A clinical perspective on musculoskeletal infection treatment strategies and challenges.

A Clinical Perspective on Musculoskeletal Infection Treatment Strategies and Challenges Abstract Rohan A. Shirwaiker, PhD Bryan D. Springer, MD Mark J. Spangehl, MD Grant E. Garrigues, MD David W. Lowenberg, MD David N. Garras, MD Jung U. Yoo, MD Paul S. Pottinger, MD

Orthopaedic implants improve the quality of life of patients, but the risk of postoperative surgical site infection poses formidable challenges for clinicians. Future directions need to focus on prevention and treatment of infections associated with common arthroplasty procedures, such as the hip, knee, and shoulder, and nonarthroplasty procedures, including trauma, foot and ankle, and spine. Novel prevention methods, such as nanotechnology and the introduction of antibiotic-coated implants, may aid in the prevention and early treatment of periprosthetic joint infections with goals of improved eradication rates and maintaining patient mobility and satisfaction.

O

From the Edward P. Fitts Department of Industrial and Systems Engineering and the Joint Department of Biomedical Engineering, North Carolina State University, Raleigh, NC (Dr. Shirwaiker), the OrthoCarolina Hip and Knee Center, Charlotte, NC (Dr. Springer), Mayo Clinic, Phoenix, AZ (Dr. Spangehl), Department of Orthopaedic Surgery, Duke University Medical Center, Durham, NC (Dr. Garrigues), the Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA (Dr. Lowenberg), Midwest Orthopaedics at Rush, Chicago, IL (Dr. Garras), Oregon Health & Science University, Portland, OR (Dr. Yoo), and University of Washington, Seattle, WA (Dr. Pottinger). J Am Acad Orthop Surg 2015;23 (suppl 1):S44-S54 http://dx.doi.org/10.5435/ JAAOS-D-14-00379 Copyright 2015 by the American Academy of Orthopaedic Surgeons.

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rthopaedic fracture fixation and joint implants are responsible for improving the quality of life for millions of patients worldwide, and the number of arthroplasty and nonarthroplasty procedures is steadily rising. In 2010, just over 1 million total hip and knee arthroplasties (THA and TKA, respectively) were performed in the United States; this number is projected to rise to .4 million by 2030.1,2 Unfortunately, the risk of musculoskeletal infection associated with primary or revision prosthetic implantation procedures remains a formidable challenge. Such infections have significant clinical and socioeconomic consequences; they are associated with increased patient morbidity and sometimes, mortality, as well as increased length of stay, resulting in increased healthcare costs. Reported infection rates vary between 1% to 5% for primary and revision hip and knee arthroplasties and could be as high as 30% for orthopaedic trauma procedures in which open wounds and contamination increase the risk for infection.3,4 The problem is compounded by the growing presence of antibiotic-resistant pathogens, such as methicillin-resistant Staphylococcus

aureus (MRSA), which lack reliable treatment regimens.

Arthroplasty-associated Infections Infections After Hip and Knee Arthroplasty THA and TKA are the most common joint arthroplasty procedures, and their numbers continue to rise steadily. Although the success of these procedures and their benefits to patients are well documented in the literature, failures related to periprosthetic joint infection (PJI) continue to be a concern. PJI accounts for the most common cause of early failures in TKA and is the third most common cause of failure in THA.5-7 Common treatment options for infection include irrigation and débridement with retention of components, direct or single-stage exchange, or staged reconstruction with interim placement of an antibiotic spacer. However, variable successes have been reported. For example, irrigation and débridement with polyethylene exchange, a common

Journal of the American Academy of Orthopaedic Surgeons

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Rohan A. Shirwaiker, PhD, et al

strategy used in the treatment of acute postoperative or late acute hematogenous infection, is associated with a lower morbidity and cost, but concern remains regarding the limited and inconsistent success of this procedure in the literature. Published studies describe a range of 20% to 85% for successful outcomes with this approach.8-11 Various reports have shown improved outcomes with appropriate patient selection (ie, host factors), the type of infecting organisms, and the use of antibiotic beads with repeat irrigation and débridement.8,12-14 Biofilm-related PJIs are the most challenging and are associated with the highest failure rates. Both mechanical and chemical biofilm disruption agents may prove highly useful in treating these challenging infections. Outcome measures in the treatment of PJI have focused on eradication of infection, with little insight into the functional outcomes of patients. Recent data suggest that two-stage exchange arthroplasty in which all infected, necrotic, and prosthetic material is removed in the initial stage, long considered the benchmark in the United States, has a treatment success rate of 80% to 90%, but functionally, patients do poorly.15-20 The use of articulating spacers has been shown to improve patient-related outcome measures both in the interim stage and following reimplantation;5,6,21-23 however, a prolonged period of immobility and the necessity for a second surgery create significant hurdles for patients to overcome. In addition to the added morbidity of a two-stage exchange, patients with a chronic PJI have a higher mortality rate compared with patients undergoing

aseptic revision.24 These data highlight the significant treatment challenges clinicians face when current modalities may ultimately be harmful to patients. Future directions should focus on novel methods of infection prevention and improving eradication rates while maintaining patient mobility and satisfaction. Increased interest has been expressed in the role of single-stage exchange arthroplasty for the treatment of PJI. Although this method is not universally accepted in the United States as a treatment option, the literature suggests eradication rates similar to that of two-stage exchange.25,26 In addition, the economic benefits of a single-stage exchange have been shown to be superior to those of a two-stage exchange. Before becoming widely accepted, however, strict criteria and standardization of treatment principle for a single-stage exchange should be better elucidated. The development of PJI is an interaction of the host and the environment, but much attention is currently focused on host factors only. New technology may allow us to focus on minimizing bacterial colonization from an environmental standpoint. Most of the infecting strains of bacteria that cause PJI are biofilmproducing organisms. Once formed, the biofilm creates an environment in which bacterial susceptibility to antibiotics is limited and disruption of the biofilm is difficult.27 Prevention of biofilm formation on implants and the ability of implants to repel biofilm formation have received much attention. The introduction of nanotechnology has the potential to allow for the application of biofilmresistant material to implants.28 In addition, the introduction of antibiotic-coated implants may aid in the

initial prevention and early treatment of PJI.29

Infections After Shoulder Arthroplasty More than 45,000 total shoulder arthroplasty procedures are performed annually in the United States, and, similar to that of THA and TKA procedures, the trend is a sustained, rapid increase.30,31 Meanwhile, the incidence of total elbow arthroplasty in some countries is steady or even declining because improved medical antirheumatic therapy is being used to treat rheumatoid arthritis, the most common indication.32 Given this disparity, most research has been dedicated to the larger public health issue of periprosthetic shoulder infection (PSI). The traditional definition of PJI33-35 shows a very low rate of PSI, with prevalence for primary shoulder arthroplasty as low as 0.7%36 and as high as 15.4% for revision surgery.33 Unfortunately, the traditional definition of PJI does not take into account our current understanding of nonsuppurative microorganisms, such as Propionibacterium acnes and coagulase-negative Staphylococcus. Although the pathogenic implications of these bacteria are a current area of discussion, P acnes is now recognized as the most common cause of PSI.37-41 The discrepancy between traditional musculoskeletal pathogens and P acnes leads to significant diagnostic challenges.42 This difficulty in diagnosis leads to treatment uncertainty, which is considered the biggest challenge in the management of potential shoulder infections. Unlike more familiar infection agents, P acnes does not reliably cause erythema, purulence, wound drainage, or an elevated

Dr. Springer or an immediate family member is a member of a speakers’ bureau or has made paid presentations on behalf of DePuy and Ceramtec; serves as a paid consultant to ConvaTec, Polaris, and Stryker; and serves as a board member, owner, officer, or committee member of the American Joint Replacement Registry. Dr. Spangehl or an immediate family member has received research or institutional support from DePuy, Stryker, and Vidacare, and serves as a board member, owner, officer, or committee member of the American Academy of Orthopaedic Surgeons. Dr. Garrigues or an immediate family member is a member of a speakers’ bureau or has made paid presentations on behalf of Synthes and Tornier; serves as a paid consultant to Synthes and Tornier; has received research or institutional support from Arthrex, Tornier, and Zimmer; and has received nonincome support (such as equipment or services), commercially derived honoraria, or other non–research-related funding (such as paid travel) from DJ Orthopaedics and Zimmer. Dr. Lowenberg or an immediate family member is a member of a speakers’ bureau or has made paid presentations on behalf of Stryker; serves as a paid consultant to Stryker; and serves as a board member, owner, officer, or committee member of the Foundation for Orthopaedic Trauma. Dr. Yoo or an immediate family member has received royalties from Osiris Therapeutics. None of the following authors or any immediate family member has received anything of value from or has stock or stock options held in a commercial company or institution related directly or indirectly to the subject of this article: Dr. Shirwaiker, Dr. Garras, and Dr. Pottinger.

April 2015, Vol 23, Supplement 1


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A Clinical Perspective on Musculoskeletal Infection Treatment Strategies and Challenges

erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, white blood cell (WBC) differential, or interleukin 6 (IL-6) level.34,37,43,44 Aspiration of synovial fluid and intraoperative pathologic analysis of frozen sections for acute inflammation have been shown to be ineffective for diagnosis.38,39,43 Currently, no commercially available preoperative or intraoperative test reliably predicts P acnes culture growth.38 The only standard for P acnes diagnosis is long-hold cultures of tissue obtained with arthroscopic biopsy,45 via open biopsy, or at the time of revision surgery.38 The mean time to growth of the organism ranges from 7 to 13 days but can take up to 3 weeks; this factor only adds to the diagnostic challenge.43,46 Practically, physicians evaluating a painful and/or loose shoulder arthroplasty should still follow the same algorithm as that used for diagnosis of a PJI of the hip or knee. Although the tests mentioned earlier are not helpful for diagnosis of P acnes, the most common cause of PSI, approximately one third to one half of PSIs are caused by suppurative pathogens, and these tests will have utility in those cases.39,47 Treatment options for PSI include antibiotic suppression, irrigation and débridement with prosthesis retention, resection arthroplasty, one-stage exchange, staged reimplantation, arthrodesis, and amputation. Antibiotic suppression alone has shown poor outcomes, with persistent, symptomatic infection in most patients.48 This treatment strategy should be considered an option for patients only when the surgical risks are overwhelming secondary to medical comorbidities. Both Coste et al48 and Sperling et al49 reported their experience with débridement and implant retention with recurrence rates of 12% and 50%, respectively. Although Coste et al48 reported a low recurrence rate, 63% of their patients required revision surgery, and functional outcomes remained poor. This approach may be helpful for acute infections, but it is rarely indicated because most PSIs present in a subacute or chronic manner.48,49 One-stage exchange arthroplasty has shown promising results.50 The advantages include less destruction/dissection, immediate reconstruction, avoidance of

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secondary adhesions, less patient angst, and lower hospitalization costs.51 Ince et al50 reported encouraging results using this method in treating predominantly subacute and late infections. Advocates of this method report that when cultures are unexpectedly positive for P acnes at the time of revision surgery, only 6% to 10% of patients exhibit any signs of persistent infection.35,52 Modeled after what has been demonstrated in the hip and knee arthroplasty literature, two-stage reimplantation is currently the most common treatment of Articulating antibiotic choice.53,54 cement spacers allow for the preservation of a soft-tissue envelope and can often act as the definitive implant in a patient with minimal functional demands.55-57 Failure rates for infection clearance have been reported between zero and 36%.48,49,57-59 Nonetheless, both the surgeon and the patients should be aware that the subjective outcomes of revision for infection are the least favorable compared with revisions for any other indication.59 In the patient with low functional demands and a higher surgical risk, resection arthroplasty is an option to consider because it can provide pain relief in addition to low infection recurrence rates, frequently at the expense of function.60 Recurrence rates have been reported between zero and 30%.48,61-63 As a general protocol, any painful, loose shoulder arthroplasty should be evaluated with a thorough history to elicit for wound drainage issues and constitutional symptoms; serology should include an ESR and a CRP level. If these studies are positive, suspicion should be directed toward a traditional prosthetic joint infection that is caused by common pathogens such as S aureus, coagulasenegative Staphylococci, or gram-negative bacteria. However, if the traditional signs and symptoms are negative, there is still a concern for infection, in this case due to P acnes. In this scenario, we generally proceed to surgery with long-hold cultures taken at the time of the procedure. Frozen sections are also obtained. If there is an obvious mechanical cause for implant loosening (ie, subscapularis failure with glenoid loosening), we consider single-stage surgery in select patients. Otherwise, two-stage exchange

arthroplasty with postoperative parenteral antibiotics is considered from an infection perspective because P acnes cannot be reliably ruled out before the long-hold culture results are finalized 2 weeks after surgery. If the cultures are negative, antibiotics are stopped, and we proceed with reimplantation. If more than one fifth of the cultures are positive, we continue a full 6-week course of antibiotics before proceeding with reimplantation. Because bony and soft-tissue deficits frequently accompany these cases, reverse total shoulder arthroplasty may be helpful during the reimplantation/reconstructive phase for patients without significant upper extremity strength demands. Finally, we acknowledge that in the case of P acnes, there is still uncertainty whether two-stage revision arthroplasties are superior to single-stage procedures in terms of overall durable shoulder function and comfort. These factors apply provided that patients are able to tolerate prolonged oral antibiotic treatment following a single-stage procedure with aggressive débridement, humeral head exchange, and glenoid removal. Thus, the choice between single-stage and two-stage reconstruction remains at the discretion of the treating surgeon until further longterm clinical outcomes provide guidance.

Nonarthroplastyassociated Infections Infections After Musculoskeletal Trauma Surgery The incidence of traumatic injuries, especially those caused by motorized vehicles, has increased significantly throughout the world. In Africa, trauma is now designated as an epidemic.64 The late effects of long bone fractures, especially open injuries, are chronic osteomyelitis and infected nonunion. The Centers for Disease Control and Prevention has estimated the incidence of osteomyelitis in the United States to be 2 per 10,000 persons. This number is most likely underestimated and is certainly much higher in Third World countries.




Table 1 Cierny-Mader Staging System for Osteomyelitis Stage

Anatomic Type

1

Medullary

2

Superficial; no full-thickness involvement of cortex

3

Full-thickness involvement of a cortical segment of bone; endosteum is involved, implying intramedullary spread Infection is permeative, involving a segmental portion of the bone

4

Typical Etiology

Treatment

Infected intramedullary nail

Removal of the infected implant and isolated intramedullary débridement Chronic wound, leading to colonization Remove layers of infected bone until and focal involvement of a superficial viable bone is identified area of bone under the wound Noninvolved bone is present at same Direct trauma with resultant axial level, so the osteomyelitic devascularization and seeding of portion can be excised without the bone compromising skeletal stability Major devascularization with Resection leads to a segmental or colonization of the bone near-segmental defect, resulting in loss of limb stability

Reproduced from Lowenberg DW: Nonunions, malunions, and osteomyelitis, in Boyer MI, ed: AAOS Comprehensive Orthopaedic Review, ed 2. Rosemont, IL, American Academy of Orthopaedic Surgeons, 2014, pp 275-284.

Orthopaedic surgeons face many challenges in the treatment of posttraumatic osteomyelitis, not the least of which is proper training in this subspecialty during residency. Few orthopaedic surgeons specialize in the treatment of osteomyelitis, and no fellowships for this subspecialty exist in the United States at this time. Along these same lines, the average orthopaedic surgeon encounters possibly one case of trauma-related osteomyelitis every 3 years. With this rate of infrequency, these cases do not allow the practitioner to expand his or her clinical knowledge. Goodacre65 best stated the role of pathogens in musculoskeletal infections when he wrote that “. . .many pathogens did not initially evolve as pathogens, but simply take on this role as a result of a lack of ability of the host to maintain homeostasis.” Nowhere is this truer than in posttraumatic infections and, in particular, osteomyelitis. These pathogens create a symbiotic state in their newfound host environment and have found the perfect mechanism to accomplish this with the biofilm state. It is important to understand that these microbes do not behave as a single organism but rather act as a true multicellular entity once the mature biofilm biosphere is formed. They are then 103 times less sensitive to antibiotics because of their sessile growth phase state. The biofilm also provides a selective barrier to penetration by

antibiotics, and the sessile phase bacteria are protected by the semi-hydrophobic biofilm matrix. Classification of the area of osteomyelitis using the Cierny-Mader classification is extremely useful because it helps tailor treatment (Table 1). Treatment and eradication of an infection of bone requires a four-stage treatment algorithm.66 The first stage involves the removal of all necrotic and compromised bone and surrounding soft tissue, creating a void. Antibiotic beads or vacuum-assisted devices are then needed to manage the dead space, along with provisional bony stabilization. The surgical team should select fixation that allows for later reconstruction. Once a healthy and viable wound bed is established, the third stage addresses softtissue reconstruction. This may require flaps, muscle transfers, or other procedures. Bony reconstruction is the fourth and final stage. In confined defects, this may be accomplished with simple bone grafting, but in segmental defects, more complex alternatives are required, including that of bone transport.

Infections After Foot and Ankle Surgery The rate of foot and ankle infections after elective surgery has been reported to range between zero and 6.5% in the normal adult nonimmunocompromised population.67,68 This rate is higher than that

in other parts of the body and is attributed to the unique environment of the foot and the native organisms.69 Several patient-related factors alter the risk of infection. Careful preoperative evaluation and counseling, as well as risk stratification and optimization, are essential to prevent postoperative infections in this patient population. Patients with systemic conditions, such as poorly controlled diabetes, peripheral vascular disease, thyroxine-supplemented patients, and patients who are steroid dependent, are at a much higher risk for infection.68,70-72 Diabetics with neuropathy are at a tenfold greater risk of infection than is the normal population and at a sixfold greater risk compared with patients with uncomplicated diabetes.72 In contrast to common perception, however, perioperative use of diseasemodifying agents in patients with rheumatoid arthritis does not increase the risk of infection.73 Smoking and malnourishment are among the highest preventable causes of periprosthetic foot infections; therefore, smoking cessation and nutritional optimization are crucial to reduce risk.68 Proper surgical technique, including skin preparation, draping, surgical scrub, and meticulous soft-tissue management, is critical to the prevention of infections. Ostrander et al74 reported continued contamination even after prepping in the foot. Skin preparation with



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chlorhexidine and alcohol prep has been shown to be the most effective combination for reducing preoperative bacterial loads, although many other combinations have been proposed.75-79 However, no studies show their effect on infection rates. Additionally, the length of the surgical procedure is directly related to the risk of infection.68 Preoperative antibiotics, when given within 60 minutes before the time of incision, have been shown to reduce the risk of periprosthetic infections dramatically, regardless of their timing relative to tourniquet inflation.80,81 However, postoperative outpatient oral antibiotic treatment remains controversial. Little consensus exists in the literature regarding optimal methods of prevention or detection of periprosthetic foot and ankle infections. Preoperative and postoperative foot baths have been highly debated and understudied.82,83 Additionally, most foot and ankle surgeries lead to increased foot swelling and pain; therefore, early recognition of periprosthetic infections is difficult. This situation is further complicated by the fact that most patients retain their postoperative dressings for 1 to 2 weeks. Finally, wound complications are not uncommon after certain procedures; these can lead to the risk of infection and deteriorated outcomes. Infection markers and novel infection proteins have not been studied in foot and ankle surgery. However, periprosthetic infections are rarely missed because of the paucity of soft-tissue coverage and the obvious symptoms of infections in foot and ankle patients. A high index of suspicion and early and aggressive treatment of suspected infection are essential for optimizing patient outcomes. Postoperative superficial cellulitis typically presents with warmth of the skin, tenderness, and erythema without fluctuance or joint involvement. S aureus and b-hemolytic streptococci are the most common causative organisms. Treatment should consist of 7 to 10 days of oral antibiotics and frequent evaluations. Surgical intervention may be necessary. Deep infections and abscess formation are also serious complications. Aggressive treatment is always warranted to salvage the lower extremity.

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Presentation usually involves increased pain, skin warmth, possible fluctuance, leukocytosis, and fevers. Plain radiographs, MRI, and needle aspiration may be helpful in making the diagnosis. Early surgical débridement and targeted, culture-based antibiotic treatment are necessary. Multiple irrigations and débridements also may be necessary. Current and future research in periprosthetic foot and ankle infections should be directed at identifying the optimal skin preparation as it relates to infection rates, diagnostic criteria and markers of infection, postoperative management protocols to reduce infections, wound management optimization, and appropriate antibiotic regimens.

Infections After Spine Surgery The best estimate of the incidence of infection after spinal surgery is high at 4%.84 Timely diagnosis is often delayed because most spine infections are deep seated, and a surgeon’s reliance on the status of the wound often delays the diagnosis. One third of patients with postoperative spinal infections do not have wound drainage. Because many patients tend to have significant postoperative pain that may not be related to infection, a patient’s report of pain is often not taken into consideration as a sign of infection. Radiographic tests, such as MRI, may show fluid collection, but fluid is often present in noninfected spines for weeks following the surgery. Lack of a fever and a normal WBC count are often misleading clues, as well. The combination of these factors may account for a rather lengthy interval between the surgery and diagnosis.85 The CRP level appears to be the most accurate modality for identification of infection, although it remains elevated for 2 to 3 weeks after surgery, even in the absence of infection.86,87 Obtaining a CRP level at discharge may provide a baseline for comparison because the levels should steadily decline over time. However, obtaining the levels as a routine procedure is controversial given the low rate of infection. Obtaining CRP levels at two separate times, along with the presence of higher levels at the second

time point, may be indicative of infection, but this has not yet been proven. Obtaining fluid or tissue samples for identification of organisms is often not standardized and is considered inadequate. Wound swabbing should be avoided because this does not allow differentiation between skin flora contamination and skin flora infection. What constitutes adequate tissue sampling has not been well established. However, cultures at multiple separate sites may be needed to adequately differentiate certain nonvirulent organism (eg, S epidermidis, P acnes) infection versus a contamination. Infection with these organisms is becoming more prevalent.88 Identification of these organisms may also require a prolonged incubation period.89 Unfortunately, a cost-benefit analysis associated with multiple and prolonged cultures has not been assessed and cannot be routinely recommended for all cases, especially when the suspicion is low. A promising report describes looking for more than five white blood cells per high-field magnification on pathologic specimens to diagnose infection in spine wounds.90 However, the process cannot be used to identify the offending organism, and it may not improve diagnosis compared with what is possible with multiple and prolonged cultures. There is no debate as to the need for good surgical débridement. However, whether instrumentation is helpful or detrimental to the eradication of infection is not known. Some reports suggest that well-fixed implants do not interfere with the eradication of postoperative infection.87,91 An investigation by Mohamed et al92 suggests that internal stabilization may actually assist in treating spinal infection. However, maintenance of a less than well-fixed implant is controversial. MRI or CT may be helpful in tracking infection from posterior tissue to the anterior vertebral body,93 but whether this information can be used in the choice of implant retention versus removal is yet to be resolved. Although the use of a suction drain after surgical débridement is well accepted, the recent use of vacuum-assisted devices is much more controversial. Successful eradication of infection and maintenance of instrumentation is reported,94 but there




Figure 1

Suggested algorithm to assess “penicillin allergy”

is also a reported risk of excessive bleeding leading to death.95 Furthermore, there is a danger of uncontrolled drainage of cerebrospinal fluid and neurologic injury from either recognized or unrecognized dural tears. With early diagnosis, identification of the organism, surgical treatment, and antibiotics, good results and retention of implants are possible after postoperative spine infection. However, an optimal and cost-effective diagnostic and treatment algorithm still needs to be refined.

Clinical Perspective on Antibiotic Prophylaxis Antibiotics play an important role in the prevention of periprosthetic infections; antibiotic prophylaxis has become part of the standard of care for arthroplasty and nonarthroplasty procedures. Based on older placebo-controlled data, approximately 50 patients need to receive perioperative prophylaxis to prevent one infection.96 The number needed to harm is even more elusive, but the risk of major events, such as anaphylaxis or Clostrid-

ium difficile infection, is greatly outweighed by the benefit of this practice. Evidence-based guidelines for perioperative antimicrobial prophylaxis are clear. The proper drug or drugs should be prescribed, dosed at the right time, and stopped on time.97 However, questions still arise frequently in clinical practice. One dilemma that arises is when cefazolin is the prophylactic drug of choice, but the patient says that he or she is allergic to penicillin. Approximately 10% of Americans believe they are allergic to penicillin, but only about 10% of these persons actually have a true, immunologically mediated reaction to penicillin. Most patients are inaccurately labeled as penicillin allergic and can safely receive b-lactam antibiotics.98,99 This is important to note because cefazolin has a strong track record of providing a favorable balance of coverage and tolerability.100 Most patients considered to be allergic can be assessed by history alone; those who remain of concern can safely undergo pre-pen skin testing in an allergist’s office. To help orthopaedic surgeons decide whether a patient labeled as penicillin allergic should receive cefazolin or a sec-

ond-line agent, a suggested algorithm is given in Figure 1. When determining the optimum antibiotic dose for obese patients undergoing elective arthroplasty, it is important to note that obese patients may benefit from higher doses of antibiotics, assuming their renal function is normal. Although proper skin preparation technique should result in a small organism burden in the field, the risk of surgical site infection falls when antibiotic concentration rises in the wound. Unfortunately, modest clinical evidence suggests that drug distribution through the larger soft-tissue mass of obese patients may result in unacceptably low antibiotic delivery to the surgical field.101 These patients are at higher risk of infection than are lean patients, presumably for a variety of reasons, including insulin resistance, hyperglycemia, and tension on the skin closure. Antibiotic dosing is an easily modifiable factor, and current Infectious Diseases Society of America guidelines address this concern (Table 2). A higher dose of cefazolin may still be infused quickly, but the challenge with higher doses of vancomycin relate to the increased amount of time required to administer it fully. Because of concern for histamine-mediated red man syndrome, the suggestion is to give larger doses over 90 or 120 minutes. This protocol may pose challenges for workflow in the operating room because, ideally, the full dose should be administered before tourniquet inflation and incision. However, at some centers, the infusion may be started in preoperative holding. If this is not feasible, then anesthesiology can prioritize starting the infusion as soon as possible after the patient arrives in the operating room so that much of the dose is administered before the surgery begins. Cefazolin remains the dependable prophylactic choice, and it should always be given fully before making the incision. Furthermore, there is no national regulatory requirement that the full vancomycin dose be administered before incision, only that the infusion begin before incision. Other questions regarding antibiotic prophylaxis remain unresolved and are open for further clinical investigation, such as tailoring prophylaxis for special populations. For example, should anti-MRSA



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Table 2 Suggested Antimicrobial Prophylaxis for Prosthetic Joint Implantation Surgerya Surgical Indication

Antibiotic

Standard prosthetic joint implantation prophylaxis

Dosing Regimen

Cefazolin

History of MRSA or positive screen: Give in addition to cefazolin

Concerning history of b-lactam allergy or positive skin test

Okay to use even with “pen allergic” in chart Vancomycin

Vancomycin alone (do not add cefazolin)

#120 kg = 2 g over 20 min .120 kg = 3 g over 20 min 50-70 kg = 1 g over 60 min 71-100 kg = 1.5 g over 90 min .120 kg = 2 g over 120 min 50-70 kg = 1 g over 60 min 71-100 kg = 1.5 g over 90 min .120 kg = 2 g over 120 min

Redosing Interval 3h

8h

8h

a Based on current Infectious Diseases Society of America guidelines. MRSA = methicillin-resistant Staphylococcus aureus Adapted with permission from Bratzler DW, Dellinger EP, Olsen KM, et al: Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm 2013;70(3):195-283.

coverage be included in all elective arthroplasties, or should it be used only for procedures deemed to be at high risk (eg, history of infection or colonization)? Should prophylaxis for shoulder arthroplasties include more aggressive coverage of P acnes (eg, replace cefazolin with ceftriaxone)? Orthopaedic surgeons and infectious disease specialists should be encouraged to examine their own local clinical experience and respond in a rational fashion. For example, if an orthopaedic surgeon experiences a considerable number of MRSA periprosthetic infections, then coverage of that organism is reasonable to consider. However, there is no standardized definition of what constitutes a considerable number. Furthermore, this finding should trigger a thoughtful, open investigation of whether other remediable factors might contribute to the increased infection rate. Finally, specific centers or individual providers should be encouraged to track and share their experience so that the efficacy of various regimens can be measured. Another area of discussion is the use of an efficacious regimen of cefazolin and vancomycin for MRSA coverage for arthroplasty prophylaxis, compared with the use of ceftaroline alone. Ceftaroline is

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a new cephalosporin antibiotic with the unique characteristic of covering both MRSA and methicillin-sensitive S aureus aggressively, as well as many common gastrointestinal gram-negative rods. It can be administered quickly, it has predictable pharmacology, and single doses are generally very well tolerated. This valuable drug is not currently indicated for surgical prophylaxis, and concerns for resistance with widespread use are warranted. However, if careful studies are performed, it may prove to be an attractive option for this role in patients who require MRSA coverage in their prophylactic regimen. The issue of patients receiving oral antibiotic prophylaxis before major or minor dental care is a topic of discussion. Patients may become bacteremic as a result of dental procedures, and the use of antibiotics immediately before dental work can reduce the bacteremia. Although organisms typically associated with the oral microbiome are not commonly cultivated from infected prosthetics,102 many senior surgeons have personal experience with this scenario. Furthermore, many patients with periprosthetic infection report undergoing elective dental care in the weeks or months before infection diagnosis,

raising that as a possible source. Unfortunately, confounding is difficult to exclude because routine dental care is so common. The situation is analogous to whether dental antibiotic prophylaxis should be offered to prevent infective endocarditis. Indications recommending dental prophylaxis for infective endocarditis have been significantly reduced based on concerns for the risk of adverse effects and toxicity and a paucity of convincing data.103 However, the physiology of bacterial clearance from prosthetics differs from that of the bloodstream. The current Infectious Diseases Society of America guidelines on prosthetic joint infections leave this as an open question.104 Conversely, the International Consensus on Periprosthetic Joint Infection achieved strong consensus (81% agreement) that the use of dental antibiotic prophylaxis in patients who have undergone total joint arthroplasty should be individualized based on patient risk factors and the complexity of the dental procedure to be performed.105 In summary, data to settle this important question are lacking, and it is difficult to envision the implementation of a prospective randomized trial that would provide adequate answers. Judicious use of antibiotics in




select cases, especially within the first 2 years post implantation, may be warranted.

Summary Orthopaedic fracture fixation and joint implants are responsible for improving the quality of life of millions of patients worldwide, and the number of arthroplasty and nonarthroplasty procedures is steadily rising. Unfortunately, the risk of musculoskeletal infection associated with primary or revision prosthetic implantation procedures continues to be a problem because such infections have significant clinical and economic consequences. Orthopaedic surgeons need to have a working understanding of the current perioperative prophylaxis and treatment strategies for infections associated with the most common arthroplasty procedures (ie, hip, knee, shoulder) and nonarthroplasty procedures (ie, trauma, foot, ankle, spine). Future directions should focus on novel methods of infection prevention and improving eradication rates while maintaining patient mobility and satisfaction.

Authors’ Contribution Each author has equally participated in preparation of this paper, including literature review, manuscript writing, and revisions.

Acknowledgments The authors acknowledge the contributions of the 2014 AAOS-ORS Musculoskeletal Infection Symposium Chairs and participants during the ideation and conception of this manuscript.

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