Laboratory Diagnosis of Prosthetic Joint Infection, Part II

Laboratory Diagnosis of Prosthetic Joint Infection, Part II

Clinical Microbiology Newsletter Vol. 33, No. 9 $99 May 1, 2011 Laboratory Diagnosis of Prosthetic Joint Infection, Part II* ...

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Clinical Microbiology Newsletter Vol. 33, No. 9


May 1, 2011

Laboratory Diagnosis of Prosthetic Joint Infection, Part II* Eric Gomez, M.D.1 and Robin Patel, M.D.,1,2 1Division of Infectious Diseases, Department of Medicine, 2Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota

Abstract Prosthetic joint infection (PJI), although a rare complication of primary or revision arthroplasty, is reported more frequently as the number patients undergoing arthroplasty increases. Accurate diagnosis of PJI is essential for adequate management and outcome. Although multiple tests have been applied, in some cases, differentiation of PJI from aseptic loosening of the prosthesis remains a challenge. Here, we review the current diagnostic laboratory modalities used for the diagnosis PJI. In Part I of this twopart article, components of the preoperative evaluation of the patient and the histology of the intraoperative evaluation were discussed. Part II of the article discusses the remaining components of the intraoperative evaluation, including periprosthetic tissue and sonicate fluid cultures. In addition, recent investigational approaches for the diagnosis of PJI, antimicrobial susceptibility testing, and management of PJIs are reviewed. Periprosthetic tissue cultures Gram stain of periprosthetic tissue is rarely clinically helpful due to low sensitivity (0 to 30%) (38 to 42). Identification and susceptibility testing of the microorganism(s) involved in prosthetic joint infection (PJI) are critical to appropriate selection of antimicrobial therapy. However, bacterial detection with conventional periprosthetic tissue cultures has a sensitivity between 37% and 61% (11,43,44). The poor sensitivity of periprosthetic tissue culture may relate to the relative concentration of organisms on the implant surface per se and not specifically in the surrounding tissue. Some organisms causing PJI may be slow growing due to either their phenotypic state (i.e., biofilm) or inherent characteristics (e.g., Propionibacterium acnes) (44,45). Administra*Editor’s Note: Part I of this article appeared in the April 15, 2011 issue of Clinical Microbiology Newsletter (CMN Vol. 33, No. 8).

Corresponding Author: Robin Patel, M.D., Mayo Clinic, 200 First St. SW, Rochester, MN 55905. Tel: 507-538-0579 Fax: 507284-4272. E-mail: [email protected] Clinical Microbiology Newsletter 33:9,2011

tion of antimicrobials within 3 months of arthroplasty revision is associated with negative cultures (46,47). To increase the sensitivity of culture, some authors advocate the culture of at least five separate tissue samples (48). Also, extended incubation of periprosthetic cultures improves the sensitivity of cultures. Schäfer et al. (49) obtained five tissue cultures from 284 patients undergoing hip or knee arthroplasty revision and incubated them for 14 days. The median time to positivity was 4 days. At day 7 of incubation, 73.6% of positive cultures had been detected) and at day 13, all positive cultures were detected. A good proportion of late cultures was due to Propionibacterium species and peptostreptococci, indicating that the benefit of prolonged incubation applies mainly to anaerobic cultures. One concern about prolonging incubation time is potential enhanced recovery of contaminants; however, that was not the case in this study. Late growers with ≥2 positive cultures were associated with histopathologic acute inflammation (P < 0.001), which suggests that they were not contaminants. The median time to detection of con© 2011 Elsevier

taminants was 7 days. The specificity of periprosthetic tissue cultures is also an issue. False-positive results can be due to contamination during surgery, transport to the laboratory, or processing of specimens (50). Several studies (51-53) have shown that positive intraoperative cultures are often encountered in patients undergoing primary joint implantation with no other evidence of infection. Such cultures not only represent contamination with skin flora, but also do not predict subsequent development of PJI. Dietz et al. (51) found that 58% of patients undergoing clean orthopedic surgery had positive intraoperative cultures. None of the patients with positive cultures developed subsequent infection. The most common organisms isolated were coagulase-negative Staphylococcus species, followed by Propionibacterium

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species. The problems with specificity translate into difficulties in determining the clinical significance of growth of common skin flora in intraoperative cultures. Recognized pathogens, such as Staphylococcus aureus, beta-hemolytic streptococci, Streptococcus pneumoniae, and members of the Enterobacteriaceae, are less likely than coagulase-negative staphylococci and Propionibacterium species to be considered contaminants and should raise the suspicion of infection, prompting some authors to consider any growth in culture significant (21,51,54). On the other hand, the significance of less virulent skin flora organisms in cultures should be carefully assessed to avoid misclassifying contaminants as pathogens. In a study of coagulase-negative staphylococci recovered from patients with suspected orthopedic infections (62% arthroplasty revisions), only 36% of isolates were considered clinically significant (55). Among the clinically significant isolates, Staphylococcus epidermidis was the most commonly species isolated (81%), followed by Staphylococcus lugdunensis (7%), Staphylococcus capitis (7%) and Staphylococcus caprae (5%). Special distinction should be made for S. lugdunensis, as it can cause a more aggressive infection, behaving like S. aureus (56). P. acnes, an anaerobic gram-positive bacillus that forms part of the human skin flora, was for many years considered a culture contaminant. However, recently, P. acnes has been considered a pathogen in PJI, especially PJI involving shoulder implants. In a study of prosthetic shoulder infections from the Mayo Clinic (10), P. acnes was the second most common organism isolated (after Staphylococcus spp.), causing two-fifths of the microbiologically confirmed cases of PJI. However, as


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with coagulase-negative staphylococci, culture results with P. acnes should be interpreted with caution, especially single positive cultures. Dramis et al. (57) reported 56 patients with total joint replacements (only one shoulder implant) who had positive synovial fluid aspirate and/or tissue cultures for P. acnes. The majority did not receive antimicrobial treatment, and subsequent infection developed in just one patient. Only eight patients had ≥2 positive cultures (two of whom were treated with antimicrobial agents), and none developed subsequent infection. In a report of 75 revision shoulder arthroplasties without overt clinical findings of infection and with positive intraoperative cultures (mostly single positive cultures), Topolski et al. (58) reported that P. acnes was the most commonly isolated organism (60%). The majority of patients did not receive antimicrobial treatment, and only 10 required a second revision arthroplasty. In an effort to increase the specificity of tissue cultures, Kamme and Lindberg (54) proposed that by using a standardized method of multiple sample collection, pathogens can be differentiated from contaminants. Thirty-one patients undergoing primary arthroplasty (control) and 63 undergoing arthroplasty revisions were studied. Five tissue specimens were taken from the joint with separate sterile instruments for each specimen. Patients in the control group and those with aseptic loosening had ≤2 positive tissue cultures. In contrast, patients with PJI had five positive tissue cultures. However, the definition of infected cases was not clear. Atkins et al. (48), using a mathematical model, determined that five tissue samples are needed to obtain good sensitivity and specificity. The authors propose that, using a cutoff of ≥2 positive tissue cultures out of 5 samples, the microbiolog-

© 2011 Elsevier

ical diagnosis of infection can be made. In this study, acute inflammation on histopathology was used to define infection, and all samples were taken with a fresh scalpel blade to decrease the chance of contamination. Other authors have reported that by increasing the number of specimens taken, the specificity, but not the sensitivity, improves (59). Swab cultures (of capsular membrane, bone or synovial fluid) have limitations compared to tissue and synovial fluid cultures. Levine et al. reported that the inoculation of intraoperativelycollected synovial fluid inoculated into blood culture bottles achieved higher sensitivity (92%) than tissue (46%) or swab (64%) cultures (60). Swab cultures were more prone to contamination, as 50% of cultures showed polymicrobial growth compared to one-third of positive blood culture bottles. A Spanish study (61) also showed that intraoperatively collected synovial fluid cultured using blood culture bottles was superior to tissue and swab cultures, without false-positive results. Swab cultures had a high rate of false-positive results due to contamination with coagulase-negative Staphylococcus spp. and Propionibacterium spp. Anaerobes are more commonly isolated using blood culture bottles than with swabs and tissue cultures, showing that loss of viability of bacteria during transport may account for some false-negative culture results (60). Sonicate fluid cultures The growth of bacteria in biofilms may elude detection by periprosthetic tissue cultures. Sampling biofilm bacteria is a strategy used to diagnose PJI. Surgical scraping of the prosthesis surface has shown higher sensitivity than periprosthetic tissue culture, indicating a higher bacterial load on the biomaterial surface (44). However, scraping seems to be insufficient to

Clinical Microbiology Newsletter 33:9,2011

remove the biofilm and risks introduction of contaminants (62). An efficient method to disrupt the biofilm is the use of sonication (63). With sonication, ultrasound waves are propagated in a liquid medium to create microscopic air bubbles that explode, due to high surface tension, generating high energy that can disrupt the biofilm (63). In a study (64) using an in vitro model of implant infection, treatment of an inert surface with sonication yielded higher bacterial recovery (39.9 colony-forming units [CFU] per plate) than when no sonication was used (1.6 CFU per plate) (64). Sonication has been used in the diagnosis of infection of multiple types of medical devices, including orthopedic devices (65-67), vascular grafts (68), breast implants (69), vascular catheters (70), cardiac devices (71), and ureteral stents (72). Tunney and colleagues (73) used sonication to dislodge bacteria from the prosthesis, obtaining more positive cultures with sonicate fluid than with the conventional periprosthetic tissue cultures. The sonication technique proposed by Tunney et al. was modified by Trampuz et al. and evaluated in the diagnosis of PJI. In a study of 331 patients (252 patients with aseptic failure and 79 with PJI), sonicate fluid cultures had a sensitivity of 78.5% and tissue cultures had a sensitivity of 60.8% (P < 0.001), with specificities of 98.8 and 99.2%, respectively (43). The improved sensitivity of sonicate-fluid cultures was predominant in the group of patients who had received prior antimicrobial therapy. It is important to note that a cutoff to define clinically significant results should be applied to sonication culture results; failure to apply such a cutoff will substantially lower specificity. Figure 2 describes the sonication procedure initially used in the study by Trampuz et al. with a modification that was introduced subsequently (11). Sonicate fluid cultures have a shorter time to positivity than periprosthetic tissue cultures. In a retrospective review of patients who underwent revision arthroplasty and sonication of the implant, sonicate tissue cultures were positive on average after 1 day (for coagulase-negative staphylococci, enterococci, and streptococci) compared to tissue cultures which were positive after 2 days (74). Clinical Microbiology Newsletter 33:9,2011

Figure 2. Procedure for orthopedic implant sonication used at Mayo Clinic. Ringer’s solution (400 ml) is added to the container, which is vortexed for 30 seconds. Then, the container is subjected to sonication in a Bransonic 5510 ultrasound bath (Branson, Danbury, CT) for 5 minutes (40 kHz frequency). The container is vortexed for another 30 seconds. A 100-fold concentration step has been added since the original procedure described by Trampuz et al. (43) Sonicate fluid is placed in a 50 ml tube and centrifuged at 3,150 x g for 5 minutes. The supernatant is aspirated, and 0.1 ml of specimen is inoculated to a sheep blood agar plate which is incubated aerobically for 4 days and a CDC anaerobic plate, which is incubated for 14 days.

Table 2. New approaches for the diagnosis of PJI Diagnosis of PJI

Microbiological diagnosis of PJI




Molecular methods


Immunofluorescence microscopy


Synovial fluid biomarkers (IL-6, IL-1β) a

TNF-α, tumor necrosis factor alpha.

Synovial fluid biomarkers Deirmengian et al. (75) evaluated gene expression of neutrophils in synovial fluid obtained from native joint

S. aureus septic arthritis and neutrophils from crystal-induced arthritis (gout). Using microarrays, neutrophils from infected synovial fluid showed a specific gene expression signature (126 genes) different from that of patients with gout. Some genes, such as cytokine genes, had been previously noted to be up-regulated when neutrophils were exposed to bacteria. Based on these results, the authors (76) reported a subsequent study evaluating a select number of biomarkers from synovial fluid for the diagnosis of PJI in 53

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Investigational approaches for the diagnosis of PJI Several new non-culture methods have been reported for the diagnosis and the microbial identification of PJI. Some of these new methods look promising but are not yet in routine use for the assessment of septic arthroplasty failure (Table 2).


patients (14 PJI and 37 aseptic failures). Of 23 biomarkers tested, interleukin 6 (IL-6) and IL-1β were found to be 100% sensitive and specific for the diagnosis of PJI. Compared to C-reactive protein, erythrocyte sedimentation rate, and synovial fluid leukocytes, IL-6 and IL-1β had higher accuracy (100% versus 80%). As there is a “distinctive” expression of certain biomarkers with bacterial exposure that is different from that with other inflammatory noninfectious processes, patients with systemic inflammatory disease were included in this study (two patients with PJI and three patients with aseptic failure). Although this is a promising approach for the diagnosis of PJI, including in patients with inflammatory disease, further clinical studies are needed. Serologic detection of microorganisms Kamme and Lindberg (54) evaluated the immunologic response of patients with PJI against the organism isolated from tissue culture. Patient’s serum antibody titers against P. acnes and peptostreptococci were compared to antibody titers in normal human sera. Although there was a trend toward higher antibody titers in patients with peptostreptococcal PJI, the authors determined that this test had limited diagnostic value. Detecting antibodies against organisms associated with PJI, although a fairly easy test to perform, lacks specificity due to the low basal antibody titers against organisms, such as coagulase-negative staphylococci, which are part of the normal human flora. However, Rafiq et al. (77) identified and reported the use of a short-chain-length form of cellular lipoteichoic acid of coagulase-negative staphylococci for the detection of gram-positive bacterial PJI with good results. Fifteen patients with proven gram-positive PJI and 32 control patients were tested for antibodies against lipoteichoic acid. Patients with a history of infection not related to the prosthesis 6 months prior to the study were excluded. IgG levels were elevated in 14 of the infected patients and in only 1 patient of the control group, corresponding to a sensitivity of 93% and specificity of 97%. Immunofluorescence microscopy Direct visualization of bacteria from sonication fluid with pathogen-targeted 66

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antibodies (immunofluorescence microscopy [IFM]) has been used as a nonculture method for the microbiological diagnosis of PJI. Tunney et al. (78) developed monoclonal antibodies to P. acnes and polyclonal antibodies against Staphylococcus species and used them on sonicate fluid. Large aggregates of bacteria were visualized with a fluorescence microscope in all patients with positive cultures and in 47 out of 89 prostheses with negative cultures. However, as no clear definition of PJI was provided, it is difficult to assess the performance of IFM in this study. According to the authors, contaminating bacteria were differentiated from pathogens, as contaminants appeared as single bacteria or small aggregates, whereas pathogens appeared as large aggregates. Piper et al. (11) evaluated the use of IFM for the diagnosis of prostheticshoulder infection, using monoclonal antibodies against P. acnes and staphylococci. The sensitivity of IFM to detect P. acnes and staphylococci was 67% and 58%, respectively. IFM did not improve microbiological detection compared to sonicate fluid cultures, as all IFM-positive specimens had positive cultures. Molecular methods Some authors (79) have stated that biofilm infections cannot be reliably diagnosed using cultural methods, as prior antimicrobial use, low metabolic activity of sessile bacteria within biofilms, fastidious growth characteristics of the organisms present, loss of viability during transport, small-colony variants, and/or the presence of generally viable but nonculturable organisms could result in negative cultures. Molecular methods may theoretically overcome these issues. However, the limited available studies using PCR for the diagnosis of PJI have shown mixed results. In a study of 34 patients with PJI, Vandercam et al. (80) evaluated the use of broad-range PCR using 16S ribosomal RNA (rRNA) genes on intraoperative samples (tissue, synovial fluid, and/or swabs) at the time of revision arthroplasty. PCR improved bacterial detection from 64.7% to 91.2% compared to cultures. Moojen el al. (81) used 16S rRNA PCR and reverse line blot hybridization on intraoperative tissue of 76 patients undergoing orthope© 2011 Elsevier

dic surgeries (57 arthroplasty revisions). PCR had a sensitivity and specificity of 81 and 96%, respectively compared to cultures. Tunney et al. (78) detected bacterial DNA in prosthesis sonicates by broad-range PCR amplification of a region of the bacterial 16S rRNA gene with universal primers in all culturepositive samples and in a further 64% of the culture-negative samples. Molecular methods may show an advantage over cultures in patients with prior antimicrobial use. Using broadrange PCR, bacterial DNA has been detected in synovial fluid up to 22 days after starting antimicrobial therapy in patients with septic arthritis and PJI, even though cultures were negative (82,83). Achermann et al. (84) evaluated a real-time multiplex PCR test (SeptiFast; Roche Diagnostics, Basel, Switzerland) performed on sonicate fluid for the diagnosis of PJI. This system is commercially available in Europe for identification of a limited number of bacterial and fungal pathogens typically isolated from blood. Pathogens were identified by tissue culture, sonicate fluid culture, and sonicate fluid PCR in 65%, 64%, and 78% of PJI cases, respectively. Among the patients with PJI who received antibiotics prior to resection arthroplasty, PCR of sonicate fluid detected the offending pathogen in 100% of cases compared to 42% with culture methods. On the other hand, De Man et al. (85) reported that the use of PCR on intraoperative specimens (synovial fluid and/or periprosthetic tissue) had low sensitivity in patients with recent antimicrobial agent use. Although there was a small number of patients (n = 26), the authors concluded that PCR was highly specific (94% versus 71%) but that it had low sensitivity (50% versus 58%) compared to culture. False-positive PCR is always a concern as DNA from non-viable bacteria can contaminate patient specimens and even reagents, and amplicon contamination may occur. Clarke et al. (86) reported that 29% of patients undergoing primary total hip arthroplasty without infection had positive PCR (16S rRNA) results from intraoperative samples (tissue and synovial fluid), which was most likely due to contamination at the time of specimen collection. Panousis et al. (87) also showed low specificity (74%) of broad-range PCR Clinical Microbiology Newsletter 33:9,2011

from intraoperative synovial fluid samples in 92 patients undergoing arthroplasty revision. RNA may be a better target than DNA for PCR detection, as it is only present in viable bacteria and has a very short half-life, making it a less likely cause of contamination. Bergin et al. (89) used reverse transcriptionquantitative PCR targeting 16S rRNA on preoperative joint aspirates for the diagnosis of PJI. The authors showed sensitivity of 71% and specificity of 100%. Molecular techniques have the disadvantage of not being able to provide antimicrobial susceptibility results, which is important in the management of PJI. One strategy to overcome this limitation is molecular detection of resistance determinants, such as with detection of the methicillin-resistance gene, mecA, using PCR (89,90). Antimicrobial susceptibility testing Current methods of antimicrobial susceptibility testing use suspended planktonic cells, which might not be representative of the bacterial population within biofilms. Bacteria in biofilms can survive antimicrobial agent concentrations 1,000-fold higher than their corresponding planktonic forms (91). Researchers have developed multiple in vitro models of biofilms that have been adapted for antimicrobial susceptibility testing (92). One of the most common methods used is the peg lid biofilm assay, of which the Calgary Biofilm Device (CBD) is a prototype. The CBD consists of multiple polystyrene pegs lying on an incubation tray (93). Biofilm forms along the peg, which is later exposed to various antimicrobial concentrations. The pegs are subjected to sonication, followed by quantitative culture of the sonicate fluid to determine the minimum biofilm eradication concentration, which is the minimum concentration of antimicrobial agent needed to eradicate the biofilm. Although the clinical utility of biofilm antimicrobial susceptibility testing has not been assessed, Sandoe et al. (94) tested 58 enterococcal isolates from patients with intravascularcatheter-related bloodstream infection to determine the minimal biofilm inhibitory concentration (MBIC) using the CBD. In a small subset of patients, salvage of the catheter was attempted with antimicrobial treatment. In these patients, no correlation between the Clinical Microbiology Newsletter 33:9,2011

MBIC and outcome was found. Further studies are needed to determine the clinical utility of such testing. Management of PJIs The goal of therapy in patients with PJI is to eradicate or control the infection while maintaining a functional joint. This can be achieved through a multidisciplinary approach involving an orthopedic surgeon, an infectious diseases specialist, and a clinical microbiologist. Current surgical treatment strategies include débridement and retention, resection arthroplasty with immediate or delayed reimplatation (one-stage versus two-stage revision), arthrodesis, and amputation. Resection arthroplasty with or without delayed reimplantation is performed in patients presenting with subacute or chronic PJI. In one-stage revision, the prosthesis and cement are removed and a new prosthesis is placed during the same procedure (95-101). This procedure is performed in healthy patients with good soft tissue and bone structures with PJI caused by antimicrobial-susceptible organisms (thus, the microbiology of infection should be known prior to the procedure). If a patient is not a candidate for a one-stage revision, resection arthroplasty with delayed reimplantation can be performed. In two-stage revision, all the hardware is removed and reimplantation of the joint is performed in a subsequent surgery weeks to months later (102-105). In debridement and retention of the prosthesis, the devitalized bone and soft tissue are removed and the polyethylene cover is exchanged, leaving the prosthesis in place. Debridement and retention are indicated in patients with acute hematogenous and/or acute postoperative infection (usually within 4 weeks from the index surgery) and with well-fixed components in the absence of a sinus tract. Arthroplasty resection without subsequent reimplantation of the joint (Girdlestone procedure) and arthrodesis (obliteration of the joint), are seldom used to control the infection. While these procedures often lead to infection eradication, they are associated with limited joint function (106-108). In selected cases where surgery cannot be performed (e.g., high surgical risk), conservative treatment with antimicrobial therapy alone is used in order to contain the infection to the joint (109-110). On rare occasions and © 2011 Elsevier

when all other treatment options have failed, amputation of the limb involved can be used as a last resort to control the infection (111). Antimicrobial treatment should be based on in vitro antimicrobial susceptibility testing. Antimicrobials can be delivered systemically or locally into the joint. Local antimicrobial delivery systems through antimicrobial-impregnated cement or spacers are used in an attempt to improve the chances of eradicating the infection (112). The antimicrobial drug(s) can be mixed with cement (polymethylmethacrylate), which when applied to the joint space, will gradually release the antimicrobial drug(s) over time in the joint space and bone cement interface (113). Systemic antimicrobial drugs can be provided through the parenteral or oral (when agents with high bioavailability are used [e.g., fluoroquinolones]) route. In cases of rifampin-susceptible staphylococcal infections treated with débridement and retention, rifampin-based regimens (e.g., a quinolone and rifampin) have been shown to be more efficacious than non-rifampin-based regimens (e.g., quinolone alone) (114-116). Rifampin should always be combined with another antibiotic to prevent the emergence of rifampin resistance during treatment. Although the optimal duration of antimicrobial therapy has not been defined with randomized studies, for hip and knee PJI treated with debridement and retention, rifampin-based regimens are commonly administered for 3 and 6 months, respectively. For PJI treated with one- or two-stage arthroplasty revisions, 4 to 6 weeks of antimicrobial treatment is usually provided.

Summary There has been much progress made in recent years in the diagnosis of PJI, but there remain limitations to current diagnostic methods. Inflammatory markers and synovial and periprosthetic tissue cultures have limited sensitivity and specificity. Histopathology has good specificity and positive predictive value but somewhat limited sensitivity. The sensitivity of cultures has improved with the use of implant sonication; however, cases of culture-negative PJI still occur. PCR may improve the microbial detection in PJI, but further development is needed for clinical use to ensure that, 0196-4399/00 (see frontmatter)


with potentially improved sensitivity, specificity is not compromised. Currently, there is no single test that can accurately identify PJI. With the current armamentarium of tests, the best diagnostic approach requires a combination of multiple laboratory tests along with clinical assessment. New diagnostic methods and/or improvement of current methodologies for the diagnosis of PJI is still needed.



Aknowledgements We thank Natalia Franch-Gomez for her assistance with the illustrations and Elie F. Berbari, M.D., for reviewing the section on management of PJI. References 38. Chimento, G.F., S. Finger, and R.L. Barrack. 1996. Gram stain detection of infection during revision arthroplasty. J. Bone Joint Surg. Br. 78:838-839. 39. Ghanem, E. et al. 2009. Periprosthetic infection: where do we stand with regard to Gram stain? Acta Orthop. 80:37-40. 40. Della Valle, C.J. et al. 1999. The role of intraoperative Gram stain in revision total joint arthroplasty. J. Arthroplasty 14:500-504. 41. Morgan, P. M. et al. 2009. The value of intraoperative Gram stain in revision total knee arthroplasty. J. Bone Joint Surg. Am. 91:2124-2129. 42. Johnson, A.J. et al. 2010. Should gram stains have a role in diagnosing hip arthroplasty infections? Clin. Orthop. Relat. Res. 468:2387-2391. 43. Trampuz, A. et al. 2007. Sonication of removed hip and knee prostheses for diagnosis of infection. N. Engl. J. Med. 357:654-663. 44. Neut, D. et al. 2003. Detection of biomaterial-associated infections in orthopedic joint implants. Clin. Orthop. Relat. Res. 413:261-268. 45. Ince, A. et al. 2004. Is “aseptic” loosening of the prosthetic cup after total hip replacement due to nonculturable bacterial pathogens in patients with lowgrade infection? Clin. Infect. Dis. 39:1599-1603. 46. Berbari, E.F. et al. 2007. Culture-negative prosthetic joint infection. Clin. Infect. Dis. 45:1113-1119. 47. Malekzadeh, D. et al. 2010. Prior use of antimicrobial therapy is a risk factor for culture-negative prosthetic joint infection. Clin. Orthop. Relat. Res. 468:2039-2045. 48. Atkins, B.L. et al. 1998. Prospective evaluation of criteria for microbiol68

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