For the culture-negative PJIs in this study, multivariate analysis revealed that risk factors for treatment failure were knee joint involvement (adjusted odds ratio [OR], 4.60; p = 0.002) and surgical management with irrigation and debridement (adjusted OR, 3.10; p = 0.031). There was no difference in risk for patients treated with monotherapy or combination antibiotic therapy (OR, 0.612; p = 0.560).
In the present study, culture-negative PJI was associated with poor outcomes and a high rate of salvage procedures. Furthermore, we found that irrigation and debridement had a low rate of eradication of infection, with a success rate of only 55.6%.
Given the poor outcomes associated with culture-negative PJI, it is important to identify the infecting organism. However, the sensitivity of routine cultures for identifying the infecting organisms in PJI is low, ranging from 39% to 70% in reported studies7,12,14,15. Several factors are associated with failure to isolate a microorganism and decreased yield on culture. First, premature administration of antibiotics may compromise culture yield; thus, antibiotic treatment should be withheld until organisms are grown on culture5,6. However, multiple studies have demonstrated that perioperative administration of prophylactic antibiotics has no influence on culture yield12,16-21. Tetreault et al. reported that intraoperative cultures yielded the same organisms as preoperative cultures in 82% (28 of 34) and 81% (25 of 31) of patients randomized to receive antibiotics before the skin incision or after specimens were obtained for culture, respectively20. A randomized study by Bedenčič et al. revealed no difference in the organisms grown from samples obtained before and after antimicrobial prophylaxis (OR, 0.99; p = 0.99)19. Despite this evidence, the recommendation of the International Consensus Meeting on PJI is that mandatory withholding of antibiotics is not justified but that “in cases in which PJI is diagnosed or suspected and a pathogen has yet to be identified, the use of prophylactic antibiotics is dependent upon clinical judgment.”12 Culturing techniques may also influence culture yield, particularly for less-virulent organisms such as Propionibacterium acnes or coagulase-negative Staphylococcus7. The use of blood culture bottles and flasks instead of conventional agar and broth cultures is 1 strategy that has been shown to improve the yield of positive cultures of both synovial fluid and tissue specimens in cases of PJI14,16. In addition, extending the incubation period and obtaining a sufficient number of samples may also increase the sensitivity of culture7,12. Current recommendations state that 3 to 5 distinct intraoperative tissue samples should be obtained and sent for aerobic and anaerobic cultures in suspected cases of periprosthetic joint infection12. Furthermore, it has been proposed that as many as 10 periprosthetic samples should be collected when infection with a low-virulence organism is suspected14.
As has been mentioned, increasing the incubation period may also increase the culture yield, particularly for low-virulence organisms. For instance, P. acnes has a prolonged incubation period (median, 6 days) before it can be identified on routine culture18. During this period, clinical suspicion of infection in addition to aspiration results should be considered and appropriate treatment for PJI should be administered until the results of culture are known.
While the preferred method of treatment for PJI when routine cultures are negative has not been determined, several studies have investigated treatment outcomes following culture-negative PJI5,9,22-24. Choi et al. found that infection control was actually greater for a group of 40 PJIs that had negative cultures of specimens from at least 3 separate areas than it was for 135 PJIs that had positive cultures (p = 0.006)22. Additionally, Li et al. reported a reinfection rate of 7.34% for patients with culture-negative PJI, compared with 11.1% for patients with culture-positive PJI (p = 0.94)9. Berbari et al. reported a treatment failure-free survival rate of 94% in a series of 60 PJIs for which cultures were negative after being incubated for 7 days5. One possible explanation for the high success rates for those culture-negative PJIs is that the infections may have been caused by less-virulent organisms, which are easier to treat than those caused by more virulent organisms such as methicillin-resistant S. aureus (MRSA)1. In contrast, the present study and several others have demonstrated equivalent and even worse outcomes for culture-negative PJIs compared with culture-positive PJIs. Huang et al., in a study in which 90% of patients had cultures of specimens from at least 2 locations, reported that the failure rate was 73% for both culture-negative PJIs and culture-positive PJIs (p = 1.0)23. Furthermore, in a multivariate analysis, Mortazavi et al. found that culture-negative PJI was a predictor of failure for 2-stage exchange arthroplasty of the knee (OR: 4.5; 95% CI, 1.3 to 15.7)25. While these culture-negative PJIs may be caused by less-virulent organisms, the inability to target a specific organism may explain these less-than-optimal results. However, throughout the literature and as found in our study, survivorship was better after 2-stage exchange arthroplasty than it was after irrigation and debridement. For instance, Berbari et al. reported a 5-year survivorship, defined as treatment success, of 94% (95% CI, 85% to 100%) for 2-stage exchange compared with 71% (95% CI, 44% to 100%) for irrigation and debridement5. In contrast, in our study, the overall survivorship at 5 years was dismal (65.3%). These low rates of eradication highlight the importance of minimizing the rate of PJI by employing medical optimization, perioperative strategies, and careful patient selection. The improved treatment outcomes in other studies may potentially be attributable to the fact that some joints believed to have had culture-negative PJI may not actually have been infected.
New technologies, such as improved culturing techniques or next-generation sequencing, are needed to help identify the infecting organism in order to tailor antibiotic treatment. Recent evidence suggests that next-generation sequencing may provide increased sensitivity in isolating organisms (at a rate of up to 89% for culture-negative PJI) that cannot be identified using conventional culture26-29. Such sequencing allows the identification of organisms within a sample by high-throughput parallel sequencing of all the microbial DNA present, followed by comparison of the generated sequence reads against a bioinformatic database of all known microorganisms. While previously cost-prohibitive, the price of this diagnostic technique has dramatically decreased in recent years, making it accessible for clinical use26,27. The technique may be particularly useful when there is strong clinical suspicion of infection but cultures or other diagnostic tests are negative12,27. In addition, several studies have demonstrated that sonication can improve the likelihood of identifying an organism through the removal of biofilm from the implant30-33. While sonication is a time-intensive procedure that requires specialized equipment and may not be available to many, the International Consensus Meeting on PJI recommended that it be used in cases of suspected or proven PJI for which preoperative cultures of aspirate do not yield positive culture and antibiotics were administered previously12,30-32.
The present study had a number of limitations. First, the study was retrospective and there was limited information regarding premature antimicrobial therapy for these patients because it was poorly documented in the medical record. In addition, patients who had had a 1-stage exchange were not included in the study because culture-negative PJI was considered a contraindication and only 8 patients at our institution were treated with 1-stage exchange arthroplasty. Additionally, we included patients in whom surgery was performed for PJI even though MSIS criteria may not have been met as it was very difficult to fulfill minor criteria when not a single positive culture was present. The rationale for inclusion of those patients was that serological markers and other aspiration results are lower in patients with low-virulence organisms such as coagulase-negative Staphylococcus or P. acnes, and many of these culture-negative PJIs are thus likely to arise from such organisms. Furthermore, only a 1-year minimum follow-up was used in our study. The sampling techniques, including the number of cultures and incubation periods, were variable among the surgeons and dependent on each surgeon’s suspicion of infection. Antibiotic information was unavailable for many patients because the orthopaedic and infectious-disease medical records were distinct and because many patients were followed by physicians unaffiliated with our institution. There was variability in the sampling technique between surgeons despite a generalized institutional protocol. Additionally, because many different surgeons treated these patients, different perioperative treatment strategies were used. Antibiotic therapy and treatments were very heterogeneous and could not be fully explored.
In summary, the present study demonstrates that culture-negative PJI is a relatively frequent finding and has an unacceptable rate of treatment failure. Because of the poor outcomes associated with culture-negative PJI, every effort should be made to isolate the infecting organism prior to surgical intervention. Methods such as extending the incubation period for culture samples, withholding antibiotics until samples have been sent for culture, and using molecular techniques can help in isolating the infecting organism.
Investigation performed at the Rothman Institute at Thomas Jefferson University, Philadelphia, Pennsylvania
Disclosure: No external funding was received for this study. On the Disclosure of Potential Conflicts of Interest forms, which are provided with the online version of the article, one or more of the authors checked “yes” to indicate that the author had a relevant financial relationship in the biomedical arena outside the submitted work and “yes” to indicate that the author had a patent and/or copyright, planned, pending, or issued, broadly relevant to this work (http://links.lww.com/JBJSOA/A52).
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