Skip to main content
  • ASM
    • Antimicrobial Agents and Chemotherapy
    • Applied and Environmental Microbiology
    • Clinical Microbiology Reviews
    • Clinical and Vaccine Immunology
    • EcoSal Plus
    • Eukaryotic Cell
    • Infection and Immunity
    • Journal of Bacteriology
    • Journal of Clinical Microbiology
    • Journal of Microbiology & Biology Education
    • Journal of Virology
    • mBio
    • Microbiology and Molecular Biology Reviews
    • Microbiology Resource Announcements
    • Microbiology Spectrum
    • Molecular and Cellular Biology
    • mSphere
    • mSystems
  • Log in
  • My alerts
  • My Cart

Main menu

  • Home
  • Articles
    • Current Issue
    • Accepted Manuscripts
    • Archive
    • Minireviews
  • For Authors
    • Submit a Manuscript
    • Scope
    • Editorial Policy
    • Submission, Review, & Publication Processes
    • Organization and Format
    • Errata, Author Corrections, Retractions
    • Illustrations and Tables
    • Nomenclature
    • Abbreviations and Conventions
    • Publication Fees
    • Ethics Resources and Policies
  • About the Journal
    • About IAI
    • Editor in Chief
    • Editorial Board
    • For Reviewers
    • For the Media
    • For Librarians
    • For Advertisers
    • Alerts
    • RSS
    • FAQ
  • Subscribe
    • Members
    • Institutions
  • ASM
    • Antimicrobial Agents and Chemotherapy
    • Applied and Environmental Microbiology
    • Clinical Microbiology Reviews
    • Clinical and Vaccine Immunology
    • EcoSal Plus
    • Eukaryotic Cell
    • Infection and Immunity
    • Journal of Bacteriology
    • Journal of Clinical Microbiology
    • Journal of Microbiology & Biology Education
    • Journal of Virology
    • mBio
    • Microbiology and Molecular Biology Reviews
    • Microbiology Resource Announcements
    • Microbiology Spectrum
    • Molecular and Cellular Biology
    • mSphere
    • mSystems

User menu

  • Log in
  • My alerts
  • My Cart

Search

  • Advanced search
Infection and Immunity
publisher-logosite-logo

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Accepted Manuscripts
    • Archive
    • Minireviews
  • For Authors
    • Submit a Manuscript
    • Scope
    • Editorial Policy
    • Submission, Review, & Publication Processes
    • Organization and Format
    • Errata, Author Corrections, Retractions
    • Illustrations and Tables
    • Nomenclature
    • Abbreviations and Conventions
    • Publication Fees
    • Ethics Resources and Policies
  • About the Journal
    • About IAI
    • Editor in Chief
    • Editorial Board
    • For Reviewers
    • For the Media
    • For Librarians
    • For Advertisers
    • Alerts
    • RSS
    • FAQ
  • Subscribe
    • Members
    • Institutions
Minireview

Staphylococcus aureus Osteomyelitis: Bone, Bugs, and Surgery

Kenneth L. Urish, James E. Cassat
Karen M. Ottemann, Editor
Kenneth L. Urish
aArthritis and Arthroplasty Design Group, The Bone and Joint Center, Magee-Womens Hospital of the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
bDepartment of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
cDepartment of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA
iDepartment of Bioengineering, and Clinical and Translational Science Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
James E. Cassat
dDepartment of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
eDepartment of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, USA
fDepartment of Pediatrics, Division of Pediatric Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tennessee, USA
gVanderbilt Institute for Infection, Immunology, and Inflammation (VI4), Vanderbilt University Medical Center, Nashville, Tennessee, USA
hVanderbilt Center for Bone Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Karen M. Ottemann
University of California, Santa Cruz
Roles: Editor
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
DOI: 10.1128/IAI.00932-19
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

ABSTRACT

Osteomyelitis, or inflammation of bone, is most commonly caused by invasion of bacterial pathogens into the skeleton. Bacterial osteomyelitis is notoriously difficult to treat, in part because of the widespread antimicrobial resistance in the preeminent etiologic agent, the Gram-positive bacterium Staphylococcus aureus. Bacterial osteomyelitis triggers pathological bone remodeling, which in turn leads to sequestration of infectious foci from innate immune effectors and systemically delivered antimicrobials. Treatment of osteomyelitis therefore typically consists of long courses of antibiotics in conjunction with surgical debridement of necrotic infected tissues. Even with these extreme measures, many patients go on to develop chronic infection or sustain disease comorbidities. A better mechanistic understanding of how bacteria invade, survive within, and trigger pathological remodeling of bone could therefore lead to new therapies aimed at prevention or treatment of osteomyelitis as well as amelioration of disease morbidity. In this minireview, we highlight recent developments in our understanding of how pathogens invade and survive within bone, how bacterial infection or resulting innate immune responses trigger changes in bone remodeling, and how model systems can be leveraged to identify new therapeutic targets. We review the current state of osteomyelitis epidemiology, diagnostics, and therapeutic guidelines to help direct future research in bacterial pathogenesis.

OSTEOMYELITIS: HISTORICAL PERSPECTIVES, CLINICAL PRESENTATION, AND DIAGNOSIS

Osteomyelitis, technically defined, is an inflammatory state of bone most commonly caused by infection. Three clinical mechanisms lead to bone infection: osteomyelitis resulting from the spread of a contiguous source (trauma or surgical contamination), osteomyelitis occurring secondary to vascular insufficiency or neuropathy (e.g., diabetic foot ulcers), and acute hematogenous osteomyelitis, which is more common in pediatric patients (1, 2). Each clinical pattern has its own unique characteristics, risk factors, presentation, and etiology. Across all mechanisms leading to osteomyelitis, Staphylococcus aureus is the most common organism (1, 3, 4). This includes methicillin-resistant S. aureus (MRSA), which is responsible for a large proportion of antimicrobial-resistant infections in the United States. Accordingly, this review will focus on the role of S. aureus in osteomyelitis. The review will also highlight a basic approach to the diagnosis and treatment of osteomyelitis to help direct future research on bacterial pathogenesis.

Osteomyelitis causes substantial morbidity and mortality and is a major challenge in orthopedic surgery. In trauma, one of the most devastating complications from open fractures is infection, which is a primary mechanism for fracture nonunion (5). In total joint arthroplasty, one of the most common major surgical procedures, the primary cause for failure is infection (6–9). Diabetic foot ulcers are the most common cause for below-knee amputations in the developed world. In the pediatric population, a septic joint is one of the few emergent conditions in orthopedics that demand immediate operative intervention in most cases (2). All of these disease processes highlight the difficulty in eradicating osteomyelitis and the frequent failure of treatment modalities. As such, mortality can be as high as 8% (10).

Osteomyelitis is a historically significant disease. Although initially described by Hippocrates, it was first recognized as a type of infective abscess in medulla in the 18th century (11). Before the appreciation of infectious etiologies, the inflammatory component in bone had long been observed, leading to the term of osteomyelitis—an inflammation of bone. Prior to the advent of penicillin, the only relevant treatment approach was surgery, where the classic tenants of debridement were developed (12). The surgical author of this article respectfully notes the important contribution of penicillin, a nonoperative approach, that dramatically altered treatment when it was initially reported (13) but also observes later reports that gentle debridement can be used as a monotherapy alone in specific cases (14). Surgical versus conservative approaches to the treatment of osteomyelitis echo broader debates between surgery and medicine, and it is reasonable to assume this was one of the first respectful and collegial battlegrounds between the fields (15).

A standard approach to diagnosing osteomyelitis is based on clinical suspicion. Symptomatic presentation includes pain in an extremity and, in pediatrics, frequently a swollen extremity with possible redness. Initial evaluation includes measurement of serum C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), radiographs, and a blood culture. CRP levels typically are elevated before the ESR, but ESR decreases significantly more slowly than CRP (16). This can allow CRP to monitor acute response to treatment (17). It is important to note that elevated ESR and CRP levels are nonspecific for osteomyelitis. Many different inflammatory states will have an elevated ESR and CRP, but it is atypical for a patient with acute osteomyelitis to have a normal ESR and CRP level. Osteolytic lesions around the involved bone, described as “rat bite” in nature, can help aid in the diagnosis. Radiographs cannot not rule out osteomyelitis, as it takes up to 2 weeks in children and longer in adults for imaging findings to be present. However, radiographs are important to rule out other diagnoses, including fracture and malignancy. Malignancy, in particular, can masquerade as infection and infection can appear as a malignancy, and so careful evaluation is always warranted. Definitive imaging of osteomyelitis should be completed with magnetic resonance imaging (MRI), which is considered the gold standard for imaging of osteomyelitis, as the associated inflammation can be observed much earlier in the disease process than with plain films (18). Computed tomography (CT), scintigraphy, and ultrasound have also been used to diagnose osteomyelitis, especially in those cases where patients have contraindications to MRI. For CT, contrast should be used when possible to delineate possible abscess formation. Following imaging, cultures should be obtained to guide therapy. This is typically accomplished through percutaneous biopsy or by direct sampling of bone during open debridement. It is important to appreciate that cultures may not always be positive, and this is termed culture-negative infection. Here, the bone is infected but an organism is unable to be cultured (19).

OSTEOMYELITIS PATHOPHYSIOLOGY

All osteomyelitis cases are not the same. The pathophysiology and etiology are dependent on the mechanism of disease development, the anatomic location in bone, and structural differences between adults and children. Acute hematogenous osteomyelitis is hypothesized to be associated with the venous architecture of certain anatomic locations within the skeleton, such as around the lumber spine or physes (growth plates). Blood vessels in these areas are thought to have relatively turbulent blood flow, to have limited phagocytic lining cells, and to be more susceptible to injury, creating a potential nidus for escape of bacteria from the bloodstream. Osteomyelitis is also associated with trauma, surgery, soft tissue spread, or periprosthetic implants, where contiguous infection or traumatic inoculation of microorganisms leads to establishment of bone infection. A final type of osteomyelitis is associated with vascular insufficiency, such as in chronic wounds of patients with peripheral vascular disease or diabetes, where limited blood flow or repetitive trauma create a nidus for infection and dysregulate immune responses (20, 21). Other host factors such as edema, tobacco use, immune status, metabolic disease, and malnutrition also contribute to the incidence and severity of osteomyelitis (22). Diabetes plays an especially important role, as it both perturbs the immune response and compromises the macrovascular and microvascular blood supply.

As mentioned above, acute hematogenous osteomyelitis is typically associated with venous pooling that is either physiologic or occurs after subacute trauma, and transient bacteremia subsequently results in deposition of microbes near the metaphysis (23). Acute hematogenous osteomyelitis is significantly more common in the pediatric population given the vascular architecture of the physes. Prior to ∼12 to 18 months of age, transphyseal vessels allow bacteria in the metaphysis to migrate to the epiphysis. Bacteria can also migrate through local vasculature and the Haversian and Volkmann canal systems to spread throughout an entire long bone. Inflammation from the initial immune response results in increased intramedullary pressure and decreased blood flow. S. aureus also contributes to bone thrombosis through the production of coagulases, which in conjunction with local inflammation, leads to bone necrosis (23, 24). A subperiosteal abscess will develop if the infection violates the metaphyseal cortex. This is the result of the increased inflammation and pressure from edema and purulence. The periosteum provides a major portion of the local blood supply to bone. Periosteal elevation from inflammation and purulence therefore limits local perfusion, leading to further necrosis. Necrotic bone segments become a nidus for chronic infection and are known as sequestra. In response to the formation of sequestra, the periosteum provides progenitor cells that contribute to local bone growth, and this walls off the infection with new mineralized bone, forming a pathological lesion known as an involucrum (20). Sequestrum and involucrum formation are not typically visualized until after ∼6 weeks of infection and are more indicative of chronic infection. A final bone lesion that can form in subacute or chronic osteomyelitis is a Brodie’s abscess, which occurs when sclerotic bone surrounds a purulent cavity (Fig. 1).

FIG 1
  • Open in new tab
  • Download powerpoint
FIG 1

Typical features of chronic osteomyelitis. Initial inflammation and infection in the metaphysis lead to necrotic bone becoming a nidus for chronic infection, known as a sequestrum. In an attempt to control the infection, new bone mineralizes around the sequestrum and is termed the involucrum. Active infection results in the formation of a sinus to the outer periosteum where a periosteal abscess can develop. (Copyright Kenneth L. Urish.)

There are important differences in the pathogeneses between pediatric and adult osteomyelitis and their sequalae. The most important difference involves the role of the physis in pediatric osteomyelitis and the connected risk of developing septic arthritis. The physis, or growth plate, is a specific well-defined area in bone between the epiphysis and metaphysis where the majority of longitudinal growth occurs until the child reaches their final height. It is composed completely of cartilage. The physis is a natural barrier to the spread of infection, as blood vessels and the interconnections of osteons do not cross this cartilage surface. In the hip, shoulder, elbow, and ankle, the joint capsule extends beyond the physis to the metaphysis. Once subacute osteomyelitis breaks through the cortex, it allows rapid spread into the joint. This is the clinical reason why septic arthritis is more common in the hip, elbow, and ankle in children than in the knee. An exception includes infants below 1 year of age, where the physis is well vascularized and allows bacteria to spread directly into the epiphysis and joint (24, 25) (Fig. 2).

FIG 2
  • Open in new tab
  • Download powerpoint
FIG 2

Pathogenesis of osteomyelitis-associated septic arthritis. Thrombosis of the venous and arterial vascular loops in the metaphysis leads to decreased blood flow, bacterial attachment, and acute infection. (A) The physis forms a physical barrier preventing spread of the infection into the epiphysis. (B) As the infection spreads, it reaches the metaphyseal periosteum and develops a periosteal abscess. In the hip, shoulder, elbow, and ankle, the joint capsule attaches below the physis. (C) This allows the periosteal abscess to circumvent the vascular barrier of the physis and invade the joint, resulting in a septic joint (25). (Copyright Kenneth L. Urish.)

INFECTIOUS ETIOLOGIES OF OSTEOMYELITIS

As noted above, the term “osteomyelitis” technically refers to inflammation of bone, which can result from both infectious and noninfectious etiologies. One particularly important noninfectious etiology of osteomyelitis that can mimic infection is chronic nonbacterial osteomyelitis (CNO), which is also known as chronic recurrent multifocal osteomyelitis (CRMO). CNO is an autoinflammatory disease that triggers sterile bone lesions that may affect one or more locations in the skeleton, and the clinical presentation can be strikingly similar to that of infectious osteomyelitis (26). Although the cause of CNO has not been fully elucidated, recent studies have implicated specific genetic loci (27, 28). Readers are directed to several excellent reviews on this topic for more information (26, 27, 29).

The vast majority of cases of osteomyelitis are caused by infection. Although fungal species such as Blastomyces, Coccidioides, Candida, and Aspergillus cause osteomyelitis in certain clinical scenarios, bacteria are the preeminent microbial agents of human osteomyelitis. The likelihood of isolating a given bacterial species from infected bone is heavily influenced by the mechanism of disease development (i.e., hematogenous, posttraumatic, or contiguous spread), host comorbidities, and environmental exposures.

Broadly speaking, acute hematogenous osteomyelitis is typically a monomicrobial disease, whereas osteomyelitis stemming from trauma or contiguous infection is often polymicrobial. The Gram-positive bacterium Staphylococcus aureus is the most frequently isolated etiologic agent of osteomyelitis across all disease mechanisms and is discussed in greater detail below. Although S. aureus causes the vast majority of acute hematogenous osteomyelitis cases, Streptococcus pyogenes, Streptococcus pneumoniae, and Kingella kingae are also important causes (30, 31). Unlike staphylococcal and streptococcal spp., Kingella kingae, a fastidious Gram-negative coccobacillus, often presents indolently and occurs most frequently in children of less than 3 to 5 years of age (32). In neonates, two additional bacterial causes of acute hematogenous osteomyelitis include group B Streptococcus and enteric Gram-negative bacteria, reflecting their known prevalence as agents of sepsis in this age group (33).

The microbiology of osteomyelitis following trauma is dependent on the mechanism and severity of injury, the presence of environmental contamination, and whether or not indwelling devices are required to stabilize damaged bone. The incidence of infection following skeletal trauma ranges from as low as 2% for low-grade open fractures to up to 50% for the most severe injuries (34–37). This clinical observation forms the basis for administration of short courses of prophylactic antibiotics in the setting of open fracture, a practice confirmed to reduce infection incidence in clinical trials and by a Cochrane Database systemic review (38, 39). In open fractures without gross environmental contamination, osteomyelitis typically is caused by skin flora, with a preponderance of cases caused by S. aureus and coagulase-negative staphylococci. However, in open fractures with gross contamination, an array of environmental organisms, including Gram negatives (e.g., Pseudomonas aeruginosa, Enterobacter cloacae, and Escherichia coli), other Gram positives (e.g., Bacillus and Enterococcus spp.), anaerobes (e.g., Clostridium spp), and nontuberculous mycobacteria, can also lead to subsequent osteomyelitis (20, 38, 40–42). Moreover, patients with high-grade open fractures and extensive soft tissue damage are at enhanced risk of nosocomial infection with pathogens such as methicillin-susceptible S. aureus (MSSA)/MRSA and multidrug-resistant Gram negatives, possibly due to the propensity for delayed wound closure and operative fixation (41, 43). When these injuries are sustained during combat, the microbiology of Gram-negative infection expands to include particularly drug-resistant organisms such as Acinetobacter baumannii (44, 45). Unfortunately, cultures of open fractures at initial operative intervention are poorly predictive of subsequent osteomyelitis etiologies; therefore, apart from injury severity, it is difficult to predict which patients will progress to infection (46–48).

Osteomyelitis following contiguous infection most commonly occurs in patients with neuropathic or vascular insufficiency wounds, decubitus ulcers, and severe or penetrating trauma to soft tissues. This mode of osteomyelitis is particularly common in individuals suffering from diabetes, where up to one-quarter of all patients will develop extremity ulcers, and of these, a substantial proportion will involve bone (49, 50). These infections are almost always polymicrobial, with S. aureus, coagulase-negative staphylococci, group B streptococci, enterococci, and Gram-negative bacilli frequently isolated from bone biopsy specimens (51, 52). Yet, traditional cultures almost certainly underestimate the microbial diversity of chronic wound infections involving bone. 16S sequencing studies have revealed a complex chronic wound microbiome that is dynamic and compositionally different from the surrounding skin (53–57).

S. aureus deserves special consideration as an etiologic agent of osteomyelitis given its prevalence across all mechanisms of osteomyelitis development and based on the considerable focus on staphylococcal pathogenesis within the osteomyelitis literature. The preeminence of S. aureus as an etiologic agent of osteomyelitis is likely driven by two factors. First, approximately 25% to 30% of the global population is thought to be colonized by S. aureus, with estimates reaching 50% to 70% when considering health care workers and transient colonization (58). Second, staphylococci produce many virulence factors, including adhesins, cytolytic toxins, immunoevasion factors, superantigens, and antioxidant systems (59–61). The involvement of specific S. aureus virulence factors in the pathogenesis of osteomyelitis has been inferred from animal models and observation studies in humans and is discussed in greater detail below.

Although a wide variety of microorganisms are recognized as etiologic agents of osteomyelitis, it is important to note that cultures from affected bone during osteomyelitis may be negative. Depending on the patient population under study, osteomyelitis is culture negative in up to 30% to 40% of cases, with chronic infections being the least likely to yield a pathogen (62–66). In some cases of culture-negative osteomyelitis, an offending microbe is not isolated due to preceding antibiotic therapy. However, in other cases, the modality of microbiology sampling (i.e., open debridement versus image-guided biopsy) and the presence of low bacterial load or fastidious organisms (e.g., Kingella and Propionibacterium acnes) impact culture positivity. The potential for false-negative culture results has led many infectious disease clinicians to advocate for withholding antibiotics prior to microbiologic sampling in select cases of osteomyelitis. For those patients who require operative debridement, this is likely an optimal practice. However, data are conflicting regarding the extent to which preculture antibiotics impact subsequent culture results. In pediatric acute hematogenous osteomyelitis, for example, short courses of empirical antibiotics do not appear to significantly impact culture positivity (64–68). Yet, these observations must be balanced against the clear improvement in patient outcomes, including antibiotic deescalation and exclusion of alternative diagnoses (e.g., CNO), which have been shown to stem from clinical practice guidelines that encourage deferral of antibiotics before source culture (69).

TREATMENT OF OSTEOMYELITIS

The mainstays of osteomyelitis treatment are targeted antimicrobial therapy, source control, and correction of medical comorbidities. Targeted antimicrobial therapy, by definition, requires identification of the offending microorganism by source or blood culture. Bone culture may not be feasible in all patients prior to administration of empirical antibiotics. Source control entails debridement of necrotic bone, drainage and irrigation of abscessed tissue, and removal of infected hardware if feasible. Correction of hyperglycemia and amelioration of peripheral vascular disease are critical components of therapy in patients with osteomyelitis related to chronic wounds.

Treatment of osteomyelitis is improved by evidenced-based clinical guidelines that focus on various aspects of care, including coordination of multidisciplinary care, risk stratification, and antimicrobial therapy. Copley and colleagues established clinical care guidelines (CCG) in the context of a Multi-Disciplinary Musculoskeletal Infection Program at Children’s Hospital of Dallas (70). The CCG involved daily rounding with orthopedics, pediatrics, infectious disease, nursing, and social work services. Patients with suspected musculoskeletal infection were enrolled in a clinical algorithm with interventions based on initial MRI findings and lab work. A key to the success of this clinical pathway was the creation of a dedicated MRI slot for children with suspected musculoskeletal infection, enabling immediate transition to the operating room if necessary. Patients enrolled in the CCG were significantly more likely to have a blood culture drawn before antibiotic administration, to have a pathogen identified, to have fewer antibiotic changes, and to receive a longer duration of oral therapy. The same research group went on to create guidelines for culture of musculoskeletal infection aimed at minimizing low-yield cultures in those children without suggestive clinical histories (65). Spruiell et al. similarly reported the implementation of a multidisciplinary CCG for pediatric musculoskeletal infections at Children’s Hospital Colorado (69). Key elements of this CCG were an emphasis on obtaining at least 2 blood cultures prior to antibiotics, early transition to oral antibiotics, avoidance of long-term intravenous access when feasible, and coordination of care between services. After implementation of the CCG, the authors noted significant reductions in length of stay, duration of intravenous (i.v.) therapy, fever duration, and time to culture, with a trend toward increased frequency of pathogen identification. In addition to CCGs, several groups have created classification and scoring systems to predict disease severity and adverse outcomes. Copley et al. created a scoring system for assessment of severity in acute hematogenous osteomyelitis using clinical (respiratory rate, intensive care unit [ICU] admission, febrile days), laboratory (CRP), and radiographic (evidence of disseminated infection) findings (71). This scoring system performed well on both initial and subsequent validation cohorts, and correlated with length of stay (71, 72). Mignemi et al. also established a classification system for musculoskeletal infection severity with significant correlation to hospital outcomes and inflammatory markers (73). Collectively, these tools allow clinicians to stratify patients according to severity and make personalized treatment decisions.

Before reviewing evidenced-based guidelines for the provision of antibiotic therapy for osteomyelitis, it is important to consider antibiotic penetration into bone. Two recent systematic reviews compiled pharmacokinetic data on antibiotic penetration into bone (74, 75). Most of the data on antibiotic penetration into human bone is obtained by administering doses to patients who subsequently undergo total hip or knee arthroplasties. In these studies, most antibiotic classes had substantial penetration into bone, with median serum/bone concentrations ranging from approximately 0.1 to 0.9 (75). However, pharmacology studies in healthy tissue failed to model elements of infection such as bacterial biofilm, abscess formation, and necrotic bone, which could dramatically impact antibiotic penetration in the setting of osteomyelitis. This highlights the important role of surgery in the debridement of necrotic and nonviable tissue to improve antibiotic delivery, as discussed below (7). Furthermore, there has been a greater appreciation for the increased antibiotic tolerance of biofilms (9, 76–80). Finally, the characteristic structure of staphylococcal communities within abscesses is such that the bacteria are shielded from innate immune cells, and potentially antibiotics, by a rim of fibrin and other host factors (81).

There are several evidenced-based clinical guidelines related to antimicrobial treatment of osteomyelitis. A central focus of each guideline is tailoring of therapy based on source culture results. However, empirical therapy is a mainstay of osteomyelitis care for patients who are suspected to have severe or disseminated disease, for patients who have pending source cultures, and for patients in which source culturing was not feasible. Empirical therapy decisions have been heavily influenced by the emergence of community-acquired MRSA and are also shaped by local antibiograms, patient history, and disease severity. Clindamycin is a particularly common choice for empirical antibiotic coverage of suspected S. aureus osteomyelitis, but utility can be limited by resistance patterns (>20% at some institutions) and the fact that it is a bacteriostatic antibiotic and therefore not ideal for patients who are critically ill. Additionally, recent antibiotic susceptibility trends in pediatric S. aureus isolates indicate an overall increase in the incidence of MSSA relative to that of MRSA and a trend toward increased clindamycin resistance in MSSA isolates (82). Collectively, these observations underlie the common practice of targeting both MSSA and MRSA in empirical therapy for osteomyelitis.

For MRSA implant-associated osteomyelitis, the IDSA (Infectious Disease Society of America) recommends empirical therapy with an i.v. agent (vancomycin or daptomycin) plus rifampin for the initial 2 weeks, followed by rifampin plus another oral agent (fluoroquinolone, trimethoprim-sulfamethoxazole, a tetracycline, or clindamycin) to complete 3 to 6 months of therapy in early-onset infections (83). Long-term suppressive oral antibiotic therapy is recommended for those patients in whom debridement and hardware removal are not feasible. For pediatric acute hematogenous osteomyelitis, the IDSA guidelines recommend empirical vancomycin therapy, with the consideration of i.v. clindamycin for patients who do not have ongoing bacteremia and in hospitals where clindamycin resistance is historically low (83). A minimum duration of 4 to 6 weeks is recommended. For native vertebral osteomyelitis, IDSA guidelines recommend empirical coverage of staphylococci, streptococci, and Gram-negative bacilli with a combination of vancomycin and a third- or fourth-generation cephalosporin (84). Empirical therapy should be tailored based on culture results and then targeted parenteral or highly bioavailable oral antibiotics given for 6 weeks. Finally, IDSA recommendations for diabetic foot osteomyelitis include an initial parenteral regimen followed by prolonged oral therapy, but there are insufficient data to support a particular empirical regimen or duration of therapy (85). In addition to IDSA guidelines, the European Society for Pediatric Infectious Disease (ESPID) has published clinical practice guidelines for pediatric osteomyelitis (86). ESPID guidelines recommend prompt initiation of empirical therapy after cultures are obtained, with regimens targeting both MSSA and MRSA in regions where MRSA prevalence is higher than 10% to 15% of all S. aureus infections. A typical regimen would therefore include clindamycin with or without an antistaphylococcal beta-lactam. For children with severe infection or at high risk of clindamycin-resistant MRSA, vancomycin is a preferred empirical agent, with or without the inclusion of clindamycin or an antistaphylococcal beta-lactam. Furthermore, coverage for Kingella kingae with a first-generation cephalosporin such as cefazolin should be included for young children (<5 years) with osteomyelitis. Duration of therapy is a minimum of 3 to 4 weeks, with an early switch to oral antibiotics guided by susceptibility patterns and clinical improvement of the patient (86). Although initially a controversial aspect of therapy for osteomyelitis, there is now compelling data that prolonged intravenous therapy is not superior to oral therapy for acute hematogenous osteomyelitis and may in fact lead to more complications (69, 87).

The role of surgery in osteomyelitis follows a standard surgical principle for infection: debridement (12). General indications for operative intervention include the presence of a subperiosteal or soft tissue abscess, osseous sequestrum, or signs of chronic infection such as in the sinus tract. Other indications include when the infection fails to respond to initial antibiotic therapy or concurrent septic joint arthritis (24, 88, 89). Surgery serves an important role in improving the local environment during osteomyelitis through debridement of the devitalized tissue, decompression of the bacterial burden, and enhancement of antibiotic delivery. During debridement of necrotic bone, viable tissue is identified by punctate bleeding on the bone and wound edges. Tissue that has no bleeding is not viable and should be removed as a central tenet of surgical management.

Surgical indications for osteomyelitis are dependent on etiology. In acute hematogenous osteomyelitis, surgical debridement is common but not absolutely necessary depending on the infectious lesion and severity of disease. Yet, there is still an important role for the surgeon for diagnostic biopsy of infected bone to identify the causative organism, although in some institutions, this procedure is often performed by interventional radiology. Osteomyelitis typically requires debridement when surrounding soft tissue is involved. Classic examples include adult diabetic foot ulcers, open fractures and trauma, septic joints, and periprosthetic joint infection. For diabetic ulcers, debridement is typically reserved for wounds that have deeply progressed to involve bone. In this scenario, surgical debridement is essential to create a viable wound bed and remove necrotic tissue. In orthopedic trauma, a main principle in the management of open fractures, which have a high risk of developing infection, is urgent irrigation and debridement to prevent infection and promote healing (5, 90–92). Early surgical intervention, antibiotics, and stabilization of the fracture are tenets of what has been termed “damage control orthopedics” in a trauma setting (93, 94). In osteomyelitis associated with implant infections such as periprosthetic joint infection, surgery serves an equally important role, where both surgery and antibiotics are critical to successful treatment of the infection (9, 19, 77, 79, 80, 95).

An additional advantage of surgery is the ability to provide local delivery of antibiotics at high doses. A common technique is to use antibiotic-laden poly(methyl methacrylate) (PMMA), otherwise known as bone cement. Here, antibiotics are added to the PMMA powder prior to the start of polymerization. A typical mix includes 1 g of vancomycin and 1 g of either gentamicin or tobramycin per bag of PMMA. High viscosity Palacos cement should be used, as it has been shown to have superior elution properties. It is important to appreciate that antibiotic elution is only for a limited time period of a few days (96, 97). The advantages include the ability to locally deliver high doses of antibiotic, fill dead space, and maintain soft tissue tension. The disadvantage is that it requires an additional surgery to remove. There are a variety of other new local antibiotic delivery methods being developed that are beyond the scope of this review (98).

BACTERIAL PATHOGENESIS IN THE CONTEXT OF BONE INFECTION

Much of our current understanding of bacterial pathogenesis and host-pathogen interactions during osteomyelitis is derived from animal models, the vast majority of which have used S. aureus as a model pathogen. Most animal models of osteomyelitis involve traumatic inoculation of a bacterial pathogen, with or without implant placement (99). Modeling hematogenous osteomyelitis has proven more difficult, although several groups have reported success using a preceding implant surgery (100–102), and at least one group has had success studying hematogenous S. aureus osteomyelitis without a preceding bone injury (103). Animal studies of osteomyelitis are conducted in both rodents and larger animals, an appropriate strategy given the wealth of genetic tools available for mice, balanced with the comparative difficulty of stabilizing murine fractures.

S. aureus has a wide array of virulence factors that promote invasion of, and survival within, host tissues (59–61, 104). This includes adhesins, cytolytic toxins and exoenzymes, immunoevasion factors, and superantigens. Of particular importance to the initiation of osteomyelitis are the microbial surface components recognizing adhesive matrix molecules (MSCRAMM) group of adhesins. MSCRAMMs are proteins with IgG-like subdomains that are capable of binding components of the extracellular matrix, such as collagen, fibrinogen, bone sialoprotein, and fibronectin (59). The staphylococcal adhesin Cna enables binding to collagen and contributes to the pathogenesis of osteomyelitis (105–107), although strains that lack collagen binding capability in vitro have been isolated from human cases of osteomyelitis (108). Several S. aureus adhesins are capable of binding fibrinogen, including bone sialoprotein binding protein (Bbp), clumping factors A and B (ClfA and ClfB), fibronectin binding proteins A and B (FnBPA and FnBPB), extracellular matrix binding protein (Emp), the extracellular adherence protein (Eap), and the staphylococcal coagulases (Coa and vwBP). The direct role of these proteins in human osteomyelitis has not been fully delineated, although the coagulases and fibrinogen binding are critical for staphylococcal abscess formation and survival in other murine models (81). Interestingly, some adhesins appear to have a more pronounced role in osteomyelitis associated with medical comorbidity. Farnsworth et al. found that S. aureus isolated from obese/type 2 diabetic mice displayed upregulation of four adhesin genes (clfA, clfB, bbp, and sdrC), and inactivation of clfA reduced infection severity in obese but not wild-type mice (109). Finally, the ability to bind bone matrix sialoprotein was found to be enhanced among S. aureus isolates from patients with osteomyelitis compared to that among endocarditis isolates (110, 111). The surface proteins responsible for this binding were later identified (112, 113), and antibodies to one of these proteins, Bbp, might have diagnostic value for osteomyelitis (114).

Adhesion to host tissues is a critical first step in the pathogenesis of osteomyelitis. However, after establishment of infection, S. aureus faces a hostile host environment due to innate immune defenses and nutrient limitation. These host factors are counteracted by staphylococcal toxins and degradative exoenzymes that incapacitate immune cells and liberate nutrients (60). Some of these secreted factors have been linked to the pathogenesis of osteomyelitis. For example, phenol-soluble modulins (PSMs), amphipathic peptides with broad cytolytic and immunomodulatory activity, trigger murine and human osteoblast cell death and contribute to bone destruction during osteomyelitis (115–117). The alpha-type PSMs, in particular, are both necessary and sufficient for the cytolytic activity of S. aureus supernatants toward primary osteoblasts in cell culture (116). Two additional staphylococcal toxins, Panton-Valentine leukocidin (PVL) and alpha-hemolysin (Hla), contribute to osteomyelitis pathogenesis and extraosseous complications in a rabbit model (118). Furthermore, passive immunotherapy with antibodies against both Hla and ClfA improved outcomes in a murine hematogenous implant model (100). Understanding the full contribution of staphylococcal toxins to osteomyelitis pathogenesis will likely require human studies in addition to animal models, however, as some toxins have species specificity (119). To this end, PVL has been associated with enhanced disease in pediatric patients with acute hematogenous osteomyelitis (120). Moreover, the host immune response to S. aureus leukocidins can be used as a culture-independent diagnostic in children with musculoskeletal infection (121, 122).

In addition to cytolytic toxins that induce death of innate immune cells, S. aureus also expresses both surface-bound and secreted immunoevasion factors (61). S. aureus protein A (Spa) promotes immune evasion through the ability to bind Fc regions of antibodies, interfere with complement activation, and serve as a B-cell superantigen (123–125). In addition to these functions, protein A may contribute to the pathogenesis of staphylococcal osteomyelitis by altering both osteoblast and osteoclast biology. Spa binds directly to osteoblasts via tumor necrosis factor receptor-1 (TNFR-1), leading to increased receptor activator of NFκB-ligand (RANK-L) expression and activation of apoptosis (126–128). In differentiating osteoclasts, Spa interacts with TNFR-1 and the epidermal growth factor (EGF) receptor to promote osteoclastogenesis and bone destruction (129). Another immune evasion protein, the major histocompatibility complex (MHC) class II analog protein Map, has also been found to contribute to the pathogenesis of osteomyelitis by interfering with T-cell function and promoting chronic infection (130).

Given the important roles of multiple staphylococcal virulence factors in invasive infection, it is not surprising that there has been a considerable research focus on S. aureus regulatory proteins that control virulence factor production. The accessory gene regulator (agr) locus encodes a peptide quorum-sensing system that controls expression of multiple toxins, proteases, and protein A. Agr was one of the first regulatory loci linked to the pathogenesis of staphylococcal osteomyelitis. Research by Gillaspy et al. in a rabbit model of acute osteomyelitis clearly indicated a role for Agr in disease severity, although inactivation of Agr did not eliminate the ability of staphylococci to colonize bone (131). Subsequent studies in mice revealed that genetic inactivation or pharmacologic inhibition of Agr decreases bone destruction during acute osteomyelitis (116, 132). These observations partly reflect the direct regulation of PSMs by AgrA (116, 133, 134). However, although the Agr system clearly contributes to the pathogenesis of acute osteomyelitis, its expression may not be favorable during chronic infection, as many staphylococcal isolates from human osteomyelitis cases have agr mutations (135, 136). A second S. aureus regulator strongly linked to the pathogenesis of osteomyelitis is the staphylococcal accessory regulator SarA. Inactivation of SarA reduces virulence in murine models of both acute hematogenous and posttraumatic osteomyelitis (115, 137, 138). The major mechanism by which SarA promotes invasive infection is through repression of proteases, and protease null strains of S. aureus are hypervirulent in multiple models of invasive infection (115, 139–141). A similar dysregulation of protease activity partially underlies the significant attenuation of S. aureus sae locus mutants, which have reduced bacterial burdens and cortical bone destruction during experimental osteomyelitis, although direct regulation of staphylococcal virulence factors by Sae is also an important determinant of pathogenesis (116, 137). Finally, the staphylococcal respiratory response (Srr) two-component system was discovered to be essential for S. aureus survival during osteomyelitis using transposon sequencing (Tn-Seq) (133). The srr locus was shown to contribute to osteomyelitis, in part, through coordinating bacterial responses to the hypoxic environment of infected bone. This study also identified a total of 213 genes that contributed to bacterial survival in bone, a large number of which encode hypothetical proteins that will require further research to elucidate their connection to osteomyelitis pathogenesis.

Staphylococcal virulence factors are a major determinant of osteomyelitis pathogenesis, but the host responses to bacteria in bone are equally important and dictate tissue responses that contribute to adverse outcomes. Many of the innate immune responses that are necessary to control bacterial replication during invasive infection have important roles as modulators of bone homeostasis (142, 143). For example, interleukin-1 (IL-1) cytokine signaling is necessary for host defenses against S. aureus in multiple infection models, including osteomyelitis (142, 144, 145). Yet, IL-1 is also an important regulator of osteoclastogenesis, having initially been identified as “osteoclast activating factor” (146). In line with these observations, the IL-1 receptor (IL-1R) was demonstrated to contribute to infection-associated trabecular bone loss and osteoclastogenesis during osteomyelitis (144). Moreover, inhibition of inflammasomes, multiprotein enzymatic complexes that process IL-1R ligands, reduces bone destruction during osteomyelitis (147). Understanding if such immunomodulatory therapies could be deployed in human infection requires further research. Finally, S. aureus can invade and persist within both osteoblasts and osteoclasts, leading to substantial alterations in cell physiology (148–151). To what extent invasion of osteoblasts and osteoclasts by S. aureus contributes to human disease is a topic for future research, as this has been observed in vitro but not in vivo.

CONCLUSIONS AND OPPORTUNITIES FOR FUTURE RESEARCH

Osteomyelitis remains a clinical challenge and is best approached with evidenced-based clinical care guidelines and a multidisciplinary team. Although recent changes in antibiotic susceptibility patterns have dictated empirical antibiotic selection, the treatment of osteomyelitis is largely unchanged over the past decades and centers on source control, tailored antibiotic therapy, and correction of medical comorbidities. Studies using animal models have shed light on host and bacterial factors that contribute to the pathogenesis of osteomyelitis and offer hope for new therapeutic targets, drug delivery strategies, and immunomodulatory therapies to lessen the incidence and morbidity of osteomyelitis.

There are ample opportunities for future research on osteomyelitis. In the clinical arena, continued attention to interdisciplinary clinical care guidelines and severity classification will drive improved care at both the local and national levels. Ongoing changes in antimicrobial susceptibility patterns will require continued vigilance to assist in empirical antibiotic selection. Moreover, standard in vitro antibiotic susceptibility testing is unlikely to model the complexity of bacterial physiology in vivo, where factors such as biofilm, abscess formation, nutrient deprivation, and tissue hypoxia might render bacteria more tolerant of antibiotics (152). Whether or not new local and bone-targeted delivery agents can overcome these factors to enhance treatment of osteomyelitis is an important area for future study (153). Furthermore, compelling data from both animal models and human samples indicate that S. aureus can directly invade the osteocyte lacuno-canicular network, which may have important ramifications for treatment failure (154, 155). This research also speaks to the fact that S. aureus exists within architecturally distinct niches during infection, such as within bone marrow abscesses, sequestra, or the canalicular network or on the surface of intact cortical bone or implants. It is likely that heterogeneity in bacterial physiology exists within these distinct niches; therefore, animal models that homogenize entire infected bones, although necessary, may miss critical facets of host-pathogen interactions during osteomyelitis. Accordingly, new methodology should be developed to study host-pathogen interactions during osteomyelitis in a spatially resolved manner. On the host side, infection induces significant changes in bone remodeling that may contribute to a failure of antibiotic delivery or efficacy. Observations from the emerging scientific discipline of osteoimmunology indicate that many of the proinflammatory responses to bacterial pathogens in bone have important effects on osteoblast and osteoclast biology and thereby contribute to dysregulation of bone homeostasis during osteomyelitis (143). Whether or not these host responses can safely be targeted to mitigate bone destruction without significantly impacting critical innate immune responses remains to be determined. Recently, the International Consensus Meeting on Musculoskeletal Infection was convened, which outlined additional major challenges in the field and future research objectives (156–158). In summary, understanding both the bacterial and host factors that contribute to antibiotic tolerance or failure is therefore a key direction for future research.

ACKNOWLEDGMENTS

K. L. Urish is supported in part by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS K08AR071494), the National Center for Advancing Translational Science (NCATS KL2TR0001856), the Orthopaedic Research and Education Foundation, and the Musculoskeletal Tissue Foundation. J. E. Cassat is supported by National Institute of Allergy and Infectious Diseases (NIAID R01AI132560 and K08AI113107) and a Career Award for Medical Scientists from the Burroughs Wellcome Fund.

  • Copyright © 2020 American Society for Microbiology.

All Rights Reserved.

REFERENCES

  1. 1.↵
    1. Kremers HM,
    2. Nwojo ME,
    3. Ransom JE,
    4. Wood-Wentz CM,
    5. Melton LJ, III,
    6. Huddleston PM, III
    . 2015. Trends in the epidemiology of osteomyelitis: a population-based study, 1969 to 2009. J Bone Joint Surg Am 97:837–845. doi:10.2106/JBJS.N.01350.
    OpenUrlAbstract/FREE Full Text
  2. 2.↵
    1. Peltola H,
    2. Paakkonen M
    . 2014. Acute osteomyelitis in children. N Engl J Med 370:352–360. doi:10.1056/NEJMra1213956.
    OpenUrlCrossRefPubMedWeb of Science
  3. 3.↵
    1. Jagodzinski NA,
    2. Kanwar R,
    3. Graham K,
    4. Bache CE
    . 2009. Prospective evaluation of a shortened regimen of treatment for acute osteomyelitis and septic arthritis in children. J Pediatr Orthop 29:518–525. doi:10.1097/BPO.0b013e3181ab472d.
    OpenUrlCrossRefPubMedWeb of Science
  4. 4.↵
    1. Peltola H,
    2. Paakkonen M,
    3. Kallio P,
    4. Kallio MJ
    , Osteomyelitis-Septic Arthritis Study Group. 2010. Short- versus long-term antimicrobial treatment for acute hematogenous osteomyelitis of childhood: prospective, randomized trial on 131 culture-positive cases. Pediatr Infect Dis J 29:1123–1128. doi:10.1097/INF.0b013e3181f55a89.
    OpenUrlCrossRefPubMed
  5. 5.↵
    FLOW Investigators, Bhandari M, Jeray KJ, Petrisor BA, Devereaux PJ, Heels-Ansdell D, Schemitsch EH, Anglen J, Della Rocca GJ, Jones C, Kreder H, Liew S, McKay P, Papp S, Sancheti P, Sprague S, Stone TB, Sun X, Tanner SL, Tornetta P, III, Tufescu T, Walter S, Guyatt GH. 2015. A trial of wound irrigation in the initial management of open fracture wounds. N Engl J Med 373:2629–2641. doi:10.1056/NEJMoa1508502.
    OpenUrlCrossRefPubMed
  6. 6.↵
    1. Urish KL,
    2. Qin Y,
    3. Li BY,
    4. Borza T,
    5. Sessine M,
    6. Kirk P,
    7. Hollenbeck BK,
    8. Helm JE,
    9. Lavieri MS,
    10. Skolarus TA,
    11. Jacobs BL
    . 2018. Predictors and cost of readmission in total knee arthroplasty. J Arthroplasty 33:2759–2763. doi:10.1016/j.arth.2018.04.008.
    OpenUrlCrossRef
  7. 7.↵
    1. Urish KL,
    2. Bullock AG,
    3. Kreger AM,
    4. Shah NB,
    5. Jeong K,
    6. Rothenberger SD
    , Infected Implant Consortium. 2018. A multicenter study of irrigation and debridement in total knee arthroplasty periprosthetic joint infection: treatment failure is high. J Arthroplasty 33:1154–1159. doi:10.1016/j.arth.2017.11.029.
    OpenUrlCrossRef
  8. 8.↵
    1. Li BY,
    2. Urish KL,
    3. Jacobs BL,
    4. He C,
    5. Borza T,
    6. Qin Y,
    7. Min HS,
    8. Dupree JM,
    9. Ellimoottil C,
    10. Hollenbeck BK,
    11. Lavieri MS,
    12. Helm JE,
    13. Skolarus TA
    . 2019. Inaugural readmission penalties for total hip and total knee arthroplasty procedures under the hospital readmissions reduction program. JAMA Netw Open 2:e1916008. doi:10.1001/jamanetworkopen.2019.16008.
    OpenUrlCrossRef
  9. 9.↵
    1. Shah NB,
    2. Hersh BL,
    3. Kreger AM,
    4. Sayeed A,
    5. Bullock AG,
    6. Rothenberger SD,
    7. Klatt B,
    8. Hamlin B,
    9. Urish KL
    . 2020. Benefits and adverse events associated with extended antibiotic use in total knee arthroplasty periprosthetic joint infection. Clin Infect Dis 70:559–565. doi:10.1093/cid/ciz261.
    OpenUrlCrossRef
  10. 10.↵
    1. Noskin GA,
    2. Rubin RJ,
    3. Schentag JJ,
    4. Kluytmans J,
    5. Hedblom EC,
    6. Smulders M,
    7. Lapetina E,
    8. Gemmen E
    . 2005. The burden of Staphylococcus aureus infections on hospitals in the United States: an analysis of the 2000 and 2001 Nationwide Inpatient Sample Database. Arch Intern Med 165:1756–1761. doi:10.1001/archinte.165.15.1756.
    OpenUrlCrossRefPubMedWeb of Science
  11. 11.↵
    1. Klenerman L
    . 2007. A history of osteomyelitis from the Journal of Bone and Joint Surgery: 1948 to 2006. J Bone Joint Surg Br 89:667–670. doi:10.1302/0301-620X.89B5.19170.
    OpenUrlCrossRefPubMed
  12. 12.↵
    1. Orr HW
    . 2006. The treatment of acute osteomyelitis by drainage and rest. 1927. Clin Orthop Relat Res 451:4–9. doi:10.1097/01.blo.0000238778.34939.66.
    OpenUrlCrossRefPubMed
  13. 13.↵
    1. Dennison WM
    . 1948. Haematogenous osteitis in children; preliminary report on treatment with penicillin. J Bone Joint Surg Br 30B:110–123.
    OpenUrlWeb of Science
  14. 14.↵
    1. Harris NH,
    2. Kirkaldy-Willis WH
    . 1965. Primary subacute pyogenic osteomyelitis. J Bone Joint Surg Br 47:526–532.
    OpenUrlPubMed
  15. 15.↵
    1. Subramanian P,
    2. Kantharuban S,
    3. Subramanian V,
    4. Willis-Owen SA,
    5. Willis-Owen CA
    . 2011. Orthopaedic surgeons: as strong as an ox and almost twice as clever? Multicentre prospective comparative study. BMJ 343:d7506. doi:10.1136/bmj.d7506.
    OpenUrlAbstract/FREE Full Text
  16. 16.↵
    1. Unkila-Kallio L,
    2. Kallio MJ,
    3. Eskola J,
    4. Peltola H
    . 1994. Serum C-reactive protein, erythrocyte sedimentation rate, and white blood cell count in acute hematogenous osteomyelitis of children. Pediatrics 93:59–62.
    OpenUrlAbstract/FREE Full Text
  17. 17.↵
    1. Paakkonen M,
    2. Peltola H
    . 2014. Acute osteomyelitis in children. N Engl J Med 370:1365–1366. doi:10.1056/NEJMc1402234.
    OpenUrlCrossRef
  18. 18.↵
    1. Connolly LP,
    2. Connolly SA,
    3. Drubach LA,
    4. Jaramillo D,
    5. Treves ST
    . 2002. Acute hematogenous osteomyelitis of children: assessment of skeletal scintigraphy-based diagnosis in the era of MRI. J Nucl Med 43:1310–1316.
    OpenUrlAbstract/FREE Full Text
  19. 19.↵
    1. Hersh BL,
    2. Shah NB,
    3. Rothenberger SD,
    4. Zlotnicki JP,
    5. Klatt BA,
    6. Urish KL
    . 2019. Do culture negative periprosthetic joint infections remain culture negative? J Arthroplasty 34:2757–2762. doi:10.1016/j.arth.2019.06.050.
    OpenUrlCrossRef
  20. 20.↵
    1. Lew DP,
    2. Waldvogel FA
    . 2004. Osteomyelitis. Lancet 364:369–379. doi:10.1016/S0140-6736(04)16727-5.
    OpenUrlCrossRefPubMedWeb of Science
  21. 21.↵
    1. Schmitt SK
    . 2017. Osteomyelitis. Infect Dis Clin North Am 31:325–338. doi:10.1016/j.idc.2017.01.010.
    OpenUrlCrossRef
  22. 22.↵
    1. Cierny G, III,
    2. Mader JT,
    3. Penninck JJ
    . 2003. A clinical staging system for adult osteomyelitis. Clin Orthop Relat Res 414:7–24. doi:10.1097/01.blo.0000088564.81746.62.
    OpenUrlCrossRefPubMed
  23. 23.↵
    1. Calhoun JH,
    2. Manring MM,
    3. Shirtliff M
    . 2009. Osteomyelitis of the long bones. Semin Plast Surg 23:59–72. doi:10.1055/s-0029-1214158.
    OpenUrlCrossRefPubMed
  24. 24.↵
    1. Song KM,
    2. Sloboda JF
    . 2001. Acute hematogenous osteomyelitis in children. J Am Acad Orthop Surg 9:166–175. doi:10.5435/00124635-200105000-00003.
    OpenUrlCrossRefPubMed
  25. 25.↵
    1. Dormans JP,
    2. Drummond DS
    . 1994. Pediatric hematogenous osteomyelitis: new trends in presentation, diagnosis, and treatment. J Am Acad Orthop Surg 2:333–341. doi:10.5435/00124635-199411000-00005.
    OpenUrlCrossRefPubMed
  26. 26.↵
    1. Zhao Y,
    2. Ferguson PJ
    . 2018. Chronic nonbacterial osteomyelitis and chronic recurrent multifocal osteomyelitis in children. Pediatr Clin North Am 65:783–800. doi:10.1016/j.pcl.2018.04.003.
    OpenUrlCrossRef
  27. 27.↵
    1. Cox AJ,
    2. Ferguson PJ
    . 2018. Update on the genetics of nonbacterial osteomyelitis in humans. Curr Opin Rheumatol 30:521–525. doi:10.1097/BOR.0000000000000530.
    OpenUrlCrossRef
  28. 28.↵
    1. Cox AJ,
    2. Darbro BW,
    3. Laxer RM,
    4. Velez G,
    5. Bing X,
    6. Finer AL,
    7. Erives A,
    8. Mahajan VB,
    9. Bassuk AG,
    10. Ferguson PJ
    . 2017. Recessive coding and regulatory mutations in FBLIM1 underlie the pathogenesis of chronic recurrent multifocal osteomyelitis (CRMO). PLoS One 12:e0169687. doi:10.1371/journal.pone.0169687.
    OpenUrlCrossRef
  29. 29.↵
    1. Cox AJ,
    2. Zhao Y,
    3. Ferguson PJ
    . 2017. Chronic recurrent multifocal osteomyelitis and related diseases-update on pathogenesis. Curr Rheumatol Rep 19:18. doi:10.1007/s11926-017-0645-9.
    OpenUrlCrossRef
  30. 30.↵
    1. Funk SS,
    2. Copley LA
    . 2017. Acute hematogenous osteomyelitis in children: pathogenesis, diagnosis, and treatment. Orthop Clin North Am 48:199–208. doi:10.1016/j.ocl.2016.12.007.
    OpenUrlCrossRef
  31. 31.↵
    1. Kaplan SL
    . 2014. Recent lessons for the management of bone and joint infections. J Infect 68 Suppl 1:S51–S56. doi:10.1016/j.jinf.2013.09.014.
    OpenUrlCrossRefPubMed
  32. 32.↵
    1. Yagupsky P
    . 2015. Kingella kingae: carriage, transmission, and disease. Clin Microbiol Rev 28:54–79. doi:10.1128/CMR.00028-14.
    OpenUrlAbstract/FREE Full Text
  33. 33.↵
    1. Offiah AC
    . 2006. Acute osteomyelitis, septic arthritis and discitis: differences between neonates and older children. Eur J Radiol 60:221–232. doi:10.1016/j.ejrad.2006.07.016.
    OpenUrlCrossRefPubMedWeb of Science
  34. 34.↵
    1. Gustilo RB,
    2. Mendoza RM,
    3. Williams DN
    . 1984. Problems in the management of type III (severe) open fractures: a new classification of type III open fractures. J Trauma 24:742–746. doi:10.1097/00005373-198408000-00009.
    OpenUrlCrossRefPubMedWeb of Science
  35. 35.↵
    1. Patzakis MJ,
    2. Wilkins J
    . 1989. Factors influencing infection rate in open fracture wounds. Clin Orthop Relat Res 243:36–40.
    OpenUrlPubMed
  36. 36.↵
    1. Zalavras CG
    . 2017. Prevention of infection in open fractures. Infect Dis Clin North Am 31:339–352. doi:10.1016/j.idc.2017.01.005.
    OpenUrlCrossRef
  37. 37.↵
    1. Ostermann PA,
    2. Seligson D,
    3. Henry SL
    . 1995. Local antibiotic therapy for severe open fractures. A review of 1085 consecutive cases. J Bone Joint Surg Br 77:93–97. doi:10.1302/0301-620X.77B1.7822405.
    OpenUrlCrossRefPubMed
  38. 38.↵
    1. Patzakis MJ,
    2. Wilkins J,
    3. Moore TM
    . 1983. Use of antibiotics in open tibial fractures. Clin Orthop Relat Res 178:31–35.
    OpenUrlPubMed
  39. 39.↵
    1. Gosselin RA,
    2. Roberts I,
    3. Gillespie WJ
    . 2004. Antibiotics for preventing infection in open limb fractures. Cochrane Database Syst Rev 2004:CD003764. doi:10.1002/14651858.CD003764.pub2.
    OpenUrlCrossRef
  40. 40.↵
    1. Dellinger EP,
    2. Miller SD,
    3. Wertz MJ,
    4. Grypma M,
    5. Droppert B,
    6. Anderson PA
    . 1988. Risk of infection after open fracture of the arm or leg. Arch Surg 123:1320–1327. doi:10.1001/archsurg.1988.01400350034004.
    OpenUrlCrossRefPubMedWeb of Science
  41. 41.↵
    1. Kindsfater K,
    2. Jonassen EA
    . 1995. Osteomyelitis in grade II and III open tibia fractures with late debridement. J Orthop Trauma 9:121–127. doi:10.1097/00005131-199504000-00006.
    OpenUrlCrossRefPubMedWeb of Science
  42. 42.↵
    1. McNeil JC,
    2. Vallejo JG,
    3. Hulten KG,
    4. Kaplan SL
    . 2018. Osteoarticular infections following open or penetrating trauma in children in the post-community-acquired methicillin-resistant Staphylococcus aureus Era: the impact of Enterobacter cloacae. Pediatr Infect Dis J 37:1204–1210. doi:10.1097/INF.0000000000001991.
    OpenUrlCrossRef
  43. 43.↵
    1. Burns TC,
    2. Stinner DJ,
    3. Mack AW,
    4. Potter BK,
    5. Beer R,
    6. Eckel TT,
    7. Possley DR,
    8. Beltran MJ,
    9. Hayda RA,
    10. Andersen RC,
    11. Keeling JJ,
    12. Frisch HM,
    13. Murray CK,
    14. Wenke JC,
    15. Ficke JR,
    16. Hsu JR
    , Skeletal Trauma Research Consortium. 2012. Microbiology and injury characteristics in severe open tibia fractures from combat. J Trauma Acute Care Surg 72:1062–1067. doi:10.1097/TA.0b013e318241f534.
    OpenUrlCrossRefPubMedWeb of Science
  44. 44.↵
    1. Mende K,
    2. Stewart L,
    3. Shaikh F,
    4. Bradley W,
    5. Lu D,
    6. Krauss MR,
    7. Greenberg L,
    8. Yu Q,
    9. Blyth DM,
    10. Whitman TJ,
    11. Petfield JL,
    12. Tribble DR
    . 2019. Microbiology of combat-related extremity wounds: trauma infectious disease outcomes study. Diagn Microbiol Infect Dis 94:173–179. doi:10.1016/j.diagmicrobio.2018.12.008.
    OpenUrlCrossRef
  45. 45.↵
    1. Johnson EN,
    2. Burns TC,
    3. Hayda RA,
    4. Hospenthal DR,
    5. Murray CK
    . 2007. Infectious complications of open type III tibial fractures among combat casualties. Clin Infect Dis 45:409–415. doi:10.1086/520029.
    OpenUrlCrossRefPubMedWeb of Science
  46. 46.↵
    1. Valenziano CP,
    2. Chattar-Cora D,
    3. O'Neill A,
    4. Hubli EH,
    5. Cudjoe EA
    . 2002. Efficacy of primary wound cultures in long bone open extremity fractures: are they of any value? Arch Orthop Trauma Surg 122:259–261. doi:10.1007/s00402-001-0363-6.
    OpenUrlCrossRefPubMed
  47. 47.↵
    1. Kreder HJ,
    2. Armstrong P
    . 1994. The significance of perioperative cultures in open pediatric lower-extremity fractures. Clin Orthop Relat Res 302:206–212.
    OpenUrlPubMed
  48. 48.↵
    1. Lee J
    . 1997. Efficacy of cultures in the management of open fractures. Clin Orthop Relat Res 339:71–75. doi:10.1097/00003086-199706000-00010.
    OpenUrlCrossRefPubMed
  49. 49.↵
    1. Ramsey SD,
    2. Newton K,
    3. Blough D,
    4. McCulloch DK,
    5. Sandhu N,
    6. Reiber GE,
    7. Wagner EH
    . 1999. Incidence, outcomes, and cost of foot ulcers in patients with diabetes. Diabetes Care 22:382–387. doi:10.2337/diacare.22.3.382.
    OpenUrlAbstract
  50. 50.↵
    1. Giurato L,
    2. Meloni M,
    3. Izzo V,
    4. Uccioli L
    . 2017. Osteomyelitis in diabetic foot: a comprehensive overview. World J Diabetes 8:135–142. doi:10.4239/wjd.v8.i4.135.
    OpenUrlCrossRef
  51. 51.↵
    1. Senneville E,
    2. Morant H,
    3. Descamps D,
    4. Dekeyser S,
    5. Beltrand E,
    6. Singer B,
    7. Caillaux M,
    8. Boulogne A,
    9. Legout L,
    10. Lemaire X,
    11. Lemaire C,
    12. Yazdanpanah Y
    . 2009. Needle puncture and transcutaneous bone biopsy cultures are inconsistent in patients with diabetes and suspected osteomyelitis of the foot. Clin Infect Dis 48:888–893. doi:10.1086/597263.
    OpenUrlCrossRefPubMed
  52. 52.↵
    1. Zuluaga AF,
    2. Galvis W,
    3. Jaimes F,
    4. Vesga O
    . 2002. Lack of microbiological concordance between bone and non-bone specimens in chronic osteomyelitis: an observational study. BMC Infect Dis 2:8. doi:10.1186/1471-2334-2-8.
    OpenUrlCrossRefPubMed
  53. 53.↵
    1. van Asten SA,
    2. La Fontaine J,
    3. Peters EJ,
    4. Bhavan K,
    5. Kim PJ,
    6. Lavery LA
    . 2016. The microbiome of diabetic foot osteomyelitis. Eur J Clin Microbiol Infect Dis 35:293–298. doi:10.1007/s10096-015-2544-1.
    OpenUrlCrossRef
  54. 54.↵
    1. MacDonald A,
    2. Brodell JD, Jr,
    3. Daiss JL,
    4. Schwarz EM,
    5. Oh I
    . 2019. Evidence of differential microbiomes in healing versus non-healing diabetic foot ulcers prior to and following foot salvage therapy. J Orthop Res 37:1596–1603. doi:10.1002/jor.24279.
    OpenUrlCrossRef
  55. 55.↵
    1. Hannigan GD,
    2. Hodkinson BP,
    3. McGinnis K,
    4. Tyldsley AS,
    5. Anari JB,
    6. Horan AD,
    7. Grice EA,
    8. Mehta S
    . 2014. Culture-independent pilot study of microbiota colonizing open fractures and association with severity, mechanism, location, and complication from presentation to early outpatient follow-up. J Orthop Res 32:597–605. doi:10.1002/jor.22578.
    OpenUrlCrossRefPubMed
  56. 56.↵
    1. Kalan LR,
    2. Meisel JS,
    3. Loesche MA,
    4. Horwinski J,
    5. Soaita I,
    6. Chen X,
    7. Uberoi A,
    8. Gardner SE,
    9. Grice EA
    . 2019. Strain- and species-level variation in the microbiome of diabetic wounds is associated with clinical outcomes and therapeutic efficacy. Cell Host Microbe 25:641.e5–655.e5. doi:10.1016/j.chom.2019.03.006.
    OpenUrlCrossRef
  57. 57.↵
    1. Wolcott RD,
    2. Hanson JD,
    3. Rees EJ,
    4. Koenig LD,
    5. Phillips CD,
    6. Wolcott RA,
    7. Cox SB,
    8. White JS
    . 2016. Analysis of the chronic wound microbiota of 2,963 patients by 16S rDNA pyrosequencing. Wound Repair Regen 24:163–174. doi:10.1111/wrr.12370.
    OpenUrlCrossRef
  58. 58.↵
    1. Laux C,
    2. Peschel A,
    3. Krismer B
    . 2019. Staphylococcus aureus colonization of the human nose and interaction with other microbiome members. Microbiol Spectr 7:GPP3-0029-2018. doi:10.1128/microbiolspec.GPP3-0029-2018.
    OpenUrlCrossRef
  59. 59.↵
    1. Foster TJ
    . 2019. The MSCRAMM family of cell-wall-anchored surface proteins of Gram-positive cocci. Trends Microbiol 27:927–941. doi:10.1016/j.tim.2019.06.007.
    OpenUrlCrossRef
  60. 60.↵
    1. Tam K,
    2. Torres VJ
    . 2019. Staphylococcus aureus secreted toxins and extracellular enzymes. Microbiol Spectr 7:GPP3-0039-2018. doi:10.1128/microbiolspec.GPP3-0039-2018.
    OpenUrlCrossRef
  61. 61.↵
    1. de Jong NWM,
    2. van Kessel KPM,
    3. van Strijp J
    . 2019. Immune evasion by Staphylococcus aureus. Microbiol Spectr 7:GPP3-0061-2019. doi:10.1128/microbiolspec.GPP3-0061-2019.
    OpenUrlCrossRef
  62. 62.↵
    1. Beroukhim G,
    2. Shah R,
    3. Bucknor MD
    . 2019. Factors predicting positive culture in CT-guided bone biopsy performed for suspected osteomyelitis. AJR Am J Roentgenol 212:620–624. doi:10.2214/AJR.18.20125.
    OpenUrlCrossRef
  63. 63.↵
    1. McNeil JC,
    2. Forbes AR,
    3. Vallejo JG,
    4. Flores AR,
    5. Hulten KG,
    6. Mason EO,
    7. Kaplan SL
    . 2016. Role of operative or interventional radiology-guided cultures for osteomyelitis. Pediatrics 137:e20154616. doi:10.1542/peds.2015-4616.
    OpenUrlAbstract/FREE Full Text
  64. 64.↵
    1. Benvenuti MA,
    2. An TJ,
    3. Mignemi ME,
    4. Martus JE,
    5. Thomsen IP,
    6. Schoenecker JG
    . 2016. Effects of antibiotic timing on culture results and clinical outcomes in pediatric musculoskeletal infection. J Pediatr Orthop 39:158–162. doi:10.1097/BPO.0000000000000884.
    OpenUrlCrossRef
  65. 65.↵
    1. Section J,
    2. Gibbons SD,
    3. Barton T,
    4. Greenberg DE,
    5. Jo CH,
    6. Copley LA
    . 2015. Microbiological culture methods for pediatric musculoskeletal infection: a guideline for optimal use. J Bone Joint Surg Am 97:441–449. doi:10.2106/JBJS.N.00477.
    OpenUrlAbstract/FREE Full Text
  66. 66.↵
    1. Floyed RL,
    2. Steele RW
    . 2003. Culture-negative osteomyelitis. Pediatr Infect Dis J 22:731–736. doi:10.1097/01.inf.0000078901.26909.cf.
    OpenUrlCrossRefPubMedWeb of Science
  67. 67.↵
    1. van der Merwe M,
    2. Rooks K,
    3. Crawford H,
    4. Frampton CMA,
    5. Boyle MJ
    . 2019. The effect of antibiotic timing on culture yield in paediatric osteoarticular infection. J Child Orthop 13:114–119. doi:10.1302/1863-2548.13.180077.
    OpenUrlCrossRef
  68. 68.↵
    1. Zhorne DJ,
    2. Altobelli ME,
    3. Cruz AT
    . 2015. Impact of antibiotic pretreatment on bone biopsy yield for children with acute hematogenous osteomyelitis. Hosp Pediatr 5:337–341. doi:10.1542/hpeds.2014-0114.
    OpenUrlAbstract/FREE Full Text
  69. 69.↵
    1. Spruiell MD,
    2. Searns JB,
    3. Heare TC,
    4. Roberts JL,
    5. Wylie E,
    6. Pyle L,
    7. Donaldson N,
    8. Stewart JR,
    9. Heizer H,
    10. Reese J,
    11. Scott HF,
    12. Pearce K,
    13. Anderson CJ,
    14. Erickson M,
    15. Parker SK
    . 2017. Clinical Care guideline for improving pediatric acute musculoskeletal infection outcomes. J Pediatric Infect Dis Soc 6:e86–e93. doi:10.1093/jpids/pix014.
    OpenUrlCrossRefPubMed
  70. 70.↵
    1. Copley LA,
    2. Kinsler MA,
    3. Gheen T,
    4. Shar A,
    5. Sun D,
    6. Browne R
    . 2013. The impact of evidence-based clinical practice guidelines applied by a multidisciplinary team for the care of children with osteomyelitis. J Bone Joint Surg Am 95:686–693. doi:10.2106/JBJS.L.00037.
    OpenUrlAbstract/FREE Full Text
  71. 71.↵
    1. Copley LA,
    2. Barton T,
    3. Garcia C,
    4. Sun D,
    5. Gaviria-Agudelo C,
    6. Gheen WT,
    7. Browne RH
    . 2014. A proposed scoring system for assessment of severity of illness in pediatric acute hematogenous osteomyelitis using objective clinical and laboratory findings. Pediatr Infect Dis J 33:35–41. doi:10.1097/INF.0000000000000002.
    OpenUrlCrossRefPubMed
  72. 72.↵
    1. Athey AG,
    2. Mignemi ME,
    3. Gheen WT,
    4. Lindsay EA,
    5. Jo CH,
    6. Copley LA
    . 2019. Validation and modification of a severity of illness score for children with acute hematogenous osteomyelitis. J Pediatr Orthop 39:90–97. doi:10.1097/BPO.0000000000000879.
    OpenUrlCrossRef
  73. 73.↵
    1. Mignemi ME,
    2. Benvenuti MA,
    3. An TJ,
    4. Martus JE,
    5. Mencio GA,
    6. Lovejoy SA,
    7. Copley LA,
    8. Williams DJ,
    9. Thomsen IP,
    10. Schoenecker JG
    . 2018. A novel classification system based on dissemination of musculoskeletal infection is predictive of hospital outcomes. J Pediatr Orthop 38:279–286. doi:10.1097/BPO.0000000000000811.
    OpenUrlCrossRef
  74. 74.↵
    1. Thabit AK,
    2. Fatani DF,
    3. Bamakhrama MS,
    4. Barnawi OA,
    5. Basudan LO,
    6. Alhejaili SF
    . 2019. Antibiotic penetration into bone and joints: an updated review. Int J Infect Dis 81:128–136. doi:10.1016/j.ijid.2019.02.005.
    OpenUrlCrossRef
  75. 75.↵
    1. Landersdorfer CB,
    2. Bulitta JB,
    3. Kinzig M,
    4. Holzgrabe U,
    5. Sorgel F
    . 2009. Penetration of antibacterials into bone: pharmacokinetic, pharmacodynamic and bioanalytical considerations. Clin Pharmacokinet 48:89–124. doi:10.2165/00003088-200948020-00002.
    OpenUrlCrossRefPubMedWeb of Science
  76. 76.↵
    1. Ma D,
    2. Mandell JB,
    3. Donegan NP,
    4. Cheung AL,
    5. Ma W,
    6. Rothenberger S,
    7. Shanks RMQ,
    8. Richardson AR,
    9. Urish KL
    . 2019. The toxin-antitoxin MazEF drives Staphylococcus aureus biofilm formation, antibiotic tolerance, and chronic infection. mBio 10:8e01658-19. doi:10.1128/mBio.01658-19.
    OpenUrlCrossRef
  77. 77.↵
    1. Mandell JB,
    2. Orr S,
    3. Koch J,
    4. Nourie B,
    5. Ma D,
    6. Bonar DD,
    7. Shah N,
    8. Urish KL
    . 2019. Large variations in clinical antibiotic activity against Staphylococcus aureus biofilms of periprosthetic joint infection isolates. J Orthop Res 37:1604–1609. doi:10.1002/jor.24291.
    OpenUrlCrossRef
  78. 78.↵
    1. Mandell JB,
    2. Deslouches B,
    3. Montelaro RC,
    4. Shanks RMQ,
    5. Doi Y,
    6. Urish KL
    . 2017. Elimination of antibiotic resistant surgical implant biofilms using an engineered cationic amphipathic peptide WLBU2. Sci Rep 7:18098. doi:10.1038/s41598-017-17780-6.
    OpenUrlCrossRef
  79. 79.↵
    1. Ma D,
    2. Shanks RMQ,
    3. Davis CM, 3rd,
    4. Craft DW,
    5. Wood TK,
    6. Hamlin BR,
    7. Urish KL
    . 2018. Viable bacteria persist on antibiotic spacers following two-stage revision for periprosthetic joint infection. J Orthop Res 36:452–458. doi:10.1002/jor.23611.
    OpenUrlCrossRef
  80. 80.↵
    1. Urish KL,
    2. DeMuth PW,
    3. Kwan BW,
    4. Craft DW,
    5. Ma D,
    6. Haider H,
    7. Tuan RS,
    8. Wood TK,
    9. Davis CM, III
    . 2016. Antibiotic-tolerant Staphylococcus aureus biofilm persists on arthroplasty materials. Clin Orthop Relat Res 474:1649–1656. doi:10.1007/s11999-016-4720-8.
    OpenUrlCrossRef
  81. 81.↵
    1. Cheng AG,
    2. DeDent AC,
    3. Schneewind O,
    4. Missiakas D
    . 2011. A play in four acts: Staphylococcus aureus abscess formation. Trends Microbiol 19:225–232. doi:10.1016/j.tim.2011.01.007.
    OpenUrlCrossRefPubMedWeb of Science
  82. 82.↵
    1. Sutter DE,
    2. Milburn E,
    3. Chukwuma U,
    4. Dzialowy N,
    5. Maranich AM,
    6. Hospenthal DR
    . 2016. Changing susceptibility of Staphylococcus aureus in a US pediatric population. Pediatrics 137:e20153099. doi:10.1542/peds.2015-3099.
    OpenUrlAbstract/FREE Full Text
  83. 83.↵
    1. Liu C,
    2. Bayer A,
    3. Cosgrove SE,
    4. Daum RS,
    5. Fridkin SK,
    6. Gorwitz RJ,
    7. Kaplan SL,
    8. Karchmer AW,
    9. Levine DP,
    10. Murray BE,
    11. M JR,
    12. Talan DA,
    13. Chambers HF
    , Infectious Diseases Society of America. 2011. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 52:e18–e55. doi:10.1093/cid/ciq146.
    OpenUrlCrossRefPubMedWeb of Science
  84. 84.↵
    1. Berbari EF,
    2. Kanj SS,
    3. Kowalski TJ,
    4. Darouiche RO,
    5. Widmer AF,
    6. Schmitt SK,
    7. Hendershot EF,
    8. Holtom PD,
    9. Huddleston PM, III,
    10. Petermann GW,
    11. Osmon DR
    , Infectious Diseases Society of America. 2015. 2015 Infectious Diseases Society of America (IDSA) clinical practice guidelines for the diagnosis and treatment of native vertebral osteomyelitis in adults. Clin Infect Dis 61:e26–e46. doi:10.1093/cid/civ482.
    OpenUrlCrossRefPubMed
  85. 85.↵
    1. Lipsky BA,
    2. Berendt AR,
    3. Cornia PB,
    4. Pile JC,
    5. Peters EJ,
    6. Armstrong DG,
    7. Deery HG,
    8. Embil JM,
    9. Joseph WS,
    10. Karchmer AW,
    11. Pinzur MS,
    12. Senneville E
    , Infectious Diseases Society of America. 2012. 2012 Infectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Clin Infect Dis 54:e132–e173. doi:10.1093/cid/cis346.
    OpenUrlCrossRefPubMed
  86. 86.↵
    1. Saavedra-Lozano J,
    2. Falup-Pecurariu O,
    3. Faust SN,
    4. Girschick H,
    5. Hartwig N,
    6. Kaplan S,
    7. Lorrot M,
    8. Mantadakis E,
    9. Peltola H,
    10. Rojo P,
    11. Zaoutis T,
    12. LeMair A
    . 2017. Bone and joint infections. Pediatr Infect Dis J 36:788–799. doi:10.1097/INF.0000000000001635.
    OpenUrlCrossRef
  87. 87.↵
    1. Wood JB,
    2. Johnson DP
    . 2016. Prolonged intravenous instead of oral antibiotics for acute hematogenous osteomyelitis in children. J Hosp Med 11:505–508. doi:10.1002/jhm.2549.
    OpenUrlCrossRef
  88. 88.↵
    1. Peltola H,
    2. Unkila-Kallio L,
    3. Kallio MJ
    . 1997. Simplified treatment of acute staphylococcal osteomyelitis of childhood. The Finnish study group. Pediatrics 99:846–850. doi:10.1542/peds.99.6.846.
    OpenUrlAbstract/FREE Full Text
  89. 89.↵
    1. LaMont RL,
    2. Anderson PA,
    3. Dajani AS,
    4. Thirumoorthi MC
    . 1987. Acute hematogenous osteomyelitis in children. J Pediatr Orthop 7:579–583. doi:10.1097/01241398-198709000-00015.
    OpenUrlCrossRefPubMedWeb of Science
  90. 90.↵
    1. Anglen JO
    . 2001. Wound irrigation in musculoskeletal injury. J Am Acad Orthop Surg 9:219–226. doi:10.5435/00124635-200107000-00001.
    OpenUrlCrossRefPubMed
  91. 91.↵
    1. Gustilo RB,
    2. Merkow RL,
    3. Templeman D
    . 1990. The management of open fractures. J Bone Joint Surg Am 72:299–304. doi:10.2106/00004623-199072020-00023.
    OpenUrlFREE Full Text
  92. 92.↵
    1. Mundi R,
    2. Chaudhry H,
    3. Niroopan G,
    4. Petrisor B,
    5. Bhandari M
    . 2015. Open tibial fractures: updated guidelines for management. JBJS Rev 3:01874474-201503020-00003. doi:10.2106/JBJS.RVW.N.00051.
    OpenUrlCrossRef
  93. 93.↵
    1. Pape HC,
    2. Tornetta P, III,
    3. Tarkin I,
    4. Tzioupis C,
    5. Sabeson V,
    6. Olson SA
    . 2009. Timing of fracture fixation in multitrauma patients: the role of early total care and damage control surgery. J Am Acad Orthop Surg 17:541–549. doi:10.5435/00124635-200909000-00001.
    OpenUrlCrossRefPubMed
  94. 94.↵
    1. Pape HC,
    2. Halvachizadeh S,
    3. Leenen L,
    4. Velmahos GD,
    5. Buckley R,
    6. Giannoudis PV
    . 2019. Timing of major fracture care in polytrauma patients - an update on principles, parameters and strategies for 2020. Injury 50:1656–1670. doi:10.1016/j.injury.2019.09.021.
    OpenUrlCrossRef
  95. 95.↵
    1. Urish KL,
    2. DeMuth PW,
    3. Craft DW,
    4. Haider H,
    5. Davis CM, III
    . 2014. Pulse lavage is inadequate at removal of biofilm from the surface of total knee arthroplasty materials. J Arthroplasty 29:1128–1132. doi:10.1016/j.arth.2013.12.012.
    OpenUrlCrossRefPubMed
  96. 96.↵
    1. Slane J,
    2. Gietman B,
    3. Squire M
    . 2018. Antibiotic elution from acrylic bone cement loaded with high doses of tobramycin and vancomycin. J Orthop Res 36:1078–1085. doi:10.1002/jor.23722.
    OpenUrlCrossRef
  97. 97.↵
    1. Stevens CM,
    2. Tetsworth KD,
    3. Calhoun JH,
    4. Mader JT
    . 2005. An articulated antibiotic spacer used for infected total knee arthroplasty: a comparative in vitro elution study of Simplex and Palacos bone cements. J Orthop Res 23:27–33. doi:10.1016/j.orthres.2004.03.003.
    OpenUrlCrossRefPubMedWeb of Science
  98. 98.↵
    1. Masters EA,
    2. Trombetta RP,
    3. de Mesy Bentley KL,
    4. Boyce BF,
    5. Gill AL,
    6. Gill SR,
    7. Nishitani K,
    8. Ishikawa M,
    9. Morita Y,
    10. Ito H,
    11. Bello-Irizarry SN,
    12. Ninomiya M,
    13. Brodell JD, Jr,
    14. Lee CC,
    15. Hao SP,
    16. Oh I,
    17. Xie C,
    18. Awad HA,
    19. Daiss JL,
    20. Owen JR,
    21. Kates SL,
    22. Schwarz EM,
    23. Muthukrishnan G
    . 2019. Evolving concepts in bone infection: redefining “biofilm”, “acute vs. chronic osteomyelitis”, “the immune proteome” and “local antibiotic therapy. Bone Res 7:20. doi:10.1038/s41413-019-0061-z.
    OpenUrlCrossRef
  99. 99.↵
    1. Cassat JE,
    2. Skaar EP
    . 2013. Recent advances in experimental models of osteomyelitis. Expert Rev Anti Infect Ther 11:1263–1265. doi:10.1586/14787210.2013.858600.
    OpenUrlCrossRefPubMed
  100. 100.↵
    1. Wang Y,
    2. Cheng LI,
    3. Helfer DR,
    4. Ashbaugh AG,
    5. Miller RJ,
    6. Tzomides AJ,
    7. Thompson JM,
    8. Ortines RV,
    9. Tsai AS,
    10. Liu H,
    11. Dillen CA,
    12. Archer NK,
    13. Cohen TS,
    14. Tkaczyk C,
    15. Stover CK,
    16. Sellman BR,
    17. Miller LS
    . 2017. Mouse model of hematogenous implant-related Staphylococcus aureus biofilm infection reveals therapeutic targets. Proc Natl Acad Sci U S A 114:E5094–E5102. doi:10.1073/pnas.1703427114.
    OpenUrlAbstract/FREE Full Text
  101. 101.↵
    1. Shiels SM,
    2. Bedigrew KM,
    3. Wenke JC
    . 2015. Development of a hematogenous implant-related infection in a rat model. BMC Musculoskelet Disord 16:255. doi:10.1186/s12891-015-0699-7.
    OpenUrlCrossRef
  102. 102.↵
    1. Poultsides LA,
    2. Papatheodorou LK,
    3. Karachalios TS,
    4. Khaldi L,
    5. Maniatis A,
    6. Petinaki E,
    7. Malizos KN
    . 2008. Novel model for studying hematogenous infection in an experimental setting of implant-related infection by a community-acquired methicillin-resistant S. aureus strain. J Orthop Res 26:1355–1362. doi:10.1002/jor.20608.
    OpenUrlCrossRefPubMedWeb of Science
  103. 103.↵
    1. Horst SA,
    2. Hoerr V,
    3. Beineke A,
    4. Kreis C,
    5. Tuchscherr L,
    6. Kalinka J,
    7. Lehne S,
    8. Schleicher I,
    9. Kohler G,
    10. Fuchs T,
    11. Raschke MJ,
    12. Rohde M,
    13. Peters G,
    14. Faber C,
    15. Loffler B,
    16. Medina E
    . 2012. A novel mouse model of Staphylococcus aureus chronic osteomyelitis that closely mimics the human infection: an integrated view of disease pathogenesis. Am J Pathol 181:1206–1214. doi:10.1016/j.ajpath.2012.07.005.
    OpenUrlCrossRefPubMed
  104. 104.↵
    1. Richardson AR
    . 2019. Virulence and metabolism. Microbiol Spectr 7:GPP3-0011-2018. doi:10.1128/microbiolspec.GPP3-0011-2018.
    OpenUrlCrossRef
  105. 105.↵
    1. Elasri MO,
    2. Thomas JR,
    3. Skinner RA,
    4. Blevins JS,
    5. Beenken KE,
    6. Nelson CL,
    7. Smeltzer MS
    . 2002. Staphylococcus aureus collagen adhesin contributes to the pathogenesis of osteomyelitis. Bone 30:275–280. doi:10.1016/s8756-3282(01)00632-9.
    OpenUrlCrossRefPubMedWeb of Science
  106. 106.↵
    1. Smeltzer MS,
    2. Gillaspy AF
    . 2000. Molecular pathogenesis of staphylococcal osteomyelitis. Poult Sci 79:1042–1049. doi:10.1093/ps/79.7.1042.
    OpenUrlCrossRefPubMed
  107. 107.↵
    1. Patti JM,
    2. Jonsson H,
    3. Guss B,
    4. Switalski LM,
    5. Wiberg K,
    6. Lindberg M,
    7. Hook M
    . 1992. Molecular characterization and expression of a gene encoding a Staphylococcus aureus collagen adhesin. J Biol Chem 267:4766–4772.
    OpenUrlAbstract/FREE Full Text
  108. 108.↵
    1. Thomas MG,
    2. Peacock S,
    3. Daenke S,
    4. Berendt AR
    . 1999. Adhesion of Staphylococcus aureus to collagen is not a major virulence determinant for septic arthritis, osteomyelitis, or endocarditis. J Infect Dis 179:291–293. doi:10.1086/314576.
    OpenUrlCrossRefPubMedWeb of Science
  109. 109.↵
    1. Farnsworth CW,
    2. Schott EM,
    3. Jensen SE,
    4. Zukoski J,
    5. Benvie AM,
    6. Refaai MA,
    7. Kates SL,
    8. Schwarz EM,
    9. Zuscik MJ,
    10. Gill SR,
    11. Mooney RA
    . 2017. Adaptive upregulation of clumping factor A (ClfA) by Staphylococcus aureus in the obese, type 2 diabetic host mediates increased virulence. Infect Immun 85:e01005-16. doi:10.1128/IAI.01005-16.
    OpenUrlAbstract/FREE Full Text
  110. 110.↵
    1. Ryden C,
    2. Yacoub AI,
    3. Maxe I,
    4. Heinegard D,
    5. Oldberg A,
    6. Franzen A,
    7. Ljungh A,
    8. Rubin K
    . 1989. Specific binding of bone sialoprotein to Staphylococcus aureus isolated from patients with osteomyelitis. Eur J Biochem 184:331–336. doi:10.1111/j.1432-1033.1989.tb15023.x.
    OpenUrlCrossRefPubMedWeb of Science
  111. 111.↵
    1. Ryden C,
    2. Maxe I,
    3. Franzen A,
    4. Ljungh A,
    5. Heinegard D,
    6. Rubin K
    . 1987. Selective binding of bone matrix sialoprotein to Staphylococcus aureus in osteomyelitis. Lancet 2:515. doi:10.1016/s0140-6736(87)91830-7.
    OpenUrlCrossRefPubMed
  112. 112.↵
    1. Yacoub A,
    2. Lindahl P,
    3. Rubin K,
    4. Wendel M,
    5. Heinegard D,
    6. Ryden C
    . 1994. Purification of a bone sialoprotein-binding protein from Staphylococcus aureus. Eur J Biochem 222:919–925. doi:10.1111/j.1432-1033.1994.tb18940.x.
    OpenUrlCrossRefPubMedWeb of Science
  113. 113.↵
    1. McGavin MH,
    2. Krajewska-Pietrasik D,
    3. Rydén C,
    4. Höök M
    . 1993. Identification of a Staphylococcus aureus extracellular matrix-binding protein with broad specificity. Infect Immun 61:2479–2485. doi:10.1128/IAI.61.6.2479-2485.1993.
    OpenUrlAbstract/FREE Full Text
  114. 114.↵
    1. Persson L,
    2. Johansson C,
    3. Ryden C
    . 2009. Antibodies to Staphylococcus aureus bone sialoprotein-binding protein indicate infectious osteomyelitis. Clin Vaccine Immunol 16:949–952. doi:10.1128/CVI.00442-08.
    OpenUrlAbstract/FREE Full Text
  115. 115.↵
    1. Loughran AJ,
    2. Gaddy D,
    3. Beenken KE,
    4. Meeker DG,
    5. Morello R,
    6. Zhao H,
    7. Byrum SD,
    8. Tackett AJ,
    9. Cassat JE,
    10. Smeltzer MS
    . 2016. Impact of sarA and phenol-soluble modulins on the pathogenesis of osteomyelitis in diverse clinical isolates of Staphylococcus aureus. Infect Immun 84:2586–2594. doi:10.1128/IAI.00152-16.
    OpenUrlAbstract/FREE Full Text
  116. 116.↵
    1. Cassat JE,
    2. Hammer ND,
    3. Campbell JP,
    4. Benson MA,
    5. Perrien DS,
    6. Mrak LN,
    7. Smeltzer MS,
    8. Torres VJ,
    9. Skaar EP
    . 2013. A secreted bacterial protease tailors the Staphylococcus aureus virulence repertoire to modulate bone remodeling during osteomyelitis. Cell Host Microbe 13:759–772. doi:10.1016/j.chom.2013.05.003.
    OpenUrlCrossRefPubMedWeb of Science
  117. 117.↵
    1. Rasigade JP,
    2. Trouillet-Assant S,
    3. Ferry T,
    4. Diep BA,
    5. Sapin A,
    6. Lhoste Y,
    7. Ranfaing J,
    8. Badiou C,
    9. Benito Y,
    10. Bes M,
    11. Couzon F,
    12. Tigaud S,
    13. Lina G,
    14. Etienne J,
    15. Vandenesch F,
    16. Laurent F
    . 2013. PSMs of hypervirulent Staphylococcus aureus act as intracellular toxins that kill infected osteoblasts. PLoS One 8:e63176. doi:10.1371/journal.pone.0063176.
    OpenUrlCrossRefPubMed
  118. 118.↵
    1. Cremieux AC,
    2. Saleh-Mghir A,
    3. Danel C,
    4. Couzon F,
    5. Dumitrescu O,
    6. Lilin T,
    7. Perronne C,
    8. Etienne J,
    9. Lina G,
    10. Vandenesch F
    . 2014. α-Hemolysin, not Panton-Valentine leukocidin, impacts rabbit mortality from severe sepsis with methicillin-resistant Staphylococcus aureus osteomyelitis. J Infect Dis 209:1773–1780. doi:10.1093/infdis/jit840.
    OpenUrlCrossRefPubMed
  119. 119.↵
    1. Spaan AN,
    2. van Strijp JAG,
    3. Torres VJ
    . 2017. Leukocidins: staphylococcal bi-component pore-forming toxins find their receptors. Nat Rev Microbiol 15:435–447. doi:10.1038/nrmicro.2017.27.
    OpenUrlCrossRefPubMed
  120. 120.↵
    1. Bocchini CE,
    2. Hulten KG,
    3. Mason EO, Jr,
    4. Gonzalez BE,
    5. Hammerman WA,
    6. Kaplan SL
    . 2006. Panton-Valentine leukocidin genes are associated with enhanced inflammatory response and local disease in acute hematogenous Staphylococcus aureus osteomyelitis in children. Pediatrics 117:433–440. doi:10.1542/peds.2005-0566.
    OpenUrlAbstract/FREE Full Text
  121. 121.↵
    1. Wood JB,
    2. Jones LS,
    3. Soper NR,
    4. Xu M,
    5. Torres VJ,
    6. Buddy Creech C,
    7. Thomsen IP
    . 2019. Serologic detection of antibodies targeting the leukocidin LukAB strongly predicts Staphylococcus aureus in children with invasive infection. J Pediatric Infect Dis Soc 8:128–135. doi:10.1093/jpids/piy017.
    OpenUrlCrossRef
  122. 122.↵
    1. Thomsen IP,
    2. Sapparapu G,
    3. James DBA,
    4. Cassat JE,
    5. Nagarsheth M,
    6. Kose N,
    7. Putnam N,
    8. Boguslawski KM,
    9. Jones LS,
    10. Wood JB,
    11. Creech CB,
    12. Torres VJ,
    13. Crowe JE, Jr
    . 2017. Monoclonal antibodies against the Staphylococcus aureus bicomponent leukotoxin AB isolated following invasive human infection reveal diverse binding and modes of action. J Infect Dis 215:1124–1131. doi:10.1093/infdis/jix071.
    OpenUrlCrossRef
  123. 123.↵
    1. Missiakas D,
    2. Schneewind O
    . 2016. Staphylococcus aureus vaccines: deviating from the carol. J Exp Med 213:1645–1653. doi:10.1084/jem.20160569.
    OpenUrlAbstract/FREE Full Text
  124. 124.↵
    1. Kim HK,
    2. Falugi F,
    3. Missiakas DM,
    4. Schneewind O
    . 2016. Peptidoglycan-linked protein A promotes T cell-dependent antibody expansion during Staphylococcus aureus infection. Proc Natl Acad Sci U S A 113:5718–5723. doi:10.1073/pnas.1524267113.
    OpenUrlAbstract/FREE Full Text
  125. 125.↵
    1. Pauli NT,
    2. Kim HK,
    3. Falugi F,
    4. Huang M,
    5. Dulac J,
    6. Henry Dunand C,
    7. Zheng NY,
    8. Kaur K,
    9. Andrews SF,
    10. Huang Y,
    11. DeDent A,
    12. Frank KM,
    13. Charnot-Katsikas A,
    14. Schneewind O,
    15. Wilson PC
    . 2014. Staphylococcus aureus infection induces protein A-mediated immune evasion in humans. J Exp Med 211:2331–2339. doi:10.1084/jem.20141404.
    OpenUrlAbstract/FREE Full Text
  126. 126.↵
    1. Claro T,
    2. Widaa A,
    3. McDonnell C,
    4. Foster TJ,
    5. O'Brien FJ,
    6. Kerrigan SW
    . 2013. Staphylococcus aureus protein A binding to osteoblast tumour necrosis factor receptor 1 results in activation of nuclear factor kappa B and release of interleukin-6 in bone infection. Microbiology 159:147–154. doi:10.1099/mic.0.063016-0.
    OpenUrlCrossRefPubMedWeb of Science
  127. 127.↵
    1. Widaa A,
    2. Claro T,
    3. Foster TJ,
    4. O'Brien FJ,
    5. Kerrigan SW
    . 2012. Staphylococcus aureus protein A plays a critical role in mediating bone destruction and bone loss in osteomyelitis. PLoS One 7:e40586. doi:10.1371/journal.pone.0040586.
    OpenUrlCrossRefPubMed
  128. 128.↵
    1. Claro T,
    2. Widaa A,
    3. O'Seaghdha M,
    4. Miajlovic H,
    5. Foster TJ,
    6. O'Brien FJ,
    7. Kerrigan SW
    . 2011. Staphylococcus aureus protein A binds to osteoblasts and triggers signals that weaken bone in osteomyelitis. PLoS One 6:e18748. doi:10.1371/journal.pone.0018748.
    OpenUrlCrossRefPubMed
  129. 129.↵
    1. Mendoza Bertelli A,
    2. Delpino MV,
    3. Lattar S,
    4. Giai C,
    5. Llana MN,
    6. Sanjuan N,
    7. Cassat JE,
    8. Sordelli D,
    9. Gómez MI
    . 2016. Staphylococcus aureus protein A enhances osteoclastogenesis via TNFR1 and EGFR signaling. Biochim Biophys Acta 1862:1975–1983. doi:10.1016/j.bbadis.2016.07.016.
    OpenUrlCrossRef
  130. 130.↵
    1. Lee LY,
    2. Miyamoto YJ,
    3. McIntyre BW,
    4. Hook M,
    5. McCrea KW,
    6. McDevitt D,
    7. Brown EL
    . 2002. The Staphylococcus aureus Map protein is an immunomodulator that interferes with T cell-mediated responses. J Clin Invest 110:1461–1471. doi:10.1172/JCI0216318.
    OpenUrlCrossRefPubMedWeb of Science
  131. 131.↵
    1. Gillaspy AF,
    2. Hickmon SG,
    3. Skinner RA,
    4. Thomas JR,
    5. Nelson CL,
    6. Smeltzer MS
    . 1995. Role of the accessory gene regulator (agr) in pathogenesis of staphylococcal osteomyelitis. Infect Immun 63:3373–3380. doi:10.1128/IAI.63.9.3373-3380.1995.
    OpenUrlAbstract/FREE Full Text
  132. 132.↵
    1. Hendrix AS,
    2. Spoonmore TJ,
    3. Wilde AD,
    4. Putnam NE,
    5. Hammer ND,
    6. Snyder DJ,
    7. Guelcher SA,
    8. Skaar EP,
    9. Cassat JE
    . 2016. Repurposing the nonsteroidal anti-inflammatory drug diflunisal as an osteoprotective, antivirulence therapy for Staphylococcus aureus osteomyelitis. Antimicrob Agents Chemother 60:5322–5330. doi:10.1128/AAC.00834-16.
    OpenUrlAbstract/FREE Full Text
  133. 133.↵
    1. Wilde AD,
    2. Snyder DJ,
    3. Putnam NE,
    4. Valentino MD,
    5. Hammer ND,
    6. Lonergan ZR,
    7. Hinger SA,
    8. Aysanoa EE,
    9. Blanchard C,
    10. Dunman PM,
    11. Wasserman GA,
    12. Chen J,
    13. Shopsin B,
    14. Gilmore MS,
    15. Skaar EP,
    16. Cassat JE
    . 2015. Bacterial hypoxic responses revealed as critical determinants of the host-pathogen outcome by TnSeq analysis of Staphylococcus aureus invasive infection. PLoS Pathog 11:e1005341. doi:10.1371/journal.ppat.1005341.
    OpenUrlCrossRefPubMed
  134. 134.↵
    1. Queck SY,
    2. Jameson-Lee M,
    3. Villaruz AE,
    4. Bach TH,
    5. Khan BA,
    6. Sturdevant DE,
    7. Ricklefs SM,
    8. Li M,
    9. Otto M
    . 2008. RNAIII-independent target gene control by the agr quorum-sensing system: insight into the evolution of virulence regulation in Staphylococcus aureus. Mol Cell 32:150–158. doi:10.1016/j.molcel.2008.08.005.
    OpenUrlCrossRefPubMedWeb of Science
  135. 135.↵
    1. Suligoy CM,
    2. Lattar SM,
    3. Noto Llana M,
    4. Gonzalez CD,
    5. Alvarez LP,
    6. Robinson DA,
    7. Gomez MI,
    8. Buzzola FR,
    9. Sordelli DO
    . 2018. Mutation of Agr is associated with the adaptation of Staphylococcus aureus to the host during chronic osteomyelitis. Front Cell Infect Microbiol 8:18. doi:10.3389/fcimb.2018.00018.
    OpenUrlCrossRef
  136. 136.↵
    1. Shopsin B,
    2. Drlica-Wagner A,
    3. Mathema B,
    4. Adhikari RP,
    5. Kreiswirth BN,
    6. Novick RP
    . 2008. Prevalence of agr dysfunction among colonizing Staphylococcus aureus strains. J Infect Dis 198:1171–1174. doi:10.1086/592051.
    OpenUrlCrossRefPubMedWeb of Science
  137. 137.↵
    1. Ramirez AM,
    2. Byrum SD,
    3. Beenken KE,
    4. Washam C,
    5. Edmondson RD,
    6. Mackintosh SG,
    7. Spencer HJ,
    8. Tackett AJ,
    9. Smeltzer MS
    . 2019. Exploiting correlations between protein abundance and the functional status of saeRS and sarA to identify virulence factors of potential importance in the pathogenesis of Staphylococcus aureus osteomyelitis. ACS Infect Dis 6:237–249. doi:10.1021/acsinfecdis.9b00291.
    OpenUrlCrossRef
  138. 138.↵
    1. Blevins JS,
    2. Elasri MO,
    3. Allmendinger SD,
    4. Beenken KE,
    5. Skinner RA,
    6. Thomas JR,
    7. Smeltzer MS
    . 2003. Role of sarA in the pathogenesis of Staphylococcus aureus musculoskeletal infection. Infect Immun 71:516–523. doi:10.1128/iai.71.1.516-523.2003.
    OpenUrlAbstract/FREE Full Text
  139. 139.↵
    1. Rom JS,
    2. Atwood DN,
    3. Beenken KE,
    4. Meeker DG,
    5. Loughran AJ,
    6. Spencer HJ,
    7. Lantz TL,
    8. Smeltzer MS
    . 2017. Impact of Staphylococcus aureus regulatory mutations that modulate biofilm formation in the USA300 strain LAC on virulence in a murine bacteremia model. Virulence 8:1776–1790. doi:10.1080/21505594.2017.1373926.
    OpenUrlCrossRef
  140. 140.↵
    1. Kolar SL,
    2. Ibarra JA,
    3. Rivera FE,
    4. Mootz JM,
    5. Davenport JE,
    6. Stevens SM,
    7. Horswill AR,
    8. Shaw LN
    . 2013. Extracellular proteases are key mediators of Staphylococcus aureus virulence via the global modulation of virulence-determinant stability. Microbiologyopen 2:18–34. doi:10.1002/mbo3.55.
    OpenUrlCrossRefPubMedWeb of Science
  141. 141.↵
    1. Zielinska AK,
    2. Beenken KE,
    3. Mrak LN,
    4. Spencer HJ,
    5. Post GR,
    6. Skinner RA,
    7. Tackett AJ,
    8. Horswill AR,
    9. Smeltzer MS
    . 2012. sarA-mediated repression of protease production plays a key role in the pathogenesis of Staphylococcus aureus USA300 isolates. Mol Microbiol 86:1183–1196. doi:10.1111/mmi.12048.
    OpenUrlCrossRefPubMed
  142. 142.↵
    1. Brandt SL,
    2. Putnam NE,
    3. Cassat JE,
    4. Serezani CH
    . 2018. Innate immunity to Staphylococcus aureus: evolving paradigms in soft tissue and invasive infections. J Immunol 200:3871–3880. doi:10.4049/jimmunol.1701574.
    OpenUrlAbstract/FREE Full Text
  143. 143.↵
    1. Mbalaviele G,
    2. Novack DV,
    3. Schett G,
    4. Teitelbaum SL
    . 2017. Inflammatory osteolysis: a conspiracy against bone. J Clin Invest 127:2030–2039. doi:10.1172/JCI93356.
    OpenUrlCrossRefPubMed
  144. 144.↵
    1. Putnam NE,
    2. Fulbright LE,
    3. Curry JM,
    4. Ford CA,
    5. Petronglo JR,
    6. Hendrix AS,
    7. Cassat JE
    . 2019. MyD88 and IL-1R signaling drive antibacterial immunity and osteoclast-driven bone loss during Staphylococcus aureus osteomyelitis. PLoS Pathog 15:e1007744. doi:10.1371/journal.ppat.1007744.
    OpenUrlCrossRefPubMed
  145. 145.↵
    1. Bernthal NM,
    2. Pribaz JR,
    3. Stavrakis AI,
    4. Billi F,
    5. Cho JS,
    6. Ramos RI,
    7. Francis KP,
    8. Iwakura Y,
    9. Miller LS
    . 2011. Protective role of IL-1beta against post-arthroplasty Staphylococcus aureus infection. J Orthop Res 29:1621–1626. doi:10.1002/jor.21414.
    OpenUrlCrossRefPubMed
  146. 146.↵
    1. Dewhirst FE,
    2. Stashenko PP,
    3. Mole JE,
    4. Tsurumachi T
    . 1985. Purification and partial sequence of human osteoclast-activating factor: identity with interleukin 1 beta. J Immunol 135:2562–2568.
    OpenUrlAbstract
  147. 147.↵
    1. Zhu X,
    2. Zhang K,
    3. Lu K,
    4. Shi T,
    5. Shen S,
    6. Chen X,
    7. Dong J,
    8. Gong W,
    9. Bao Z,
    10. Shi Y,
    11. Ma Y,
    12. Teng H,
    13. Jiang Q
    . 2019. Inhibition of pyroptosis attenuates Staphylococcus aureus-induced bone injury in traumatic osteomyelitis. Ann Transl Med 7:170. doi:10.21037/atm.2019.03.40.
    OpenUrlCrossRef
  148. 148.↵
    1. Krauss JL,
    2. Roper PM,
    3. Ballard A,
    4. Shih CC,
    5. Fitzpatrick JAJ,
    6. Cassat JE,
    7. Ng PY,
    8. Pavlos NJ,
    9. Veis DJ
    . 2019. Staphylococcus aureus infects osteoclasts and replicates intracellularly. mBio 10:e02447-19. doi:10.1128/mBio.02447-19.
    OpenUrlAbstract/FREE Full Text
  149. 149.↵
    1. Yang D,
    2. Wijenayaka AR,
    3. Solomon LB,
    4. Pederson SM,
    5. Findlay DM,
    6. Kidd SP,
    7. Atkins GJ
    . 2018. Novel insights into Staphylococcus aureus deep bone infections: the involvement of osteocytes. mBio 9:e00415-18. doi:10.1128/mBio.00415-18.
    OpenUrlAbstract/FREE Full Text
  150. 150.↵
    1. Josse J,
    2. Velard F,
    3. Gangloff SC
    . 2015. Staphylococcus aureus vs. osteoblast: relationship and consequences in osteomyelitis. Front Cell Infect Microbiol 5:85. doi:10.3389/fcimb.2015.00085.
    OpenUrlCrossRef
  151. 151.↵
    1. Trouillet-Assant S,
    2. Gallet M,
    3. Nauroy P,
    4. Rasigade JP,
    5. Flammier S,
    6. Parroche P,
    7. Marvel J,
    8. Ferry T,
    9. Vandenesch F,
    10. Jurdic P,
    11. Laurent F
    . 2015. Dual impact of live Staphylococcus aureus on the osteoclast lineage, leading to increased bone resorption. J Infect Dis 211:571–581. doi:10.1093/infdis/jiu386.
    OpenUrlCrossRefPubMed
  152. 152.↵
    1. Radlinski L,
    2. Conlon BP
    . 2018. Antibiotic efficacy in the complex infection environment. Curr Opin Microbiol 42:19–24. doi:10.1016/j.mib.2017.09.007.
    OpenUrlCrossRef
  153. 153.↵
    1. Ford CA,
    2. Cassat JE
    . 2017. Advances in the local and targeted delivery of anti-infective agents for management of osteomyelitis. Expert Rev Anti Infect Ther 15:851–860. doi:10.1080/14787210.2017.1372192.
    OpenUrlCrossRef
  154. 154.↵
    1. Muthukrishnan G,
    2. Masters EA,
    3. Daiss JL,
    4. Schwarz EM
    . 2019. Mechanisms of immune evasion and bone tissue colonization that make Staphylococcus aureus the primary pathogen in osteomyelitis. Curr Osteoporos Rep 17:395–404. doi:10.1007/s11914-019-00548-4.
    OpenUrlCrossRef
  155. 155.↵
    1. de Mesy Bentley KL,
    2. MacDonald A,
    3. Schwarz EM,
    4. Oh I
    . 2018. Chronic osteomyelitis with Staphylococcus aureus deformation in submicron canaliculi of osteocytes: a case report. JBJS Case Connect 8:e8. doi:10.2106/JBJS.CC.17.00154.
    OpenUrlCrossRef
  156. 156.↵
    1. Blom A,
    2. Cho J,
    3. Fleischman A,
    4. Goswami K,
    5. Ketonis C,
    6. Kunutsor SK,
    7. Makar G,
    8. Meeker DG,
    9. Morgan-Jones R,
    10. Ortega-Pena S,
    11. Parvizi J,
    12. Smeltzer M,
    13. Stambough JB,
    14. Urish K,
    15. Ziliotto G
    . 2019. General assembly, prevention, antiseptic irrigation solution: proceedings of international consensus on orthopedic infections. J Arthroplasty 34:S131–S138. doi:10.1016/j.arth.2018.09.063.
    OpenUrlCrossRef
  157. 157.↵
    1. Saeed K,
    2. McLaren AC,
    3. Schwarz EM,
    4. Antoci V,
    5. Arnold WV,
    6. Chen AF,
    7. Clauss M,
    8. Esteban J,
    9. Gant V,
    10. Hendershot E,
    11. Hickok N,
    12. Higuera CA,
    13. Coraça-Huber DC,
    14. Choe H,
    15. Jennings JA,
    16. Joshi M,
    17. Li WT,
    18. Noble PC,
    19. Phillips KS,
    20. Pottinger PS,
    21. Restrepo C,
    22. Rohde H,
    23. Schaer TP,
    24. Shen H,
    25. Smeltzer M,
    26. Stoodley P,
    27. Webb JCJ,
    28. Witsø E
    . 2019. 2018 International Consensus Meeting on Musculoskeletal Infection: summary from the biofilm workgroup and consensus on biofilm related musculoskeletal infections. J Orthop Res 37:1007–1017. doi:10.1002/jor.24229.
    OpenUrlCrossRef
  158. 158.↵
    1. Cooper AM,
    2. Shope AJ,
    3. Javid M,
    4. Parsa A,
    5. Chinoy MA,
    6. Parvizi J
    . 2019. Musculoskeletal infection in pediatrics: assessment of the 2018 International Consensus Meeting on Musculoskeletal Infection. J Bone Joint Surg Am 101:e133. doi:10.2106/JBJS.19.00572.
    OpenUrlCrossRef

Author Bios


Embedded Image

Kenneth L. Urish, M.D., Ph.D., is an Assistant Professor at the University of Pittsburgh Department of Orthopaedic Surgery. He is Director of the Arthritis and Arthroplasty Design Laboratory. Funded by the National Institutes of Health, the group’s focus is on translational research in surgical infection. He has developed a particular interest in investigating biofilm dynamics during the infection process, including antibiotic tolerance. He is a principle investigator in a series of prospective clinical studies and involved with a series of FDA studies investigating new antibiotic and delivery devices. As an Associate Medical Director at the Magee Bone and Joint Center, his clinical practice focuses on primary and revision hip and knee arthroplasty. He has developed a strong expertise in the treatment of periprosthetic joint infection. He completed his residency at the Penn State Hershey Medical Center and fellowship at the Massachusetts General Hospital and Harvard Medical School.


Embedded Image

James E. Cassat received his M.D. and Ph.D. degrees from the University of Arkansas for Medical Sciences, where his doctoral work in Dr. Mark Smeltzer’s laboratory focused on comparative genomics and transcriptional profiling of Staphylococcus aureus. He then completed a residency in pediatrics and a fellowship in pediatric infectious diseases at Vanderbilt University Medical Center. Dr. Cassat’s postdoctoral research in the laboratory of Dr. Eric Skaar examined the bacterial virulence factors used by S. aureus to colonize and destroy bone. In 2014, Dr. Cassat joined the Vanderbilt faculty as an Assistant Professor in the Departments of Pediatrics, BME, and Pathology, Microbiology, and Immunology, where his lab studies host-pathogen interactions during osteomyelitis and how infection, inflammation, and the microbiome alter musculoskeletal cell biology. Dr. Cassat also serves as an Associate Director of the Vanderbilt Institute for Infection, Immunology, and Inflammation (VI4) and is a core faculty member of the Vanderbilt Center for Bone Biology.

View Abstract
PreviousNext
Back to top
Download PDF
Citation Tools
Staphylococcus aureus Osteomyelitis: Bone, Bugs, and Surgery
Kenneth L. Urish, James E. Cassat
Infection and Immunity Jun 2020, 88 (7) e00932-19; DOI: 10.1128/IAI.00932-19

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Print

Alerts
Sign In to Email Alerts with your Email Address
Email

Thank you for sharing this Infection and Immunity article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Staphylococcus aureus Osteomyelitis: Bone, Bugs, and Surgery
(Your Name) has forwarded a page to you from Infection and Immunity
(Your Name) thought you would be interested in this article in Infection and Immunity.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Staphylococcus aureus Osteomyelitis: Bone, Bugs, and Surgery
Kenneth L. Urish, James E. Cassat
Infection and Immunity Jun 2020, 88 (7) e00932-19; DOI: 10.1128/IAI.00932-19
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Top
  • Article
    • ABSTRACT
    • OSTEOMYELITIS: HISTORICAL PERSPECTIVES, CLINICAL PRESENTATION, AND DIAGNOSIS
    • OSTEOMYELITIS PATHOPHYSIOLOGY
    • INFECTIOUS ETIOLOGIES OF OSTEOMYELITIS
    • TREATMENT OF OSTEOMYELITIS
    • BACTERIAL PATHOGENESIS IN THE CONTEXT OF BONE INFECTION
    • CONCLUSIONS AND OPPORTUNITIES FOR FUTURE RESEARCH
    • ACKNOWLEDGMENTS
    • REFERENCES
    • Author Bios
  • Figures & Data
  • Info & Metrics
  • PDF

KEYWORDS

Staphylococcus aureus
bone
epidemiology
host-pathogen interactions
musculoskeletal infection
osteoimmunology
osteomyelitis
pathogenesis
treatment
virulence

Related Articles

Cited By...

About

  • About IAI
  • Editor in Chief
  • Editorial Board
  • Policies
  • For Reviewers
  • For the Media
  • For Librarians
  • For Advertisers
  • Alerts
  • RSS
  • FAQ
  • Permissions
  • Journal Announcements

Authors

  • ASM Author Center
  • Submit a Manuscript
  • Article Types
  • Ethics
  • Contact Us

Follow #IAIjournal

@ASMicrobiology

       

ASM Journals

ASM journals are the most prominent publications in the field, delivering up-to-date and authoritative coverage of both basic and clinical microbiology.

About ASM | Contact Us | Press Room

 

ASM is a member of

Scientific Society Publisher Alliance

 

American Society for Microbiology
1752 N St. NW
Washington, DC 20036
Phone: (202) 737-3600

Copyright © 2021 American Society for Microbiology | Privacy Policy | Website feedback

Print ISSN: 0019-9567; Online ISSN: 1098-5522