Arthroplasty & infection: The bane of the orthopaedic surgeon
Diane Quach, Mark Wilson
Saturday, June 4th, 2016
The last 50 years have ushered in an era of rapid technological development in the domain of joint replacement surgery and subsequently improved the lives of millions, both in terms of alleviation of pain and functional restoration. In spite of this technical progress, periprosthetic joint infection remains a barrier in achieving entirely successful outcomes for all joint replacement surgery patients. Once a periprosthetic joint infection has been diagnosed, there exists a vast array of adjuvant treatment modalities. A combination of clinical signs, laboratory and microbiological tests, histopathology, and imaging studies are required to meaningfully diagnose a periprosthetic joint infection, but the increasing incidence of morbid obesity, diabetes, and the rise of the ‘metabolic syndrome’ has been associated with a perceived increase, amongst clinicians, in the rate of periprosthetic joint infections. Indeed, the rising prevalence of this complication demands considerable clinical acumen from the orthopaedic surgeon. It has become increasingly challenging to treat patients who develop infections in the setting of total joint replacement. Surgical options include single or serial washouts vs. single stage or multi-stage exchange procedures, but the utilisation of adjuvant broad-spectrum intravenous antibiotics with myriad systemic side effects is required for adequate treatment. Furthermore, the emerging and proven value of the multidisciplinary team brings together orthopaedic surgeons and infectious disease physicians to act in the best interests of their patients by limiting the considerable morbidity associated with periprosthetic joint infections.
Since the developments of Charnley in the 1960s, [1-4] joint replacement surgery has revolutionised the treatment of joint pain, most commonly due to osteoarthritis, and served to restore function and productivity in an increasingly afflicted population.  Despite these technical and surgical advances, periprosthetic infections have been an important barrier in achieving successful joint replacement surgery in some patients.  In the context of an ageing population, surgeries such as this are becoming evermore prevalent, and hence the frequent review of its process is warranted to achieve the best possible patient outcomes. There are several aspects of arthroplasty that need to be taken into account. Given that prevention is always better than cure, surgical sterility and asepsis is by far the most important factor in preventing periprosthetic infections and maintaining the efficacy of joint replacement surgery as a therapeutic modality.  Contributing to this are the various adjuvant treatments included in current perioperative protocols widely used by modern orthopaedic surgeons. However, despite the multitude of additional precautions, it is revealed that infection rates persist at one to four percent in most modern facilities. [6,7] Various patient factors such as obesity and diabetes have also been implicated in the development of periprosthetic joint infections. In considering the contributing factors, an evaluation will also be made of the current treatment options and outcomes for patients in terms of quality of life and economic burden on the healthcare system. Infections of orthopaedic prostheses prove to be a considerably disastrous event for both patients and surgeons, and hence warrant close review of the options available and their value to patient management.
Current perioperative protocols
Perioperative protocols now include a multitude of adjuvant treatments that are very much part of the modern orthopaedic surgeon’s armamentarium. Regimes including perioperative antibiotic therapy, the use of ‘space suits’ by surgeons and theatre nurses, double gloving, antiseptic-coated skin adhesives, adherence to sterile surgical practices, and the utilisation of antibiotic-impregnated bone cement are just some of a number of steps taken to reduce the likelihood of superficial and deep wound infections, [8-11] which in the setting of an artificial prosthesis can lead to limb, and occasionally, life-threatening complications. 
These methods have a sound theoretical and clinical basis,  and are well-accepted in the orthopaedic surgical community as a means of preventing multiple surgeries to salvage or revise infected prosthetic joints and the toxicity of protracted, high-dose intravenous antibiotic therapy. Despite these measures, a review of the available literature reveals an infection rate of between one and four percent in most modern hospitals [6,7]; importantly, these figures are expressed to patients prior to joint replacement surgery as part of the process of informed consent, as an act of best practice. Although the use of antibiotics has a clear clinical benefit in the setting of periprosthetic infection, it is difficult to discern how useful the other approaches are in helping to reduce infection in joint replacement surgery. [9,13,14]
Basic microbiology of joint infections
Evaluation of microorganisms associated with perioperative infections demonstrate the existence of a wide range of Gram-positive and negative bacteria and fungi that may cause infection.  However, there is an overwhelming association between Gram-positive bacteria and perioperative infections, particularly Staphylococcus spp., compared to any other known causative organism. [15-17] There is particular concern for the growing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) associated with perioperative infections. [16,17] Staphylococcal spp. has also been associated with higher risk of re-infection and persistence of infection in the setting of arthroplasty.  Propionibacterium acnes is also reported to be of growing concern, especially in the context of shoulder surgery, for reasons yet to be clearly delineated. [15,18,19]
Patient factors: obesity, diabetes and immunosuppression
Obesity is fast becoming an epidemic for the Australian healthcare system. Not only has high body mass index (BMI) been implicated in the increased number of total joint replacements, owing largely to accelerated osteoarthritis (OA), but obesity as a health condition in itself complicates arthroplasty surgery and deleteriously impacts patients’ functional outcomes. Australia has one of the highest rates of obesity in the world, with a quarter of the population being classified as obese, and the incidence is increasing, with 34% of the population predicted to be obese in 2015.  Furthermore, because obesity is a risk factor for OA due to increased mechanical joint loading, the proportion of those presenting for joint replacement surgery is even greater and is also set to increase in the short to medium-term. Obesity is associated with a number of co-morbidities such as heart disease, hypertension, diabetes, and the ‘metabolic syndrome’, the latter two of which complicate surgery and independently increase the risk of periprosthetic infection.
There is, however, a degree of ambiguity in the orthopaedic literature, with arguments for and against obesity in itself being an independent risk factor for periprosthetic infection. One centre’s study demonstrated that morbid obesity, or a BMI of > 40, increases the risk of deep prosthetic infection by eight to nine times; however, obesity and a BMI of 30-39, increased the risk by two to three times. [21,22] These rates are also related to the anatomical site of the joint replacement itself. With regards to the knee, only the relationship between morbid obesity and prosthetic infections was found to be statistically significant. [22,23] Addressing the issue of surgery for obese patients is one of the modern-day challenges for orthopaedic surgeons and much work remains to be done in developing a clear framework for addressing this clinical problem.
Diabetes mellitus and hyperglycemia have been indicated as risk factors for various complications in orthopedic surgery, including surgical site infections, pneumonia, prolonged hospital admissions, stroke, and deep vein thrombosis. [24-27] This increased risk is often attributed to the common co-morbidities that exist in diabetic patients, which are of a particular vasculopathic nature.  However, it appears that a direct correlation between diabetes mellitus and incidence of periprosthetic joint infection is yet to be clearly delineated. One study has demonstrated an important distinction between controlled and uncontrolled metabolic syndrome (defined as diabetes, dyslipidemia, hypertension, and obesity) and risk of periprosthetic joint infection; however, when compared to healthy patients, both groups appeared to yield non-significant results.  Another study investigating rates of infection after total joint arthroplasty has found up to 11.4 times higher incidence of infection in diabetes mellitus patients compared to non-diabetic patients in total hip arthroplasty and 2.6 times higher in total knee replacement.  Contrary to this, it was found that the blood glucose level (BGL), measured by HbA1c readings pre- and post-operatively, were not significantly associated with infection risk.  Hence, it appears that BGL alone is not an adequate indicator of perioperative infection risk, though it remains an important risk factor for other complications, such as length of stay, in orthopaedic surgery.  Therefore, the evidence to support the direct relationship between diabetes mellitus as an independent risk factor for periprosthetic joint infections remains an area requiring further research.
Rheumatoid arthritis (RA) patients are not only at higher likelihood of requiring joint arthroplasty, but also have an innate immunosuppressed profile due to their management regimes. There is a paucity of recent literature that discusses the relationship between perioperative infections and RA. Of the available most recent data, RA patients have been indicated as being at higher risk of complications when compared to OA patients, another prominent group undergoing joint arthroplasty. RA is also reportedly associated with higher length of hospital stay, cost of hospitalisation, and need for blood product transfusion compared to OA patients.  Other studies have found that RA is associated with a higher incidence of prosthesis infection compared to matched OA controls. 
Interestingly, contrary to previous studies, a study comparing RA and ‘non-RA’ patient sequelae after total shoulder arthroplasty found that RA patients actually had lower length and less complex stays in hospital post-surgery, and that RA patients were more often routinely discharged home with fewer complications.  It has been suggested that the advent of newer RA treatments, such as disease-modifying antirheumatic drugs (DMARDs) and anti-tumour necrosis factor (anti-TNF) inhibitors may contribute to this altered risk for perioperative complications in RA patients. 
A further recent study has attempted to compare DMARDs with newer biological agents such as infliximab and rituximab, amongst many others, and their risk association need for total joint arthroplasty and associated periprosthetic infection risk.  It appears that the use of biological agents was associated with a higher and earlier, need for joint replacement when compared to DMARDs; however, it was also noted this may be attributed to the fact that patients using biological agents tend to have more aggressive RA.  Moreover, it appears that although biological agents tend to require less revision surgeries, there is no significant difference in the rate of joint infection between the two treatment regimens. 
Solid organ transplant patients
Solid organ transplant patients are becoming increasingly common as total joint arthroplasty candidates. This is due to the increased rate of solid organ transplants, but reasons for total joint arthroplasty in this group are not much different to otherwise healthy individuals and include osteonecrosis of the femoral head for total hip arthroplasty (THA), and osteoarthritis. [35-37] It has been postulated in the past that this group of patients may be more susceptible to periprosthetic infection due to their use of immunomodulators such as tacrolimus, mycophenolic acid, and corticosteroids such as prednisone.  Joint replacement surgery in this patient group has traditionally involved the prophylactic use of antibiotics, presumably for this reason, although the use of perioperative intravenous antibiotics for all patients has become standard practice in orthopaedic surgery. [35-38]
Most recent studies are largely retrospective when observing the rate of perioperative infection, as well as other complications in this highly select patient group. However, contrary to what may be presumed, the most recent literature suggests that patients undergoing THA still have low rates of periprosthetic joint infection as a perioperative complication, despite the nature of the transplant undertaken and the subsequent immunosuppression regime. [36-38] In some studies, the periprosthetic infection rate in the transplant patient group following THA was zero. [37,38] Other cases observed only one wound infection amongst the 55 THAs performed in various solid organ transplant patients.  However, the situation appears to be different for this patient group in regards to total knee arthroplasties (TKA). Two studies consistently report the rate of periprosthetic infection as being higher in TKA compared to THA. [36,37]
Another study observing only TKA reported an infection rate of 4 out of the 24 (17.3%) TKAs performed on various solid organ transplant patients. Contrary to these numbers, there have been reports of no statistically significant difference between TKA and THA, with both yielding no increased periprosthetic infection risk.  Given all of this recent evidence, it appears that we are yet unable to discern whether there is any true significance between solid organ transplant subgroups and their relative risk of periprosthetic infection in total joint arthroplasty. The conclusion may perhaps be drawn, that it is relatively safer to perform total hip replacements in this patient group compared to total knee replacements. However, one must be cognisant of the fact that most of these studies are retrospective analyses of specific patient cases with relatively small statistical power.
Patients with human immunodeficiency virus (HIV) are also becoming increasingly common candidates for total joint arthroplasty, perhaps owing to the improved efficacy of antiretroviral treatments available to the community and increased longevity of these patients in general.  One study reported that HIV patients undergoing joint replacement tend to be younger than matched controls and also yielded non-significant results in its investigation of whether this immunocompromised group will experience higher rates of periprosthetic infection.  This suggests periprosthetic infection rates in the HIV population are not as striking as they used to be in the context of total joint arthroplasty.  This has been attributed to the advent of more effective antiretrovirals and their increased uptake in this patient population, as well as more effective intravenous drug user (IVDU) education producing a lower bacteraemia risk to seed infection.  Other similar studies appear to reflect those previously found in producing either none,  or very low rates (one hip in 41 THAs)  of periprosthetic infection for total knee or hip arthroplasties in HIV patients.
Recognising perioperative joint infections
It must be borne in mind that recognising infection after total joint replacement remains clinically difficult. A combination of clinical signs, laboratory and microbiological tests, histopathology, and imaging studies are required to meaningfully suggest a prosthetic infection.  More important, is the ability to predict and diagnose the early stages of a prosthetic joint infection as prompt intervention and management has the best chance of salvaging the prosthesis and preserving optimal joint function.  Given that plain radiographs have low sensitivity and low specificity for detecting early infections, the efficacy of new imaging techniques involving scintigraphy, positron emission tomography, and computerised tomography imaging is currently under investigation, but remains contentious.  What is becoming clear is the fact that treatment of orthopaedic infections is no longer solely in the domain of the orthopaedic surgeon. Modern multidisciplinary care now demands a team approach between surgeons and infectious diseases specialists; the need for an evidence-based approach should take priority when managing both superficial and deep infections.
Treatments: antibiotic therapy & surgical revision
Infections of joint replacement components and other implantable orthopaedic hardware are some of the most disastrous events in clinical orthopaedics, especially in terms of patient outcomes, and often considerable and prolonged resource expenditure. Not only is the ordeal of having a prosthetic infection protracted with an increased risk of recurrent infections, there are also a wide range of possibly devastating outcomes, including sepsis and limb amputation.  The financial burden is also significant, with the cost of successfully treating an infected joint replacement conservatively placed at approximately $50,000 for early interventions and $100,000 for late interventions.  In revising joint replacements for infection, several important questions arise, namely, “Should failed total joints be revised in single or multi-stage operations?” and “What should be done in those situations where bone loss is considerable and metallic structural augmentation is required to restore anatomy?” These and other questions demand attention.
It has become an increasing challenge to treat patients who develop infections in the setting of total joint replacement. Literature is scarce in regards to accepted modes of treatment, particularly with hip, knee, and shoulder prostheses, and moreover, few publications specifically outline the most effective therapeutic regimes.  It is problematic for treating teams to appreciate what best clinical practice may be; indeed, the removal and revision of the prosthesis as a single or two-staged procedure is often the fallback position for orthopaedic surgeons. [7,13] The evidence suggests that this approach is one of a number of potential options. At the other end of the spectrum, reports of high rates of successful salvage of prosthesis in situ are also achievable with aggressive debridement and targeted antibiotic therapy alone. [14,43] However, the prevalence of resistant bacteria should be borne in mind and appropriate consultation with an infectious diseases physician is also wise. Moreover, there are other strategies such as MRSA screening and other prophylactic practices that increase the success of an arthroplasty, the discussion of which is beyond the scope of this article.
Patient outcomes & quality of life issues
Of the available treatment outcomes, it appears the most long-standing debate still appears to be between one-stage and two-stage revisions, in terms of surgical interventions. For patients that are unfit for surgery, long-term suppressive antibiotic therapy seems to be a viable option, though the ideal regimen is yet to be delineated.  Two-stage revision also appears to be accepted as a ‘gold-standard’ for the management of periprosthetic infections. [45-48] The most recent literature remains rather mixed about the efficacy of one-stage over two-stage revisions in hip and knee arthroplasties. Of the most recent studies, some yield better success rates [45,49] and patient-rated outcomes for one-stage revision  or lower than expected success rates for two-stage revision ; while others are in support of two-stage revision.  Nonetheless, it appears that the success rate of one-stage over two-stage or vice versa is by a small difference in percentage, suggesting perhaps that these methods are quite comparable. Other than the previously noted study, it appears that there are few other available studies that present measurable patient outcomes, aside from the success rate of the treatment method.
It has also been found that patient transfers during the two-stage revision period may negatively impact on its success rate due to various possible reasons.  Perhaps as an alternative to either one-stage or two-stage revision alone, a Singaporean hospital has introduced its findings based on a periprosthetic joint infection protocol that reflects progression from incision and drainage (washouts) to two-stage revision depending on patient outcome for the management of MRSA infections.  It reports one third of its patients being successfully treated by first-line washouts alone and an 88% success rate in the remaining patients who underwent two-stage revision as second-line treatment. In consideration of new or alternative methods to manage periprosthetic joint infection, one group found that irrigation and debridement may hold promise as a treatment method alone, with a success rate of 55.1% in their study, given its association with lower morbidity, tissue fibrosis, and better functional outcomes when compared to two-stage revision.  However, this study also found that successful treatment with single or serial washouts is significantly more likely to fail if conducted after 5 days of symptom onset or clinical detection.  Related to this discussion, it was found that pulse lavage to remove biofilm has variable efficacy and is largely dependent on prosthesis material (cobalt chrome vs. polymethyl methacrylate vs. polyethylene) and reaffirms that it alone is not adequate in the management of periprosthetic infection, but must be combined with suppressive antibiotic therapy and/or meticulous debridement for optimal results. 
It has become an increasing challenge to treat patients who develop infections in the setting of total joint arthroplasty. The surgical options of single or serial washouts with or without debridement vs. single-stage or multi-stage exchange procedures are all reasonable options, but there is no clear, uniform consensus in the literature that favours one approach over the others. The utilisation of broad-spectrum intravenous antibiotics with myriad systemic side effects is required for adequate treatment and is considered best practice. The value of the multidisciplinary team consisting of the orthopaedic surgeon and the infectious disease physician is brought to bear when these patients are at their most vulnerable. Ultimately, it falls upon the treating clinician to act in the best interests of their patients by limiting the substantial morbidity and impact on quality of life associated with periprosthetic joint infections.
Conflicts of interest
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