Biology and Diagnosis of Skeletal Infection

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 Eastern Orthopaedic Association and 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

Healthcare-associated infection (HAI) affects 1 in 31 hospitalized patients at any given time and costs the US healthcare system an estimated $9.8 billion annually, making it a major public health concern.¹^,² Among the five major HAI subtypes, surgical site infection (SSI) contributes the most toward this cost and 33% of SSI cases occur in patients who have undergone orthopaedic procedures.¹ Overall, bacteria from the Staphylococcus genera have been identified as the most common pathogens causing SSI, along with Enterobacteriaceae, Streptococci, and Enterococci.³^,⁴ Drug-resistant organisms, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE), that can colonize patients are becoming an increasing concern because of their impact on quality of life, length of stay (LOS), and overall cost of care.⁵^,⁶^,⁷ Of note, orthopaedic SSI following inpatient procedures has been reported to prolong hospital LOS by a median of 2 weeks per patient, double the readmission rates, and more than triple overall healthcare costs.⁸

Targeted prevention of musculoskeletal infection depends on risk factor assessment and the subsequent incorporation of appropriate interventions. Of 99,152 spine surgery cases from the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database, 2.3% were complicated by SSI.⁴ Among this cohort of infected patients, the significant risk factors for SSI and wound dehiscence included increased surgical time, body mass index (BMI) ≥ 30, smoking, and wound classification ≥ II.⁴ Conversely, previous studies have found the infection rate for total joint arthroplasty (TJA) to range from 1% to 2.5%.⁹ Risk factors for infection after total hip arthroplasty and total knee arthroplasty (TKA) include male gender, cardiac disease, and LOS.¹⁰ Other modifiable risk factors for SSI and PJI across the orthopaedic subspecialties include high alcohol intake, diabetes, previous joint surgery, and high Charlson Comorbidity Index (CCI).¹¹ Knowledge of such risk factors has led to targeted and evidence-based measures in the medical management of orthopaedic patients and generated new endeavors in research focused at SSI/PJI risk mitigation.

BIOLOGIC PRINCIPLES OF SKELETAL INFECTIONS

ETIOLOGY

Pathogenic organisms include bacteria, viruses, parasites, and fungi. Of these, bacteria are the most common source of musculoskeletal infection. Bacteria are prokaryotic organisms, which lack an enveloped nucleus and instead have a nucleoid of genetic material located in the cytoplasm. Bacteria also do not have membrane-bound organelles such as mitochondria and lysosomes. A consistent feature exclusive to prokaryotes is the presence of a cell wall, which allows bacteria to resist osmotic stress. Cell wall complexity can differ between species and bacteria are dichotomized into two major groups: gram-positive and gram-negative. This designation is contingent upon cell wall response of bacterium to crystal violet indium dye after an alcohol rinse. Gram-positive bacteria retain the dye and appear violet under light microscopy. Gram-negative bacteria only retain the safranin O counter-stain and appear pink under light microscopy. Additional classification based on bacteria phenotype can be done with bacteria being labeled as round (cocci) and rod-shaped (bacilli).

Bacteria can resist microbial treatment through innate or extrinsic mechanisms, creating a major challenge in the treatment of musculoskeletal infection. Innate resistance mechanisms that bacteria inherently possess preclude the action of an antibiotic against it. Examples of intrinsic resistance mechanisms that allow bacteria to evade pharmacologic therapy include enzyme-mediated destruction of antibiotics, changes in cell-wall permeability, alterations to structure, mutations in efflux mechanisms, and bypass of metabolic pathway. These aforementioned mechanisms may also be combined to enable resistance as well.

Extrinsic antibiotic resistance strategies are those that an organism acquires, for example, resistance to an antibiotic to which it was previously susceptible. This can take place because of a chance mutation in the genetic material of the microbial cell, or via the acquisition of drug-resistant genes from another drug-resistant cell through a process known as transformation. Transformation-acquired resistance is usually mediated via plasmids, small circles of double-stranded DNA which carry genes for specialized functions such as antimicrobial resistance.

BIOMATERIALS AND BIOFILM

Biomaterials such as indwelling catheters and orthopaedic prostheses are inert nonliving surfaces that can serve as an adherence site for bacteria, leading to the development of a structure known as biofilm. Biofilm is a highly structured community of bacteria cells that adopts a distinct phenotype and can be troublesome to eradicate because of its ability to respond and adapt to stressors.¹² Cell-cell communication known as quorum sensing plays a key regulatory role in the biofilm life cycle, thereby influencing motility, adhesion, cell-to-cell aggregation, virulence, and metabolic activity.¹³^,¹⁴^,¹⁵ These advanced capabilities make biofilm less susceptible to hostile environmental changes in pH, osmolarity, and temperature. Compared with planktonic bacterial cells, bacteria in biofilm are less accessible to antibiotic agents and even host immune responses. Efficient surface modification of biomaterials to prevent biofilm formation and the attachment of microorganisms is an ongoing focus of translational research.

The four-stage growth cycle of biofilm involves initiation, maturation, maintenance, and dispersion.¹³ The initiation phase of biofilm development involves adherence of the bacteria to a surface and formation of microcolonies. Bacteria subsequently produce extracellular polysaccharides which form a glycocalyx that bacterial cells embed themselves within. Other microorganisms are attracted to the surface of the substratum by physical forces including van der Waals forces, hydrophobic interactions, and gravitational forces. Chemical interactions such as ionic, hydrogen, and covalent bonding play a role as well.

Bacterial adherence is influenced by the chemical composition of the biomaterial and surface properties. Roughness, hydrophobicity/hydrophilicity, porosity, pore topology, and other surface conditions are the key factors for microbial adhesion.¹⁶ In vivo studies have identified a higher rate of bacterial adherence to stainless steel over titanium.¹⁷ Tantalum appears to be more resistant to S aureus adherence.¹⁸ When a biomaterial is implanted, its surface becomes coated with a film of plasma and extracellular matrix molecules such as fibrinogen, laminin, fibronectin, and collagen. Bacterial surface receptors facilitate adhesion via interaction with these matrix molecules. Bacterial pili and flagella are also involved in this process, particularly in gram-negative organisms.¹⁹

PRINCIPLES OF ANTIMICROBIALS

Successful treatment of musculoskeletal infection requires the utilization of appropriate surgical modalities in conjunction with targeted antimicrobial therapy. An antimicrobial is any substance of natural, semisynthetic, or synthetic origin that kills or inhibits the growth of a microorganism but causes little or no host damage. It is important to consider factors such as infection type, pathogen susceptibility, and virulence. Important patient factors include their health and nutritional status, and potential for adverse drug effects. Antibiotics are used for prophylaxis for patients with open wounds/fractures or in a preoperative setting, and to eradicate infections after their onset. They can be delivered orally, intramuscularly, intravenously, locally via antibiotic beads, powder, or spacers, or via an osmotic pump.

Successful antimicrobial therapy requires knowledge of an antimicrobial’s spectrum of activity, distribution pharmacokinetics, toxicity, synergy and antagonism with other antimicrobials, and cost. The spectrum of activity is also an important consideration when choosing an antimicrobial
directed against a specific pathogen. First, the physician must identify the pathogen(s) causing the infection. Once isolated, an antimicrobial with activity against the organism(s) causing disease can be chosen. During the selection process, it is important to consider antibiotic distribution and pharmacokinetics, because an antimicrobial’s activity against a particular bacterium can be hampered if a subtherapeutic concentration reaches the site of infection. The benefits of an antimicrobial must also outweigh the risks of use for patients, particularly in cases where risk of medicinal toxicity can outweigh the benefit of a medication’s therapeutic effects.

Other qualities of antimicrobials include their ability to produce additive (synergistic) and counteracting (antagonistic) effects when used together. For example, bacteriostatic antimicrobials can slow the killing rate of a bactericidal antimicrobial. In life-threatening infections, cost will not play a major role in choosing antimicrobial therapy; however, for mild infections such as cystitis or for antimicrobial prophylaxis, regimens may vary 10-fold in cost. Therefore, the clinician must have some understanding of the cost of various antimicrobials.

Although a current recommendation suggest a prolonged course of IV antimicrobial therapy may be necessary for musculoskeletal infection, a recent randomized control trial found oral antibiotic therapy to be noninferior to intravenous antibiotic therapy when used during the first 6 weeks for complex orthopaedic infection, as assessed by treatment failure at 1 year.²⁰ Emergent findings such as this may influence the recommendations for antibiotic treatment of musculoskeletal infection in the future.

HOST-RELATED RISK FACTORS

A number of musculoskeletal infections may be preventable through the identification and treatment of modifiable risk factors.⁴^,¹¹^,²¹^,²² Some of these risk factors include disease states such as HIV, rheumatoid arthritis, diabetes, and other local or distant infections such as urinary tract infections²³ (Table 1). Other modifiable patient risk factors include obesity, malnutrition, smoking, and poor oral health. By being aware of these factors, particularly those that are modifiable, patient optimization before surgery can be conducted to reduce the risk of infection.

Evidence-based risk stratification metrics such as those created by Tan et al²⁴ can help inform perioperative risk as well. Among TJA patients, host-related factors such as history of previous surgery, substance abuse, HIV, and a revision procedure were found to put patients at significant risk for infection. Additional risk factors included coagulopathy, renal disease, congestive heart failure, psychosis, rheumatologic disease, diabetes, anemia, male sex, liver disease, and smoking.²⁴

For elective TJA, centers often implement a multifaceted and evidence-based approach to SSI prevention. This process typically commences with a structured preoperative risk evaluation and targeting risk factor optimization. In keeping with current literature, institutions may advocate for smoking cessation; weight loss before surgery if patients have a BMI >40 kg/m²; optimizing diabetic control until HbA1c <8% or Fructosamine <292 µmol/L; and assessing nutritional parameters in selective high-risk patients.²¹ Other risk factors that may be addressed before elective orthopaedic surgery include disease-modifying agents and immunosuppressive medications, which should be stopped 2 to 4 weeks before surgery.¹¹

PERIOPERATIVE RISK FACTORS

SKIN PREPARATION

Preoperative skin preparation plays an important role in reducing the risk for SSI in patients undergoing orthopaedic surgical procedures. Bacteria found in skin flora include Staphylococci, diphtheroid organisms, Pseudomonas, and Propionibacterium.²⁵ Before being admitted for elective procedures, the Centers for Disease Control (CDC) recommends patients shower or bathe their entire body with soap (antimicrobial or nonantimicrobial) or an antiseptic agent at least one day before surgery. Per additional recommendation from the CDC, skin decolonization should take place before incision with a bactericidal antiseptic solution.²⁵^,²⁶^,²⁷ The ideal skin preparation solution should prevent the growth of pathogens for at least 6 hours after application. Previous studies, however, have found that this process may only remove up to 80% of skin flora.²⁸^,²⁹

Antiseptic skin preparation agents include iodine povacrylex and isopropyl alcohol, povidone-iodine (PI), and chlorhexidine gluconate (CHG) with isopropyl alcohol.²⁶^,³⁰ Current literature lacks evidence to support the use of one solution over another for SSI prevention, but there is an overall consensus that it should contain isopropyl alcohol.²⁶ In one study of patients undergoing shoulder surgery, preoperative cleansing with 2% CHG impregnated cloth led to the least amount of microbial growth on incision cultures compared with those who used PI or water.³¹ These findings were in agreement with those from an earlier study that also demonstrated superior performance for CHG over iodophor, isopropyl alcohol, and PI.³² On the other hand, there is evidence in the literature which shows no difference in the effectiveness of CHG compared to PI.³³

HAIR REMOVAL

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