Curr Rev Musculoskelet Med (2014) 7:96–102 DOI 10.1007/s12178-014-9217-z

TKA SYMPOSIUM (P SANCHETI, SECTION EDITOR)

Infection post-total knee replacement: current concepts Pouya Alijanipour & Javad Parvizi

Published online: 5 April 2014 # Springer Science+Business Media New York 2014

Abstract Periprosthetic joint infection is a hot topic for investigation because it represents a challenging clinical problem with considerable burden for patients, institutions, and health systems. Despite our substantial knowledge, many details in prevention, pathophysiology, diagnosis, and treatment of infectious complications following total knee arthroplasty remain to be controversial with the available evidence being insufficient and at times conflictive. This manuscript is an attempt to approach the most recently published literature regarding the aforementioned details and aims to provide the reader with an updated perspective in the management of periprosthetic joint infection of the knee. Keywords Arthroplasty . Replacement . Knee . Periprosthetic joint infection . Surgical site infection . Mortality . Cost analysis . Patient readmission . Antibiotic prophylaxis . Time factors . Bone cement . Drug resistance . Microbial . Biofilm . Infusion . Intraosseous . Coated materials . Biocompatible . Complications . Blood sedimentation . Cell count . C-Reactive protein . Biological markers . Debridement

Introduction Periprosthetic joint infection (PJI) is a concerning surgical complication because of its challenging management and considerable likelihood of becoming a disabling chronic condition. Nevertheless, our knowledge in many aspects of PJI still needs P. Alijanipour : J. Parvizi (*) The Rothman Institute of Orthopaedics at Thomas Jefferson Hospital, 125 S 9th St, Ste 1000, Philadelphia, PA 19107, USA e-mail: [email protected] P. Alijanipour e-mail: [email protected]

to be broadened. This is reflected by the existence of many controversial issues in different aspects of PJI management and is the reason why PJI continues to be a hot topic for investigation. PJI has a major impact on many aspects of life of the suffering patients including their physical and emotional health as well as family and social relationships. A recent retrospective single institutional publication compared the mortality of patients who underwent at least 1 surgical intervention secondary to PJI with patients who underwent revision surgery for aseptic failure. Compared with those undergoing aseptic revision arthroplasty, significantly higher mortality rates in PJI patients were observed at 90 days (3.7 % vs 0.8 %), 1 year (10.6 % vs 2.0 %), 2 years (13.6 % vs 3.9 %), and 5 years (25.9 % vs 12.9 %), with surgery because of PJI independently increasing the mortality up to 5-fold in comparison with surgery secondary to aseptic failure [1]. Although this study is another evidence for substantial burden of PJI on physical health of the patients, its findings should be interpreted with caution. The mechanism for this increased mortality is difficult to explain in this retrospective study, and it still remains unclear to what proportion the course of PJI by itself or type of surgical intervention influences mortality. Burden of PJI does unfortunately extend to the society and has major influence on the health care systems because of its enormous economic cost. PJI poses serious financial challenge to referral centers particularly teaching hospitals, because they receive a higher proportion of PJI cases in comparison with urban or rural hospitals [2]. In a tertiary care center, the mean annual cost in patients with PJI was calculated to be $116,383 (range: $44,416–$269,914), nearly 4 times of cost of patients with uncomplicated primary TKA ($28,249; range: $20,454–$47,957) [3]. Two retrospective single institutional studies found that 3 complications that can be related to PJI, namely arthrofibrosis, surgical site infection (SSI),and wound-related issues accounted for nearly one-half [4] to two-thirds [5] of all unplanned readmissions

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during 90 days following primary TKA. In patients who underwent revision TKA because of PJI, 90-day readmission rates were 1.8 times higher than patients who underwent primary TKA [4]. This data represents readmission to the same hospital where the index surgery was performed and might be underestimated because it does not count readmissions to other centers. Based on a California Registry (database of California Office of Statewide Health Planning and Development or OSHPD), it was shown that 17 % of SSI cases would have been missed by surveillance of the index hospital alone [6].

Prevention Prevention should be the prime concern in confronting a major challenge such as PJI. According to various guidelines, timing of the prophylactic preoperative antibiotics within a window of 1-hour prior to incision is considered as one of the most important tactics in prevention of SSI [7•]. The rationale for appropriate antibiotic timing was questioned by a retrospective study on national Veterans Affairs database of 32,459 surgical procedures including total joint arthroplasty (TJA) [8].Unlike previous similar studies, this study considered time as a continuous parameter. Interestingly, higher SSI rates were observed with antibiotic administration more than 60 minutes prior to incision. However, no difference was observed between antibiotic administrations after incision compared with within 60 minutes before incision. Moreover, vancomycin when administered as the sole prophylactic antibiotic in orthopedic procedures was associated with higher SSI occurrence compared with cefazolin (adjusted odds ratio (OR)= 1.75; 95 % confidence interval (CI), 1.16–2.65).The authors suggested the selection of timing intervals for grouping patients and type of antibiotic influenced the conclusions of earlier publications regarding relationship between antibiotic timing and SSI and concluded that strict adherence to timely antibiotic administration did not robustly correlate with improved outcome. The efficacy and cost-effectiveness of antibiotic-laden bone cements (ALBC) for primary total joint replacement continues to be a controversial preventive strategy. A retrospective analysis by the senior author did not find any difference in profile of responsible pathogens for PJI and their antibiotic resistance before and after introduction of ALBC for primary TKAs, though the incidence of PJI in TKA decreased significantly in the “after” period, which can represent the implantation of systematic use of ALBC plus many other new preventive measures during the study period [9]. A meta-analysis of 7 randomized clinical trials (RCT) with 6381 cases of TJA found use of ALBC was associated with lower incidence of deep infection in comparison with plain cement or systemic antibiotic alone, although it did not decrease the rate of superficial infection [10]. In another retrospective

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analysis, the expected rate of PJI in TKA was calculated extrapolating the trend for total hip arthroplasty. It was observed in the period during which ALBC was implemented, the incidence of PJI was 30 % less than expected. The costanalysis showed that if ALBC had been used for all primary TKAs, cost for preventing 1 case of knee PJI would have been between $2112.72 and $112,606.67 based on type of antibiotic-cement mix [11]. However, data from Canadian Joint Replacement Registry and Canada's Hospital Morbidity Database including 36,681 TKAs between 2003 and 2008 suggested, even after adjusting for possible confounders, use of ALBC was not associated with relevant decrease in 2-year revision rate because of infection, nor was it associated with an increase in revision rate because of aseptic loosening [12]. Similarly, another prospective randomized study of 2948 cases with cemented TKA, use of ALBC with erythromycin and colistin was not associated with decrease in superficial or deep SSI [13]. Furthermore, a USregistry based study of 56216 TKA procedures reported ALBC as a risk factor for deep surgical site infection (hazard ratio: 1.53) [14]. Anyhow, the characteristics of optimal cement and antibiotic for this purpose have not been defined. The available types of cement have different mechanical properties and different capacity for releasing antibiotics. Antibiotics are also different in terms of their chemical and bioavailability properties. These 2 factors can be potential missing confounding factors in the previous studies and explain discrepancy in the existing evidence. Lastly, it can be argued that use of ALBC might not be necessary for all patients and its use can better be justified in selected highrisk patients in whom characteristics are yet to be precisely described. Intraosseous antibiotic infusion through a tibial cannula after tourniquet inflation and before surgical incision was proposed as an alternative route for prophylactic antibiotic administration in a small size randomized prospective study [15]. A unique advantage of this method is obtaining high concentrations of antibiotic in surgical field tissues (10–15 times higher than systemic administration) that can be particularly helpful for prophylaxis of PJI caused by bacteria with high minimally inhibitory concentrations against cephalosporins such as coagulase negative staphylococci. The authors mentioned this method is advantageous over other local administration methods such as foot vein cannulation for its ease, reliability, and speed. However, more evidence regarding pharmacokinetics, applicability with different antibiotics, and efficacy (based on clinical outcomes) is required. An attractive field for prevention of PJI is design of biocompatible implants with coating surfaces that resist to bacterial attachment. In an in vivo rabbit model for knee PJI, the investigators utilized 27 pins with 3 different coating surfaces including pins without coating surface, pins coated with hydroxyapatite (HA), and pins coated with silver ion-doped

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nanosized calcium phosphate-based ceramic powder (developed by the authors) [16]. Based on microbiology and histology finding 6 weeks after implantation, the authors observed that silver coated implants had the least bacterial colonization and lowest proportion of positive cultures (1/9) in comparison with uncoated implants (8/9) or HA-coated implants (5/9). Pathologic exam did not find any silver particulate or adverse local tissue reaction. The study despite its design limitations (animal study, small size, single pathogenic bacteria, definition of infection, and lack of systemic safety measures such as blood levels of silver or pathologic evaluation of liver) is another stride toward the design of what has been called as intelligent orthopedic implants with particular capacity to inhibit bacterial adherence, colonization, and biofilm formation on the implant.

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arthroplasty strategy. In a recent retrospective comparative study, culture negative PJI consisted 23 % of all PJI cases and prior antibiotic and surgical therapy were reported as risk factors for such an infection. Curiously, culture negative infections were associated with more successful outcomes, which could be because of more aggressive antibiotic and surgical treatment commonly applied for this scenario [21]. Type of the pathogen may also have an important role in the outcome of treatment, which can be because of the pathogenicity of the organism, associated comorbidities, and the competency of treatment strategy. Fungal PJI is a serious challenge and has an exceptionally high rate of treatment failure, 50 % for 2-stage arthroplasty, as reported by a retrospective study [22].

Diagnosis Microbiology Better understanding of pathophysiology can be helpful for diagnosis and treatment of PJI. Application of the theory of microbial biofilm growth might be able to explain some challenging aspects of PJI [17]. Biofilm formation may explain the phenomenon of culture negative PJI. Bacteria lodged in biofilm, unlike their planktonic counterparts, may be in dormant state and cannot be easily cultivated. It can also explain the conflictive evidence that exists regarding success rate of irrigation and debridement with prosthesis retention, single stage or 2-stage exchange arthroplasty. The success or failure of medical or surgical interventions for PJI might be related to eradication of biofilm and perhaps among the factors that determine the outcome of treatment, biofilm is the most challenging. Epidemiologic studies demonstrated different trends for microbiological profile of PJI between 2 referral centers in Germany and the United States [18] and for a single American institution over a period of 14 years [19]. These studies found that PJI caused by methicillin resistant Staphylococcus aureus (MRSA) is becoming more prevalent over time [19] and it is a more serious problem in the United States than in Germany [18]. A multi-institutional study tracked the microbiological profile of 92 PJI cases, in which 2-stage exchange arthroplasty failed. Surprisingly, only one-third of patients presented identical organism at the time of failure. The prevalence of similar organism after failure was much less than expected: 37 % for Staphylococci and 16 % for other bacteria [20]. Genetic analysis of the responsible pathogens was not performed, but it could have provided us with invaluable information regarding pathophysiology of PJI. Culture negative PJI is a mysterious and uncomfortable scenario and causes uncertainty for diagnosis and treatment decisions in terms of type of antibiotic(s), duration of therapy, and the appropriate time for re-implantation in a 2-stage

Diagnosis of PJI can be challenging especially when no obvious clue for the presence of infection exists. A multicriteria approach for diagnosis of PJI has been proposed by Musculoskeletal Infection Society (MSIS) [23•]. However, in this definition and except for microbiological culture, the remaining diagnostic tests including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), synovial white blood cell (WBC) count and differential, and intraoperative histopathology exam are nonspecific and indirect indices for an inflammatory response. Similar problems exist with other assays that have been suggested as adjuvant diagnostic tests for PJI such as anti-granulocyte scintigraphy with 99 mTclabeled monoclonal antibodies [24], infrared digital telethermography [25], fluorodeoxyglucose-positron emission tomography (FDG-PET) [26], presence of lamellar hyperintense synovitis on magnetic resonance imaging [27], as well as detection of antimicrobial peptides and inflammatory cytokines in serum or synovial fluid [28]. The diagnostic characteristics of these tests need to be thoroughly verified before considering them as reliable tools, based on which serious clinical decisions are to be made. Moreover, we need novel diagnostic methods that in spite of targeting inflammatory response of the human body, they measure parameters that are unique to the pathogenic bacteria. A meta-analysis for diagnostic characteristics of synovial WBC count and differential confirmed their high accuracy for diagnosis of PJI with positive and negative likelihood ratio of 13.3 and 0.13 for WBC count, and 7.6 and 0.12 for PMN percentage. This study found preoperative aspiration was more sensitive, in terms of WBC count, than intraoperative aspiration (0.91 vs 0.77) [29].Two retrospective studies published this year suggested that separate thresholds for ESR, CRP, and synovial WBC count and differential should be considered for early postoperative vs late chronic PJI [30, 31] and for hip PJI vs knee PJI [31]. Thresholds for early

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PJI and knee PJI were suggested to be higher than late PJI and hip PJI, respectively. Another retrospective study found that high sensitivity and low sensitivity CRP were closely correlated and had similar test characteristics for PJI [32], indicating these tests can be utilized as surrogates for clinical and research purposes. Furthermore, it might unjustify use of high sensitivity CRP in routine clinical practice because of its higher cost. A few recent studies have broadened our knowledge regarding bacterial cultures in PJI. A multicenter prospective study demonstrated administration of prophylactic antibiotics before skin incision do not affect the result of microbiologic culture of intraoperative samples. Antibiotic prophylaxis does not need to be withheld until samples for bacterial culture are obtained [33]. Another prospective study discouraged use of swab cultures because they were less sensitive (70 % vs 93 %) and less specific (70 % vs 98 %) than tissue cultures [34]. This has important clinical implication because use of swabs alone for obtaining culture samples, although inexpensive and easy, can jeopardize the optimality of treatment strategy because of its potential false positive and false negative results. Another investigation suggested routine use of cultures for acid fast bacteria and fungi for presumed aseptic revisions are unjustified because of their extremely low true positive rates and considerable cost [35]. Based on a prospective study, culturing samples from draining wounds or sinuses was shown to be in concordance with deep tissue cultures only in about half of cases and was more likely to generate polymicrobial results. Moreover, superficial cultures can potentially misinform the clinician with regard to choice of antibiotic regimen and when deep cultures and other diagnostic tests are negative, they may still yield positive results [36]. New methods are being developed to improve the ability of microbiological culture in detecting pathogenic causes of PJI. A big challenge is biofilm formation particularly in chronic PJI. Bacteria are lodged in a complex biofilm matrix, which conceals them from the immune system and hinders sampling and cultivation. One investigation proposed use of DLdithiothreitol (DTT), a sulfhydryl compound with ability to liquefy the biofilm through reducing disulphide bonds between polysaccharides and neighboring proteins. The theory behind this method is DTT would alter the extracellular matrix of biofilm and free bacteria from it. Using this method on 76 explanted septic and aseptic prosthesis, the authors observed that it improved the sensitivity of sonication (71 % vs 86 %) while its specificity remained similar (94 %) [37]. Use of other molecular techniques for improvement of culture results, such as polymerase chain reaction (PCR) using different probes has also been suggested [38, 39]. Although PCR can be used as real-time assay, it is probe-dependent. Specific probes can miss less common microbes and broader probes are unable to specify the bacterial cause or distinguish mono- from polymicrobial PJI.

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Two prospective investigations evaluated the use of inflammatory biomarkers for diagnosis of PJI. One study included 124 revision arthroplasty procedures and found that procalcitonin, interleukin 6, and interferon α were not superior to CRP [40]. The other study utilized enzyme-linked immunosorbent assay (ELISA) to measure the levels of antimicrobial peptides such as human β-defensin 2, human βdefensin 3, and cathelicidin LL-37 as well as inflammatory cytokines such as interleukin (IL)-1β, IL-4, IL-6, IL-17A, interferon-γ, and tumor necrosis factor (TNF)-α in 15 patients with PJI and 20 patients with aseptic revision [28]. Although the authors interpreted the results of these tests as “promising” for detection of PJI, larger size studies are required to determine whether these markers really outperform the available routine tests.

Treatment Several therapeutic strategies are available for PJI yet controversy regarding their indication and outcome persists. Generally, it is believed that irrigation and debridement (I&D) should be done before establishment of biofilm elements. Therefore, for chronic PJI the probability of failure of I&D is high and for early postoperative PJI the sooner I&D is performed respecting to the index surgery, the better the success rate would be. In a retrospective multicenter study, although it was observed that the success rate of I&D was higher when it was done during the first month after index surgery in comparison with 31–90 days after surgery (44 % vs 24 %), only 20 % of those patients who were operated in the first 10 days after surgery had successful outcome [41]. The puzzle becomes more complicated with findings of a previous study that showed failure of I&D can be associated with failure of subsequent 2-stage arthroplasty [42]. However, pathophysiology of biofilm formation might be able to explain these confusing clinical results. Depending on type of bacteria, it takes 2–4 hours to strongly attach to the implant, 6–12 hours to develop a protective matrix on the implant, and 2–4 days to fully mature into bacteria shedding biofilm [41]. Therefore, if we presume bacterial inoculation happens during index surgery, I&D would be of benefit during the first few days after index surgery. Unfortunately, this is the period during which the patients might have not developed adequate signs and symptoms of PJI and most of surgeons would be reluctant to intervene and prefer to observe patients. Moreover, I&D are able to disrupt biofilm on the surface of prosthesis and are probably unable to address the biofilm formation at the interfaces of bone-cement-implant. Direct intra-articular (IA) administration of antibiotics through Hickman catheter has previously been suggested for treatment of PJI. A recent study from the proponents of this method measured synovial fluid levels of vancomycin

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injected intra-articularly vs intravenously. It was observed that higher peak levels and higher than minimal therapeutic levels during 24 hours could be achieved via intra-articular injection. Furthermore, the authors reported that therapeutic serum levels of vancomycin were also achieved. Whether this method leads to improved outcome in the treatment of PJI remains undetermined until prospective comparative studies with adequate sample size and follow-up are published [43]. Antibiotic impregnated cement spacers provide the possibility of local delivery of antibiotics that may obviate the need for systemic antibiotic therapy [44]. Debates regarding use of static or dynamic spacers continue. Two systematic reviews were published comparing articulating and static spacers [45, 46]. They found articulating spacers were associated with additional 10° in range of motion [45, 46], less bone loss [45] and less need for extensile approach and rotational flaps [45]. However, the final outcome was similar in both groups [45, 46], although the index of case complexity (as defined by antibiotic resistance, bone loss, and presence of draining sinus) in static group was higher [45]. Both of these reviews showed better rates of infection eradication with articulating spacers although their different inclusion criteria resulted in inconsistency in statistical significance. However, this difference was still significant even after controlling for case complexity [45]. These results were based on small size caseseries with inhomogeneous protocols and implants, in most of which adequate data for the confounding factors were unavailable. A methodologically sound prospective randomized study in this field is still lacking. Perhaps one of the most controversial issues in the management of PJI is whether 1- stage or 2-stage exchange arthroplasty is able to achieve better outcome in terms of infection eradication, functional outcome, and costefficiency [47•]. As outlined by a recent systematic review on the subject, the majority of the publications are noncomparative observational studies with studies regarding 2-stage arthroplasty outnumbering those for 1-stage arthroplasty [48]. The reinfection rate for 1-stage and 2-stage arthroplasty was reported as 0 %–13 % and 0 %–41 %, respectively, which also depends on the length of follow-up [48–50]. Both approaches have been reported to be highly successful and their success rate depends highly on the expertise and experience of the treating surgeon. However, it is possible that some patients based on their underlying general condition, type and virility of organisms and the status of bone and soft tissues might benefit more from one of these strategies. An international multi-institutional prospective randomized study with adequate power would provide us with more insight. In addition, a randomized prospective study compared tibial tubercle osteotomy (TTO) and quadriceps snip (QS) in the second stage arthroplasty of 81 patients with knee PJI over a period of 7 years. The authors reported better results for TTO group in terms of maximal flexion achieved, occurrence, and

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grade of extension lag and Knee Society Score. The complication rate was similar between 2 groups. The authors were not able to distinguish indications for each method but concluded TTO is an efficacious exposure alternative in second stage revision TKA [51]. A universally accepted definition for successful outcome after treatment of PJI is of great importance and is yet to be created. This would make the comparisons of different studies easier and would allow doing more precise meta-analysis of the available literature. A Delphi-method based study by our group attempted to define criteria for successful outcome aiming to establish basis for future research [52].

Conclusions Many issues in the field of PJI remain to be debatable. Although the expanding body of literature would provide more insight, some of the controversial aspects are yet to be based on reliable evidence. Astute orthopedic surgeons should base their practice on precise understanding of the most updated literature, sound judgment, and team wisdom. The first International Meeting on Periprosthetic Joint Infection was held in Philadelphia last year, to reevaluate the existing literature, reach consensus in numerous details of PJI management, and recognize areas in need for more investigation. International experts from different specialties were teamed up into several workgroups that worked in close contact through a social website to synthesize the available evidence. In August 2013, more than 300 of these experts attended the meeting to work face to face on the preliminary draft and vote for 207 questions/consensus statements that were presented in the general assembly of the meeting using a Delphi method. The final consensus document has been published and is accessible for the enthusiastic reader [53•].

Compliance with Ethics Guidelines Conflict of Interest Pouya Alijanipour declares that he has no conflict of interest. Javad Parvizi has board membership with Journal of Arthroplasty, Journal of Bone and Joint Surgery, Bone and Joint Journal, Philadelphia Orthopaedic Society, Eastern Orthopaedic Association, CD Diagnostics, United Healthcare, and 3 M. He has been a consultant for Zimmer, Smith & Nephew, Convatec, TissueGene, Ceramtec, PRN, and Medtronic. He has received royalties from Elsevier, Wolters Kluwer, Slac, Datatrace, and Jaypee Publishers. He has intellectual properties with CD Diagnostics and Hip Innovation Technologies. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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