Treatment of Skeletal Infections

Alexus M. Cooper, BS

Karan Goswami, MD, MRCS

Javad Parvizi, MD, FRCS

Dr. Parvizi or an immediate family member has received royalties from Corentec; serves as a paid consultant to or is an employee of CeramTec, ConvaTec, Corentec, Ethicon, Heron, Tenor, TissueGene, and Zimmer; has stock or stock options held in Alphaeon, Ceribell, Corentec, Cross Current Business Intelligence, Hip Innovation Technology, Intellijoint, Invisible Sentinel, Joint Purification Systems, MDValuate, MedAp, MicroGenDx, Parvizi Surgical Innovations, Physician Recommended Nutriceuticals, and PRN-Veterinary; and serves as a board member, owner, officer, or committee member of the Eastern Orthopaedic Association and the Muller Foundation. Neither of the following authors nor 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 chapter: Dr. Cooper and Dr. Goswami.

INTRODUCTION

Success in treating musculoskeletal infection requires an aggressive surgical approach and optimized antimicrobial therapy. The type of infection, the virulence and antimicrobial susceptibilities of the involved microorganism, potential adverse effects of the proposed antimicrobial therapy, alternative antimicrobial therapies, and the patients’ general health should be considered prior to initiation of treatment. Antimicrobials can be used for prophylaxis or treatment of infection. Antimicrobials can be delivered systemically, in the form of oral or parenteral dosing, or locally, in the form of topical solutions or local delivery devices such as antibiotic beads, powder, or spacers. The local delivery of antimicrobial agents to the site of orthopaedic infection is based on the need for high concentrations of these drugs to kill planktonic and biofilm-based bacteria. Many musculoskeletal infections require prolonged systemic antimicrobial therapy, often administered on an outpatient basis under the guidance of an infectious disease specialist in close collaboration with an orthopaedic surgeon.

ANTIMICROBIALS

BIOAVAILABILITY

Evidence in the literature on antibiotic therapy for patients with antimicrobial-resistant surgical site infection or periprosthetic joint infection (SSI/PJI) is not conclusive. When selecting antibiotics for patients, patient comorbidities, mode of administration, risk of Clostridium difficile, need for monitoring, allergy profile of the patient, intolerance, regional resistance patterns, cost, and availability should all be considered.¹ The selected antibiotic for treatment should also have good bone and soft-tissue penetration and activity against biofilm.

Using an intravenous route for antimicrobial administration has the greatest quantitative potential, as it permits a mass balance approach to be applied to distribution, clearance, and the body processes associated with excretion and metabolic elimination (eg, renal, hepatic). The administration of a drug by other routes, notably oral, introduces an uncertainty that reflects the unknown fraction that is actually absorbed.

The most important property of any nonintravenous microbial intended to treat systemic infection is its ability to distribute active ingredients to the bloodstream in an amount sufficient to cause the desired response. This
property of a dosage form has historically been identified as physiologic availability, biologic availability, or bioavailability. Bioavailability captures two essential features, namely how fast the drug enters the systemic circulation (rate of absorption) and how much of the nominal strength enters the body (extent of absorption). Given that the therapeutic effect is a function of the drug concentration in a patient’s blood, these two properties of nonintravenous dosage forms are, in principle, important in identifying the response to a drug dose.

Bioavailability following oral doses of antimicrobials may vary due to patient-related or dosage-form-related factors such as the nature and timing of meals, age, disease, genetic traits, and gastrointestinal physiology. Such factors include (1) the chemical form of the drug (eg, salt vs acid), (2) its physical properties (eg, crystal structure, particle size), and (3) an array of formulation (eg, nonactive ingredients) and manufacturing (eg, tablet hardness) variables. Furthermore, doses need to be weight-adjusted.

ELUTION CHARACTERISTICS OF ANTIBIOTIC-LOADED CEMENT SPACERS

The current standard of care for infected joint arthroplasty is considered to be two-stage revision arthroplasty including: removal of the prosthesis and cement, thorough débridement, placement of an antibiotic-impregnated cement spacer, a course of intravenous antibiotics, and a delayed second-stage revision arthroplasty. The choice of the spacer, either articulating or nonarticulating, is based on many factors, including the amount of bone loss, the condition of the soft tissues, the need for joint motion, the availability of prefabricated spacers or moulding methods, and antibiotic selection. Additionally, in nonarthroplasty infections, bone cement beads may be used to deliver antibiotics to the local area after surgical débridement.

The elution of antibiotics from bone cement depends on several factors including the type of antibiotic, amount and number of antibiotics, porosity and type of cement, and surface area of the spacer.² Masri et al investigated the long-term elution of antibiotics from poly methyl methacrylate (PMMA) bone cement in vivo in 40 patients. Their study found that effective levels of tobramycin remained four months after the surgery.³ This observation is consistent with the suggestion that at least 3.6 grams (g) of tobramycin per 40 g of bone cement, with 1 g of vancomycin, is an effective antibiotic regimen. As effective levels of vancomycin were not present four months after the surgery, Masri et al also determined that the two antibiotics acted synergistically with one another to increase the elution rates but vancomycin should not be used alone.³ This finding was consistent with the results of an in vitro study that showed that combining tobramycin and vancomycin in PMMA bone cement improved the elution rates of both antibiotics.⁴

The preparation of an antibiotic-loaded cement spacer can also impact its performance. Antibiotic release from hand-mixed and vacuum-mixed cement was found to be decreased compared with commercially available antibiotic-loaded cement; however, cost implications and the need for specific antimicrobials tailored to specificity may offset this issue.⁵ Unlike antibiotics that are commercially mixed in cement, hand-mixed antibiotics do not have a homogeneous distribution in the cement, which decreases their rate of elution from a given surface area.⁶ Vacuum-mixing decreases the porosity of the cement, which also decreases the rate of elution of the antibiotics.⁷ The elution of antibiotics from PMMA bone cement is determined by a combination of surface area and porosity.⁷ One study showed that increasing the surface area of PMMA bone cement by 40% resulted in a 20% higher rate of elution of vancomycin.⁸ Dextran has been added to cement to enhance porosity and increase antibiotic elution rates. Kuechle et al found that the addition of 25% dextran to cement increased the release of antibiotics in the first 48 hours approximately four times compared with that associated with routine preparation.⁹

APPROACH TO TREATMENT

SURGICAL DÉBRIDEMENT AND LAVAGE

The most important determinant for success of treatment for acute or chronic orthopaedic infections is the quality the surgical débridement. The primary goal of débridement is to achieve a clean viable wound with minimal trauma to the remaining soft tissue. Among a cohort of patients with chronic osteomyelitis, aggressive débridement with a wide margin (>5 mm) was found to eradicate infection in almost all cases.¹⁰ For an acute infection, the most straightforward method of débridement is incision and drainage, coupled with copious lavage. In chronic infection, a more aggressive approach is required, often due to local and systemic compromise of the host, presence of foreign bodies, and adherent biofilms.¹¹

Incisions should be made through the previous incision site, or perpendicular to the site, to avoid wound edge necrosis. In the context of osteomyelitis, all necrotic bony tissue must be excised leaving only viable bone.¹¹ If 70% or more of the original cortical bone at the level of débridement is intact, the risk of fracture is low. If a more extensive débridement is required, it may be necessary to stabilize the bone with an external or internal fixator.¹¹ Management of the resultant “dead space” created by débridement may involve local myoplasty, free tissue transfers, and the use of antibiotic-impregnated beads to eradicate any remnant pathogens. Soft-tissue procedures have also been developed to improve local blood flow and antibiotic delivery.

For cases of musculoskeletal infection in spine surgery, primary goals are contingent upon the overall status of the patient. When neurologic deficits, pain, or spinal instability have manifested secondary to infection, evaluation for
surgical intervention should be promptly considered and geared toward decompressing the spinal canal, débridement of infectious foci, and stabilizing vertebrae.¹²

TYPES OF MUSCULOSKELETAL INFECTION

OSTEOMYELITIS AND SEPTIC ARTHRITIS

Septic arthritis is a condition characterized by infection of the synovium and the joint space which causes an intense inflammatory reaction and release of proteolytic enzymes, leading to the rapid destruction of the articular cartilage.¹³ Though uncommon among the general population, the occurrence of septic arthritis among pediatric patients, with or without subsequent occurrence of osteomyelitis, is increasing.¹⁴^,¹⁵^,¹⁶

Septic arthritis in combination with osteomyelitis is common in children, with the metaphysis of long bones the most commonly affected location. Patients usually present within several days to one week after the onset of symptoms. In addition to local signs of inflammation and infection, patients have signs of systemic illness, including fever, irritability, and lethargy. Typical clinical findings include tenderness over the involved bone and decreased range of motion in adjacent joints. Kocher criteria can be used to distinguish patients presenting with septic arthritis from those with transient synovitis¹⁷ (Table 1). Based on a 2004 study validating Kocher criteria for septic arthritis risk based on presence of predictors is as follows—0 predictors: 2.0% risk, 1 predictor: 9.5%, 2 predictors: 35.0%, 3 predictors: 72.8%, 4 predictors: 93.0%.¹⁷

Acute hematogenous infection is the most common etiology for osteomyelitis and septic arthritis in children. This may be attributed to anatomic characteristics of pediatric bones such as thin cortex, loose periosteum, and directly communicating blood vessels to the metaphysis and epiphysis giving pathogens access to the joint space.¹⁸ In the shoulder, elbow, hip, and ankle joints, the capsule overlaps a portion of the adjoining metaphysis. If the focus of osteomyelitis breaks through the metaphyseal bone, it can directly infect the joint and lead to concurrent septic arthritis. Septic arthritis can also occur in patients with a history of intravenous drug use, bacteremia, gonococcal disease, and after arthroscopic procedures.¹³

TABLE 1 Kocher Criteria

Clinical Findings	Predictor Scoring
Non-weight bearing	Yes: +1 No: 0
Temperature > 38.5°C/101.3°F	Yes: +1 No: 0
ESR^a > 40 mm/hr	Yes: +1 No: 0
WBC count^b > 12,000 cells/mm³	Yes: +1 No: 0
^aESR, erythrocyte sedimentation rate. ^bWBC count, white blood cell count.
Adapted with permission from Kocher MS, Mandiga R, Zurakowski D, Barnewolt C, Kasser JR: Validation of a clinical prediction rule for the differentiation between septic arthritis and transient synovitis of the hip in children. J Bone Joint Surg Am 2004;86-A(8):1629-1635.

PATHOPHYSIOLOGY

With septic arthritis, proteolytic enzymes released from synovial cells lead to destruction of the articular cartilage.¹⁹ Interleukin-1 (IL-1) triggers the release of proteases from chondrocytes and synoviocytes in response to polymorphonuclear leukocytes and bacteria. Smith et al. showed that cartilage destruction starts to occur as early as 8 hours after infection.²⁰ Early administration of antibiotics helps to slow down the process, but even if intravenous antibiotic therapy is started within the first 24 hours of infection, significant glycosaminoglycan destruction and collagen disruption occurs. Degradation results in the loss of proteoglycans from the articular cartilage by 5 days and loss of collagen by 9 days.²¹ Impairment of the intracapsular vascular supply secondary to elevation of the intracapsular pressure and thrombosis of the vessels also play a role in the destruction of the articular cartilage.²² The common sites of involvement in children are the hip and knee, but in the adult, about 85% of cases are monoarticular, the knee being the most common.¹³

Subacute and chronic osteomyelitis typically occurs in adults. The diagnosis of osteomyelitis is usually made by a combination of clinical findings, radiography, bone scans, and magnetic resonance scans, along with the aspiration of purulent discharge from the involved area and positive blood cultures. In chronic osteomyelitis, radiographic signs of necrotic bone (sequestrum) and periosteal new bone formation (involucrum) are evident. Generally, this type of infection occurs secondary to an open wound, most often an open injury to bone and surrounding soft tissue. Bone pain, erythema, and drainage around the affected area are frequently present along with deformity, instability, local signs of impaired vascularity, limited range of motion, and altered neurologic status. The incidence of deep musculoskeletal infection from open fractures has been reported to be approximately 23%, with a 6% of cases resulting in osteomyelitis.²³ A further study divided patients with open fractures into subgroups according to comorbidities and reported a host-dependent infection rate ranging from 4% to 30%.²⁴ Factors such as altered neutrophil defense, humoral immunity, and cell-mediated immunity can increase the risk of osteomyelitis.

TREATMENT

The treatment for septic arthritis involves antibiotic therapy in conjunction with prompt consideration for surgical drainage of the affected joint via arthroscopy, arthrocentesis, or arthrotomy. In a major review done in 1990, Shaw and Kasser described open surgical drainage as the “benchmark” of treatment for acute septic arthritis.¹⁸ More recent publications have
demonstrated effective use of arthroscopic techniques, particularly with copious irrigation, for the management of septic arthritis.¹³ Though a critical “time to treatment” has not been defined yet, it is imperative that treatment be delivered expeditiously as delayed treatment may lead to undesirable outcomes.²⁵

After the initial evaluation and staging of infection, treatment of osteomyelitis includes antimicrobial therapy based on cultured organism susceptibility, débridement with management of resultant dead space, and, if necessary, stabilization of bone. In most patients with osteomyelitis, early antibiotic therapy is administered over a 4-6-week period for optimal outcomes. To reduce costs, parenteral antibiotic administration (via a peripherally inserted central catheter line) on an outpatient basis or the use of oral antibiotics can be considered. Initial first-line antibiotic choice is determined by the patient’s history and sensitivities of the isolated organism(s). Most the time, osteomyelitis can be effectively treated with antibiotics and pain medications alone. In more severe cases such as chronic osteomyelitis, aggressive débridement may be necessary. If there is an area of localized abscess, this may need to be opened, washed out, and drained. For instances where there is damaged soft tissue or bone is removed, grafting and/or stabilization may also be performed during surgery.

PERIPROSTHETIC JOINT INFECTION

OVERVIEW

Periprosthetic joint infection (PJI) is a rare, but dreaded, complication in orthopaedic surgery affecting patients that undergo arthroplasty. Unwanted effects of this complication include increased cost and utilization of medical resources and physical/emotional distress that place a taxing strain on patients and the healthcare system.²⁶ With the projected prevalence of patients with prosthetic joints expected to rise and there not yet being a “benchmark” for the diagnosis of PJI, concerted efforts to mitigate the risk and impact of this complication are in full force. Organizations such as the American Association of Orthopaedic Surgeons (AAOS), Centers for Disease Control (CDC), World Health Organization (WHO), Musculoskeletal Infection Society (MSIS), and the International Consensus Group on Musculoskeletal Infection (ICM) have developed practice guidelines for clinicians to follow based on evidence from the literature and multidisciplinary consensus drawn from experts in orthopaedic surgery and infectious disease.

FIGURE 1 Illustration demonstrating new scoring-based definition for periprosthetic joint infection (PJI). Proceed with caution in adverse local tissue reaction, crystal deposition disease, and slow growing organisms. For patients with inconclusive minor criteria, surgical criteria can also be used to fulfill definition for PJI. Consider further molecular diagnostics such as next-generation sequencing. CRP = C-reactive protein, ESR = erythrocyte sedimentation rate, LE = leukocyte esterase, PMN = polymorphonuclear, WBC = white blood cell. (Reproduced with permission from. Parvizi J, Tan TL, Goswami K, et al: The 2018 definition of periprosthetic hip and knee infection: An evidence-based and validated criteria. J Arthroplasty 2018;33[5]:1309-1314.e2.)

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