S. aureus nasal carriershas been proven to be efficacious in reducing bacterial in-fection in surgical patients.60 However, its efficacy in ortho-paedic patients is still on debate. In a study includingpatients undergoing orthopaedic surgery, endogenous S. au-reus infections occurred less frequently than in patientswho received mupirocin prophylaxis.61 In a prospective ob-servational study of patients undergoing elective total jointarthroplasty, postoperative S. aureus surgical site infec-

tions were not observed at 1-year follow-up in the groupof S. aureus nasal carriers who received decolonisation reg-imen.62 A meta-analysis showed that preoperative intrana-sal mupirocin decreases the incidence of surgical siteinfection when used as prophylaxis in nongeneral surgery,including orthopaedic surgery.63 Pre-surgical screening forS. aureus is recommended in particular in hospital with en-demic MRSA. Available data do not support wide applicationof rapid screening with molecular tests compared to con-ventional cultures.64

Conclusions

Given the projected increase in the number of PJIs in theforthcoming years in most countries, a common action toreduce the associated morbidity and mortality is stronglyencouraged in Europe. New multicenter European cohortstudies are needed to explore risk factors and pathogenesisof infections after orthopaedic surgery. European networksset up to define the best diagnostic and treatment strate-gies should be supported both at a national and interna-tional level. In particular, since the significant impact onthe quality of life of the elderly population of PJIs, futurerandomised clinical trials on prevention and treatmentneed to be designed to include this population.

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