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Hematogenous osteomyelitis in children: Management

Hematogenous osteomyelitis in children: Management
Literature review current through: Sep 2023.
This topic last updated: Aug 23, 2021.

INTRODUCTION — Osteomyelitis is an infection localized to bone. It is usually caused by microorganisms (predominantly bacteria) that enter the bone hematogenously. Other pathogenic mechanisms include direct inoculation (usually traumatic, but also surgical) or local invasion from a contiguous infection (eg, sinusitis, decubitus ulcers, deep wound infections, periodontal disease). Risk factors for nonhematogenous osteomyelitis include open fractures that require surgical reduction, implanted orthopedic hardware (such as pins or screws), and puncture wounds.

The management of hematogenous osteomyelitis in children will be discussed here. The epidemiology, microbiology, clinical features, evaluation, and diagnosis of osteomyelitis in children are discussed separately:

(See "Hematogenous osteomyelitis in children: Epidemiology, pathogenesis, and microbiology".)

(See "Hematogenous osteomyelitis in children: Clinical features and complications".)

(See "Hematogenous osteomyelitis in children: Evaluation and diagnosis".)

ONGOING DIAGNOSTIC EVALUATION — Radiographs usually are obtained in the initial evaluation of suspected osteomyelitis. However, because radiographs may be normal early in the course, empiric antimicrobial therapy may be initiated before radiographic confirmation with advanced imaging studies (eg, magnetic resonance imaging [MRI], scintigraphy) has been accomplished. (See "Hematogenous osteomyelitis in children: Evaluation and diagnosis", section on 'Radiographs'.)

For children with suspected osteomyelitis whose initial radiographs are normal, MRI or scintigraphy typically is performed within a few days to substantiate the diagnosis. If empiric antimicrobial therapy is initiated before definitive imaging studies, cultures should be obtained from blood and suspected foci of infection (if possible). (See 'Pretreatment evaluation' below.)

MRI or scintigraphy (if available) may be useful for children whose initial radiographs demonstrated soft tissue changes and periosteal reaction without characteristic changes in bone mineral density. Characteristic findings on MRI or scintigraphy support the diagnosis of osteomyelitis (table 1). (See "Hematogenous osteomyelitis in children: Evaluation and diagnosis", section on 'Advanced imaging'.)

Osteomyelitis is unlikely among children who lack characteristic findings on MRI or scintigraphy. Other types of infection and noninfectious causes of bone pain must be reconsidered. (See "Hematogenous osteomyelitis in children: Evaluation and diagnosis", section on 'Differential diagnosis'.)

INDICATIONS FOR SURGERY — Surgical intervention may be required at the time of presentation or during antimicrobial therapy if children fail to respond as expected or magnetic resonance imaging (MRI) indicates extensive bone/soft tissue involvement that requires debridement [1-4]. Consultation with an orthopedist with pediatric expertise is recommended early in the clinical course. (See "Hematogenous osteomyelitis in children: Evaluation and diagnosis", section on 'Supportive findings'.)

Indications for surgical intervention include:

Need for drainage of subperiosteal and soft tissue abscesses and intramedullary purulence

Debridement of contiguous foci of infection (which also require antimicrobial therapy)

Excision of sequestra (ie, devitalized bone)

Failure to improve after 48 to 72 hours of antimicrobial therapy (see 'Response to therapy' below)

Lesions requiring surgical intervention usually are diagnosed with MRI. Computed tomography scans and radiographs also may reveal evidence of sequestra or involucra (sheaths of periosteal bone that form around a sequestrum) and are sometimes useful to plan surgical intervention. (See "Hematogenous osteomyelitis in children: Evaluation and diagnosis", section on 'Advanced imaging'.)

ANTIMICROBIAL THERAPY

Indications — We recommend initiation of empiric antimicrobial therapy for most children with clinical features suggestive of osteomyelitis (eg, symptoms and signs of bone pain, elevated erythrocyte sedimentation rate [ESR]/C-reactive protein [CRP]) and:

Characteristic imaging abnormalities (most commonly noted on initial magnetic resonance imaging [MRI]) (table 1) (see "Hematogenous osteomyelitis in children: Evaluation and diagnosis", section on 'Advanced imaging')

Normal radiographs if advanced imaging is not immediately available (eg, within 24 hours) or feasible, particularly if they are ill appearing or have signs of sepsis; characteristic radiographic features of osteomyelitis are not usually apparent on plain radiographs until 10 days after symptom onset (see 'Ongoing diagnostic evaluation' above and "Hematogenous osteomyelitis in children: Evaluation and diagnosis", section on 'Radiographs')

In children who are otherwise well or only mildly ill appearing, administration of empiric antibiotics may be delayed for 24 to 48 hours until cultures can be obtained via surgery or interventional radiography. The rationale for this delay is that cultures from intraoperative and interventional radiology procedures are less often positive with longer periods of antimicrobial therapy prior to obtaining these specimens [5,6].

Pretreatment evaluation — Before initiating empiric antimicrobial therapy, cultures should be obtained from blood and suspected foci of infection. A minimum of one blood culture (but preferably two) should be obtained. Empiric antimicrobial therapy is adjusted according to clinical response and culture and susceptibility results (if a pathogen is isolated). (See "Hematogenous osteomyelitis in children: Evaluation and diagnosis", section on 'Microbiology' and 'Pathogen-directed therapy' below.)

Infectious disease specialist consultation may be warranted for immunocompromised patients (eg, those with sickle cell disease, chronic granulomatous disease [CGD]) because they often have infections with challenging antimicrobial susceptibility profiles. (See 'Additional coverage for other pathogens' below.)

Empiric parenteral therapy — Antimicrobial therapy for osteomyelitis often is initiated before the diagnosis is confirmed. The risk of delaying treatment for bacteremic patients may be significant, particularly for those with community-associated Staphylococcus aureus. (See 'Outcome' below and "Hematogenous osteomyelitis in children: Epidemiology, pathogenesis, and microbiology", section on 'Staphylococcus'.)

Factors in choice of regimen — Initial antimicrobial therapy for acute hematogenous osteomyelitis usually is administered parenterally. The empiric regimen is determined by the most likely pathogens and antimicrobial susceptibilities based on epidemiologic factors, including the child's age (table 2), clinical features (table 3), whether the infection is life threatening, and organisms prevalent in the community (algorithm 1). An additional consideration is the future ease of transition to an oral regimen so that indwelling intravenous (IV) catheters can be avoided. Thus, single (versus multiple) drug IV therapy and having an effective, palatable, oral counterpart may prove beneficial, particularly if no pathogens are recovered by any cultures. (See 'Switch to oral therapy' below.)

Systematic reviews of randomized and observational studies have provided a general guide to the choice of antibiotics for acute osteomyelitis in children [7-10]. In individual studies, the clinical cure rates for acute hematogenous osteomyelitis in children generally are >95 percent when empiric therapy is chosen according to age, underlying medical condition, and organisms that are prevalent in the community. Most of the cases in the systematic reviews were confirmed to be caused by gram-positive pathogens (predominantly S. aureus), but a positive culture was not always required for study inclusion.

Children younger than three months — Empiric IV antimicrobial therapy for children younger than three months should be directed against S. aureus, gram-negative bacilli, and group B Streptococcus. (See "Hematogenous osteomyelitis in children: Epidemiology, pathogenesis, and microbiology", section on 'Microbiology'.)

For empiric parenteral therapy in children younger than three months with suspected osteomyelitis, we generally provide combination therapy with an antistaphylococcal agent and a third-generation cephalosporin or cefepime (table 4 and table 5). Appropriate regimens vary with the clinical presentation and risk factors for methicillin-resistant S. aureus (MRSA) or coagulase-negative staphylococci (algorithm 1).

For infants with allergy or intolerance to cephalosporins (very uncommon in this age group), we suggest consultation with an expert in pediatric infectious diseases.

Signs of sepsis – For infants <3 months of age with signs of sepsis (eg, tachycardia, poor perfusion, hypotension), we provide empiric therapy with either (algorithm 1):

Vancomycin plus nafcillin or oxacillin plus one of the following:

-Cefotaxime (preferred if available)

-Ceftazidime

-Ceftriaxone (for infants who are not receiving IV calcium-containing solutions [11])

Vancomycin plus cefepime

Although cefepime provides activity against methicillin-susceptible S. aureus (MSSA), some experts would add nafcillin or oxacillin for optimal activity against MSSA in infants with signs of sepsis.

No signs of sepsis but with risk factors for MRSA or coagulase-negative staphylococci – Risk factors for MRSA include care in the intensive care unit for >1 week; mother with, or suspected to have, infection or colonization with community-acquired S. aureus; and increased prevalence of MRSA at the admitting institution (eg, ≥10 percent of S. aureus isolates are methicillin resistant). Prematurity and prolonged or recurrent bacteremia with coagulase-negative staphylococci despite antibiotic therapy are the primary risk factors identified for osteomyelitis with these organisms in neonates [12-14].

For infants without signs of sepsis but with risk factors for MRSA or coagulase-negative staphylococci, we provide empiric therapy with (algorithm 1):

Vancomycin, plus

One of the following:

-Cefotaxime (preferred if available)

-Ceftazidime

-Ceftriaxone (for infants who are not receiving IV calcium-containing solutions [11])

-Cefepime (a fourth-generation cephalosporin)

At some institutions, clindamycin is used as an alternative to vancomycin if <10 percent of S. aureus isolates are clindamycin resistant and the infant has localized infection with no signs of sepsis. Other experts may use a different threshold for clindamycin resistance.

No signs of sepsis and no risk factors for MRSA or coagulase-negative staphylococci – For infants without signs of sepsis and without risk factors for MRSA or coagulase-negative staphylococci, appropriate regimens include:

Combination therapy with (algorithm 1):

-One of the following antistaphylococcal agents: vancomycin, nafcillin, oxacillin

-Plus one of the following gram-negative agents: cefotaxime (preferred if available), ceftazidime, or ceftriaxone (for infants who are not receiving IV calcium-containing solutions [11])

Cefazolin is an alternative antistaphylococcal agent for infants age one to three months in whom central nervous system infection has been excluded.

Monotherapy with cefepime (a fourth-generation cephalosporin)

Although cefepime provides activity against MSSA, some experts would add nafcillin or oxacillin for additional activity against MSSA.

Children three months and older — Empiric IV antimicrobial therapy for children older than three months should be directed against S. aureus (the most common cause of hematogenous osteomyelitis in this age group) and other gram-positive organisms (eg, group A streptococci, Streptococcus pneumoniae). Broader empiric therapy may be necessary for special populations. (See 'Additional coverage for other pathogens' below.)

Agents that provide antistaphylococcal and antistreptococcal coverage include nafcillin/oxacillin, cefazolin, clindamycin, and vancomycin (table 4 and table 5). We do not generally use trimethoprim-sulfamethoxazole (TMP-SMX) for suspected community-associated MRSA (CA-MRSA) osteomyelitis in children because of the limited data supporting its efficacy and the high rate of mild adverse events (eg rash, neutropenia) [15]. (See "Staphylococcus aureus in children: Overview of treatment of invasive infections".)

The choice of regimen depends on whether the infection is life threatening (eg, the child has signs of sepsis), the local prevalence of CA-MRSA, and the susceptibility of CA-MRSA to clindamycin (algorithm 2) [1,16,17].

Coverage for gram-positive pathogens

Life-threatening infection – For gram-positive coverage in children ≥3 months with acute hematogenous osteomyelitis and signs of sepsis, we suggest vancomycin plus either nafcillin or oxacillin; we provide empiric antimicrobial therapy for other pathogens as indicated (algorithm 2). Nafcillin or oxacillin is the preferred therapy for methicillin-susceptible S. aureus (MSSA). For children unable to tolerate penicillins, we use vancomycin alone. (See 'Additional coverage for other pathogens' below.)

Non-life-threatening infection For gram-positive coverage in children ≥3 months with acute hematogenous osteomyelitis and non-life-threatening infection:

We suggest nafcillin/oxacillin or cefazolin if <10 percent of the community S. aureus isolates are methicillin resistant (algorithm 2). For children who are unable to tolerate penicillin and cephalosporin antibiotics, we suggest clindamycin if <10 percent of S. aureus isolates are clindamycin resistant. Other experts may use a different threshold for clindamycin resistance.

We suggest either vancomycin or clindamycin if ≥10 percent of the community S. aureus isolates are methicillin resistant (algorithm 2) [16,17].

-We suggest vancomycin for children who have underlying frequent contact with the health care system or who were hospitalized in the past six months because these children have an increased risk of clindamycin resistance.

-We suggest vancomycin when ≥10 percent of S. aureus isolates in the community also are resistant to clindamycin (constitutive and inducible) [18,19]. Other experts may use a different threshold for clindamycin resistance. (See "Overview of antibacterial susceptibility testing", section on 'Inducible clindamycin resistance testing'.)

-We suggest clindamycin for children with localized infection and no signs of sepsis if clindamycin resistance is not a concern based on local patterns of antimicrobial drug resistance.

Alternatives to vancomycin or clindamycin when MRSA is a concern include linezolid, ceftaroline, or daptomycin (daptomycin only if the child is ≥1 year of age and has no concomitant pulmonary involvement) [16,17,20,21]. In a multicenter trial, clinical improvement at day 5 (approximately 80 percent) and clinical cure at the test-of-cure visit (approximately 85 percent) were similar among children randomly assigned to IV therapy with daptomycin or comparator (vancomycin, nafcillin, or equivalent) for ≥4 days followed by oral therapy (78 versus 83 percent; adjusted difference -6.1, 95 % CI -19.4 to 7.4) [22]. However, MRSA accounted for only 9 percent of gram-positive isolates, and we continue to prefer vancomycin or clindamycin if MRSA is a concern.

A 2013 systematic review of three randomized trials and 22 observational studies addressing the choice of antibiotics found limited evidence to definitively guide the choice of antibiotics for acute osteomyelitis in children [9]. There is evidence from a quasi-randomized trial that first-generation cephalosporins (eg, cefazolin) and clindamycin are similarly effective treatments for acute osteomyelitis in children >3 months of age in an area with a low prevalence of MRSA and Kingella kingae [23].

Additional coverage for other pathogens — It may be necessary to add empiric coverage for pathogens other than S. aureus and other gram-positive pathogens when clinical or laboratory factors suggest a specific pathogen (table 3). (See "Hematogenous osteomyelitis in children: Epidemiology, pathogenesis, and microbiology", section on 'Microbiology'.)

Preschool children in day careK. kingae should be considered as a possible pathogen in children 6 to 36 months of age (especially those attending day care) and those with indolent osteomyelitis or a history of oral ulcers preceding the onset of musculoskeletal findings [24-32]. K. kingae usually is susceptible to cephalosporins (eg, cefazolin) but is consistently resistant to vancomycin and often resistant to clindamycin and antistaphylococcal penicillins (eg, oxacillin, nafcillin) [28,29].

We generally do not provide initial empiric coverage for K. kingae in young children because most cases of osteomyelitis in the United States are caused by S. aureus and other gram-positive pathogens. In addition, initial multidrug therapy may complicate transition to oral therapy if an organism is not identified in culture. K. kingae generally causes relatively mild musculoskeletal infections; chronic osteomyelitis and other complications requiring surgical interventions are rare [29,33,34].

For children between 6 and 36 months of age who require vancomycin or clindamycin for empiric coverage of CA-MRSA, empiric coverage for K. kingae with cefazolin may be added if the child does not improve as expected. Alternatively, cefazolin may be substituted for vancomycin or clindamycin if CA-MRSA is not identified in cultures of blood, bone, or soft tissue aspirates. (See 'Culture-negative osteomyelitis' below and "Hematogenous osteomyelitis in children: Epidemiology, pathogenesis, and microbiology", section on 'Microbiology'.)

Incomplete Haemophilus influenzae type b immunization – We add coverage for H. influenzae type b (Hib) (eg, cefotaxime, ceftriaxone) in children <2 years who have not been fully immunized against Hib (table 6) who are from areas where Hib immunization rates are low. Coverage for Hib is not necessary for children from areas with high Hib immunization rates. Regional vaccination coverage estimates for children 19 to 35 months are available from the Centers for Disease Control and Prevention.

Sickle cell disease or reptile exposure – We add empiric coverage for Salmonella and other gram-negative bacilli (eg, cefotaxime, ceftriaxone) for children with sickle cell disease. Salmonella is a common cause of osteomyelitis in children with sickle cell disease [35-37]. Salmonella should also be considered in children with osteomyelitis and reptile or amphibian exposure and/or gastrointestinal symptoms [38]. (See "Acute and chronic bone complications of sickle cell disease", section on 'Osteomyelitis and septic arthritis'.)

Chronic granulomatous disease – Addition of a third-generation cephalosporin (eg, cefotaxime, ceftriaxone) to initial empiric therapy is prudent for patients with CGD. In individuals with CGD, osteomyelitis frequently is caused by unusual organisms (eg, Aspergillus and other fungi, Serratia species, and other filamentous or gram-negative bacteria), as well as staphylococci [39,40]. Debridement combined with voriconazole has proven successful in some patients with invasive bone Aspergillus [40]. (See "Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis", section on 'Infections' and "Chronic granulomatous disease: Treatment and prognosis", section on 'Treatment'.)

Recent gastrointestinal surgery or complex urinary tract anatomy – Addition of 1) a third- or fourth-generation cephalosporin (eg, cefotaxime, ceftriaxone, cefepime) or 2) an aminoglycoside (eg, gentamicin) to the initial empiric regimen may be warranted for patients with recent gastrointestinal surgery or complex urinary tract anatomy. Such patients are at risk for infection with enteric gram-negative organisms.

Injection drug users – Organisms that cause infection among injection drug users (IDU) vary markedly between communities. Pseudomonas aeruginosa frequently has been reported among IDUs with osteomyelitis.

If P. aeruginosa osteomyelitis is a consideration, we suggest that ceftazidime be added to empiric antistaphylococcal therapy with vancomycin, nafcillin, or oxacillin; this combination covers other gram-negative bacilli as well as S. aureus. (See "Pseudomonas aeruginosa skin and soft tissue infections" and "Principles of antimicrobial therapy of Pseudomonas aeruginosa infections".)

Pathogen-directed therapy — The antimicrobial regimen can be tailored to a specific pathogen when culture and susceptibility results are available (table 7) [10]. Doses are provided in the tables (table 4 and table 5). Consultation with an expert in infectious diseases is suggested for children with an inadequate response to therapy, unusual organisms, and/or drug allergies.

Culture-negative osteomyelitis — No organism is identified in approximately 50 percent of children with suspected osteomyelitis [10]. The decision to continue empiric antibiotic therapy is based upon the initial clinical suspicion, advanced imaging studies, and response to empiric therapy. Most cases can be managed with regimens that are appropriate for culture-positive cases in a given geographical location, and failures of treatment are rare. We generally use therapy appropriate for MSSA (eg, cefazolin, nafcillin, oxacillin) and monitor for response to therapy. Other experts may use clindamycin or TMP-SMX, particularly in areas with high rates of CA-MRSA (if rates of clindamycin resistance are low). (See 'Response to therapy' below.)

However, before committing the child to a long course of antibiotic therapy, the differential diagnosis must be reconsidered and likely alternative diagnoses excluded. This is particularly important for children whose imaging studies remain negative. (See "Hematogenous osteomyelitis in children: Evaluation and diagnosis", section on 'Differential diagnosis'.)

Improvement with empiric therapy — For children who present with characteristic clinical and radiographic features of osteomyelitis and have negative cultures, but improve rapidly with empiric therapy, continuation of empiric antimicrobial therapy generally is warranted.

They may be switched to oral therapy focused on likely common pathogens (eg, S. aureus, Streptococcus pyogenes) if the clinical course is uncomplicated and they meet criteria for oral therapy. (See 'Switch to oral therapy' below.)

Continuation of empiric therapy directed toward gram-positive pathogens, particularly S. aureus, in children with culture-negative osteomyelitis is supported by a retrospective review in which outcomes were similar between 45 children with culture-positive osteomyelitis (42 percent with MSSA, 31 percent with MRSA) and 40 children with culture-negative osteomyelitis who received antistaphylococcal antibiotics [41]. A prospective study also found similar outcomes in 80 Finnish children with culture-negative osteoarticular infections who were treated with clindamycin or first-generation cephalosporins (8 also received amoxicillin or ampicillin) and 265 children with culture-positive osteoarticular infections (75 percent MSSA, 10 percent Hib, 9 percent S. pyogenes, and 5 percent S. pneumoniae) [42]. These findings may not be generalizable because the proportion of cases caused by MRSA varies geographically [10]; MRSA is commonly encountered in the United States. (See "Hematogenous osteomyelitis in children: Epidemiology, pathogenesis, and microbiology", section on 'Staphylococcus'.)

Given the possibility of MRSA osteomyelitis, with associated increased risk of complications, it is essential to monitor the clinical and inflammatory response to empiric antimicrobial therapy in children with culture-negative osteomyelitis. (See 'Response to therapy' below.)

Lack of improvement with empiric therapy — Lack of improvement or worsening during empiric parenteral antimicrobial therapy in children with clinical and radiographic features of osteomyelitis and negative cultures may indicate:

Development of a complication (eg, periosteal or soft tissue abscess, venous thrombosis)

Ineffective antimicrobial therapy (eg, unusual or resistant pathogen, polymicrobial infection, inadequate dose of antibiotic agent or failure to administer it)

A diagnosis other than osteomyelitis

The evaluation and management of these possibilities is discussed below. (See 'Lack of improvement or worsening' below.)

Response to therapy

Monitoring response — The response to therapy is assessed with serial clinical, laboratory, and imaging evaluations (table 8). During hospitalization, we monitor:

Clinical status (eg, fever, pain, localized erythema or swelling, new sites of infection) at least daily.

CRP if clinical status worsens and every two to three days until CRP has demonstrated a >50 percent reduction or steady decline, then weekly.

CRP and ESR have both been used to monitor response in children with acute osteomyelitis. However, the ESR typically increases during the first several days of treatment and consequently does not usually play a role in the management during the initial hospitalization. CRP also increases early in the infection but returns to normal much more rapidly than ESR (eg, one week versus three to four weeks in a systematic review [10]), which makes it more useful in monitoring the response to therapy [43-46]. An increase in CRP on or after the fourth day of treatment (if it is not associated with surgical interventions) may be associated with a complicated clinical course (eg, prolonged symptoms, progression of radiographic changes, need for repeat surgical intervention) [47-49]. (See "Hematogenous osteomyelitis in children: Clinical features and complications", section on 'Laboratory features'.)

White blood cell (WBC) count before the switch to oral therapy if it was elevated at the time of diagnosis.

Elevations in the peripheral WBC count in children with hematogenous osteomyelitis are present in only approximately one-third of patients [10] and nonspecific. The peripheral WBC count, if initially elevated, usually normalizes within 7 to 10 days after initiation of effective antimicrobial and/or surgical therapy.

Radiographs if clinical status worsens or fails to improve (to evaluate development of complications; areas of devitalized bone [sequestra] become evident within two to four weeks); additional imaging, usually with MRI, may be necessary. (See 'Lack of improvement or worsening' below.)

Expected response — In children with acute hematogenous osteomyelitis who are receiving appropriate and effective antimicrobial therapy, clinical improvement usually occurs within three to four days. Clinical and laboratory improvement is indicated by:

Resolution of fever

Decreased pain and erythema or swelling

Decrease in peripheral WBC (if initially elevated) and a drop in CRP of ≥50 percent every two to three days

Clinical and laboratory improvement suggests that the diagnosis and choice of antimicrobial therapy are correct; continued improvement may be an indication for outpatient therapy. (See 'Switch to oral therapy' below.)

Lack of improvement or worsening — Lack of improvement or worsening is defined by:

Worsening pain or extension of infection (eg, to the adjacent soft tissues, joint)

Persistent or increasing fever, pain, and discomfort with movement after five days in toddlers and seven days in older children and adolescents

Failure of CRP to decline by ≥50 percent after one week of therapy and to continue to decline during the second week [43]

Progression of radiographic abnormalities in affected bones (eg, development of abscess, sequestra)

Patients who are not responding to treatment as expected require reevaluation and adjustment of therapy. Consultation with an expert in infectious diseases may be helpful if adjustments to antimicrobial therapy are indicated. Lack of improvement or worsening may indicate [2,4]:

Development of a complication requiring surgical intervention (eg, soft tissue, subperiosteal, or intramedullary abscess; sinus tract; sequestra) (see 'Indications for surgery' above)

Prompt evaluation is warranted and may include ESR and/or CRP, WBC count, and plain radiograph of the affected area. Further imaging, usually with MRI, or performing MRI with contrast agents may be necessary to identify a lesion requiring surgery [50]. Although repeat imaging may identify residual infection or other sites of infection, in children who have undergone surgical intervention, it can be difficult to distinguish postsurgical changes (eg, hematoma) from a recurrent abscess. (See 'Indications for surgery' above.)

Thromboembolism (see "Venous thrombosis and thromboembolism (VTE) in children: Risk factors, clinical manifestations, and diagnosis", section on 'Clinical manifestations')

Ineffective antimicrobial therapy (eg, unusual or resistant pathogen, polymicrobial infection, inadequate dose of antibiotic)

An aggressive attempt must be made to isolate or identify fastidious (eg, K. kingae) and unusual pathogens (eg, Brucella, Bartonella henselae, fungi, mycobacteria) if appropriate exposures are identified (table 3).

A bone biopsy should be obtained for histopathologic staining and culture for bacteria, mycobacteria, and fungi; injection of bone aspirates or periosteal collections into blood culture bottles is recommended to enhance recovery of Kingella [51,52]. Polymerase chain reaction (if available) can be particularly helpful for detecting K. kingae in purulent materials or bone specimens [31]. (See "Hematogenous osteomyelitis in children: Epidemiology, pathogenesis, and microbiology", section on 'Microbiology' and "Hematogenous osteomyelitis in children: Evaluation and diagnosis", section on 'Microbiology'.)

Consultation with an expert in infectious diseases may be helpful if adjustments to antimicrobial therapy are indicated. Inclusion of coverage for K. kingae (eg, penicillin, cephalosporin) may be warranted for children between 3 and 36 months of age who were initially treated with vancomycin or clindamycin.

A diagnosis other than osteomyelitis (see "Hematogenous osteomyelitis in children: Evaluation and diagnosis", section on 'Differential diagnosis')

Switch to oral therapy — There is no minimum duration of IV therapy for treatment of osteomyelitis [7]. Patients who are older than one month with uncomplicated osteomyelitis can be switched from IV to oral therapy after they have demonstrated unequivocal clinical improvement, as indicated by [53-55]:

Lack of fever for ≥48 hours

Decreased pain, erythema, or swelling

Normalization of WBC count

Consistent decrease in CRP

This usually occurs after 5 to 10 days of antimicrobial therapy [43,47,53,56,57].

Oral therapy avoids the risks of prolonged IV antibiotic administration via central venous catheters [58-60]. (See 'Response to therapy' above.)

In randomized trials and observational studies, treatment of osteomyelitis with IV antibiotics for short periods (approximately seven days) followed by oral therapy was as successful as longer courses of parenteral therapy [7,9,10,58,60].

Prerequisites – Our prerequisites for switching to oral from parenteral therapy include:

Age ≥1 month – The gastrointestinal absorption of oral antibiotics in neonates <1 month is unpredictable [61,62]; we provide their entire course of antimicrobial therapy parenterally.

The clinical course has been uncomplicated.

The child is immune competent and fully immunized against H. influenzae and S. pneumoniae for age (table 6).

If a pathogen is identified, it is susceptible to an oral antibiotic that is available to the patient.

If cultures are negative, the child has responded as expected to empiric parenteral therapy and there is an oral regimen with a spectrum similar to the parenteral regimen.

The child has demonstrated ability to swallow, retain, and absorb an appropriate oral medication. We typically administer the initial doses of oral therapy while the child is in the hospital to ensure that the drug is tolerated.

The patient and caregiver have received appropriate education, are committed to the follow-up schedule, and are expected to adhere to the antimicrobial regimen.

Outpatient parenteral antimicrobial therapy (OPAT) may be warranted for patients with contraindications to oral therapy who have improved as expected with parenteral therapy. Insertion of a percutaneously inserted central catheter facilitates prolonged OPAT. However, catheter-related complications (eg, malfunction, displacement, bloodstream infection) occur in 30 to 40 percent of children with osteoarticular infections who are treated with OPAT [59,63].

Choice of the oral regimen — The choice of oral therapy depends upon whether an organism was isolated from blood, bone (if obtained), or other culture. Additional considerations include bioavailability and palatability of the oral medication. Consultation with an expert in infectious diseases may be helpful in choosing the optimal oral agent, particularly if the child has an unusual pathogen or allergy to antibiotics.

When an organism is isolated, the susceptibility pattern can be used to determine an appropriate drug (table 7).

When an organism is not isolated, oral therapy is directed toward the most likely pathogen(s) given the child's age (table 2) and clinical presentation (table 3). The chosen regimen should have a spectrum similar to that provided by the parenteral therapy that was associated with improvement. As examples, a child who improved with cefazolin may be switched to cephalexin; a child who improved with parenteral clindamycin may be switched to oral clindamycin.

To ensure adequate bone penetration, antibiotics administered orally for hematogenous osteomyelitis generally are given in higher doses than those for treatment for other infections and recommended in package inserts (table 9) [53,64-66]. Doses of penicillins, cephalexin, and cefadroxil can be increased to 100 to 150 mg/kg per day without serious side effects [23,45,53]. We do not generally use oral TMP-SMX for CA-MRSA osteomyelitis in children because it has not been prospectively studied for this indication. However, there are some retrospective data that it may be effective [15].

Total duration

Confirmed or probable osteomyelitis — The total duration of antimicrobial therapy for children with confirmed or probable osteomyelitis is determined by the clinical and radiographic response to therapy and normalization of inflammatory markers. Although we generally treat for a minimum of four weeks, three weeks may be reasonable in children who have a good response to therapy, an identified pathogen, and rapid normalization of inflammatory markers. Treatment for more than four weeks may be necessary for children who require surgical debridement, have MRSA, or have underlying medical conditions [10]. (See "Hematogenous osteomyelitis in children: Evaluation and diagnosis", section on 'Diagnostic interpretation' and 'Outcome' below.)

We administer antimicrobial therapy until the ESR and CRP are normal [1,53,56,67], regardless of pathogen or complications. Other experts may not use normalization of ESR as a criterion for discontinuation of antimicrobial therapy or may document normalization of ESR only in children with osteomyelitis caused by MRSA [68] and in cases that have been initially complicated (eg, concomitant septic arthritis, intraosseous or periosteal abscess or lytic bone lesions at presentation, requiring repeated surgical management of soft tissue foci, delayed normalization of CRP beyond the expected 7 to 10 days).

Before discontinuing antimicrobial therapy, we also generally obtain a radiograph to make sure there are no new bone lesions (eg, devitalized bone [sequestra], lytic lesions), even if there is no clinical evidence of treatment failure. However, we discuss the need for and timing of subsequent radiographs with the pediatric orthopedist involved in the evaluation. Delaying the radiograph to allow initial or expected abnormalities to resolve is an alternative approach. (See 'Lack of improvement or worsening' above.)

A 2013 systematic review found limited evidence to strictly define the optimal duration of antimicrobial therapy for acute hematogenous osteomyelitis [9]. In a randomized trial conducted in Finland, children with culture-proven osteomyelitis recovered completely whether they were treated for 20 or 30 days, provided that they had a good clinical response and rapid normalization of CRP [69]. However, the generalizability of these results is limited because there were minimal complications and 89 percent of cases were caused by MSSA. The proportion of cases caused by MRSA varies geographically but is common in the United States [44,45]. MRSA osteomyelitis often requires increased duration of therapy. In observational studies, treatment failure appears to be more common with total duration ≤3 weeks than with treatment ≥4 weeks [7,54,70,71]. (See "Hematogenous osteomyelitis in children: Epidemiology, pathogenesis, and microbiology", section on 'Staphylococcus'.)

Osteomyelitis unlikely — Osteomyelitis is unlikely if advanced imaging studies (usually MRI or scintigraphy) are normal. Decisions about continuation and duration of antimicrobial therapy should be made on a case-by-case basis. The results of the blood culture and response to antimicrobial therapy are important considerations in this decision.

Positive blood culture, improvement with empiric therapy – Pathogen-directed antimicrobial therapy is warranted unless a source of infection other than osteomyelitis is identified. (See "Hematogenous osteomyelitis in children: Evaluation and diagnosis", section on 'Other infections'.)

Positive blood culture, no improvement with empiric therapy – Continuation of pathogen-directed antimicrobial therapy is warranted pending evaluation for other sources of bacteremia and noninfectious conditions that may have predisposed the patient to bacteremia. (See "Hematogenous osteomyelitis in children: Evaluation and diagnosis", section on 'Differential diagnosis'.)

Negative blood culture, improvement with empiric therapy – A shorter course of empiric antimicrobial therapy for a more superficial source of infection (eg, cellulitis) may be warranted. (See "Hematogenous osteomyelitis in children: Evaluation and diagnosis", section on 'Other infections'.)

Negative blood culture, no improvement with empiric therapy – Empiric antimicrobial therapy usually can be discontinued; further investigation for pathogens not covered by empiric therapy may be necessary. Noninfectious causes of musculoskeletal pain should be sought. (See "Hematogenous osteomyelitis in children: Evaluation and diagnosis", section on 'Noninfectious conditions'.)

Drug monitoring

Adverse effects – Children who are being treated with parenteral or oral antibiotic therapy for osteomyelitis require monitoring for potential adverse effects. Adverse effects of high-dose antibiotic therapy include pancytopenia, leukopenia, hepatitis [72], impaired liver or renal function, and antibiotic-associated diarrhea [73,74].

The monitoring schedule varies depending upon the drug, dose, and route of therapy. We obtain complete blood count (CBC; with differential) weekly initially, while the patient is receiving beta-lactam antibiotics (eg, penicillins, cephalosporins). It is also reasonable to obtain a biochemical profile, including serum aminotransferases, weekly while the patient is receiving penicillin antibiotics or parenteral cephalosporins, although some experts only obtain serum aminotransferases in children with underlying liver disease. Some experts also obtain laboratory studies every one to two weeks for clindamycin, although hematologic adverse effects are less of a concern. For linezolid, CBCs should be monitored weekly for therapy beyond two weeks. (See 'Follow-up' below.)

Adequacy of therapy – We monitor adequacy of therapy and adherence by following the clinical examination, sequentially monitoring CRP, and verifying normalization of the ESR at the end of therapy. This approach has replaced routine monitoring of serum bactericidal titers [75] or direct determination of antibiotic concentrations.

OTHER THERAPIES

Immobilization — Immobilization of the affected extremity may relieve pain. It also may prevent pathologic fractures when bone involvement is extensive as detected by radiography or other imaging modalities. Immobilization may be particularly important for children with osteomyelitis of the proximal femur or vertebral osteomyelitis and children with methicillin-resistant S. aureus (MRSA) osteomyelitis [76].

We suggest protected weight-bearing and activity restriction for children with risk factors for pathologic fracture until inflammatory markers have returned to normal, the involved bone appears to be healing on radiographs, and the child is pain free. Risk factors for pathologic fracture include [76]:

Prolonged hospital stay

Multiple surgical procedures

Maximum circumferential extent of abscess ≥50 percent of bone circumference on magnetic resonance imaging (MRI)

Sharp zone of diminished marrow enhancement on MRI

Infection caused by USA300-0114 pulsotype

Thromboembolism — Patients with associated deep vein thrombosis and/or septic pulmonary emboli are usually managed in conjunction with a hematologist. Management typically involves anticoagulation and continuation of antimicrobial therapy until the thrombus has resolved on Doppler imaging. (See "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome", section on 'Anticoagulant agents'.)

FOLLOW-UP — Children who are being treated as outpatients for osteomyelitis with either intravenous or oral antibiotics should be seen at one- to two-week intervals. They should be monitored for continued clinical improvement and adverse effects of high-dose antibiotic therapy (eg, pancytopenia, leukopenia, impaired liver or renal function, antibiotic-associated diarrhea, pseudomembranous colitis). At each visit, we obtain C-reactive protein (CRP) and complete blood count (with differential); we also obtain a biochemical profile, including serum aminotransferases if the patient is receiving beta-lactam antibiotics (eg, penicillins, intravenous cephalosporins). (See 'Drug monitoring' above.)

For children with complicated osteomyelitis (eg, concomitant septic arthritis, intraosseous or periosteal abscess or lytic bone lesions at presentation, requiring repeated surgical management of soft tissue foci, delayed normalization of CRP [beyond the expected 7 to 10 days]), we obtain erythrocyte sedimentation rate when treatment discontinuation is being considered. We also generally obtain radiographs of the affected area(s) before discontinuation of antibiotics to make sure there are no new bone lesions. (See 'Total duration' above.)

No specific follow-up for uncomplicated osteomyelitis is necessary after discontinuation of antibiotics in children who have had an uneventful resolution of all clinical findings, although some surgeons may elect to follow children for 6 to 12 months to assess the growth of long bones, particularly those with complicated, extensive, or poorly responsive infections. This may be of particular importance if the growth plate (physis) was affected by the focus of infection. We counsel patients to seek attention if symptoms return in the area of initial confirmed or suspected osteomyelitis, noting that recrudescences may occur after prolonged periods of time. We also counsel caregivers to watch for symptoms of Clostridioides difficile infection (eg, diarrhea, abdominal pain, abdominal distension). (See "Clostridioides difficile infection in children: Clinical features and diagnosis", section on 'Symptomatic disease'.)

OUTCOME — Most newborns, infants, and children who receive prompt, appropriate antimicrobial therapy before extensive bone necrosis develops have excellent outcomes. In systematic reviews and observational studies, >95 percent of patients have complete resolution of radiographically apparent bone damage [7,54,77].

The causative organism and location of infection may influence outcomes, particularly in neonates.

In a 2012 systematic review, risk factors for worse prognosis included [10]:

Methicillin-resistant S. aureus (MRSA) or S. pneumoniae as the infecting organism

Concurrent septic arthritis, pyomyositis, or abscess

Involvement of the hip (40 percent risk of complications), ankle (33 percent complications), or knee (10 percent complications) [78]

Positive culture

Younger age (possibly related to delays in presentation, diagnosis, and treatment)

Delay in treatment

Despite adequate therapy, recurrence of infection may occur in 1 to 2 percent of children with acute hematogenous osteomyelitis, and others may develop significant complications such as chronic osteomyelitis, limp, and leg length discrepancy [23,77].

Among neonates with osteomyelitis, the prognosis is generally better for group B streptococcal infection than staphylococcal infection [79,80]. Sequelae of neonatal osteomyelitis result from the extension of infection into the subperiosteal space and soft tissue, involvement of the growth plate, and the spread of infection into the adjacent joint space (figure 1). Destruction of the growth plate may be associated with growth disturbance (angular deformity, shortening or overgrowth of the affected bone) [81,82]. Other sequelae of neonatal osteomyelitis include osteonecrosis (avascular necrosis) of the femoral head and bony deformities. Among newborns with vertebral osteomyelitis, collapse or complete destruction of one or more vertebral bodies may occur, with kyphosis or spinal cord compression (and resultant paralysis) as late complications [83]. (See "Hematogenous osteomyelitis in children: Epidemiology, pathogenesis, and microbiology", section on 'Pathogenesis' and "Hematogenous osteomyelitis in children: Clinical features and complications", section on 'Complications'.)

Long-term sequelae are uncommon in older infants and children. However, multifocal disease, pathologic fractures, abnormal bone growth, chronic osteomyelitis, and the need for repeated surgical intervention have been reported frequently among patients with community-associated methicillin-resistant staphylococcal infection [65]. (See "Methicillin-resistant Staphylococcus aureus infections in children: Epidemiology and clinical spectrum", section on 'Community-onset'.)

In a case series of patients with S. aureus osteomyelitis from a single institution, 17 (4.7 percent) developed pathologic long-bone fractures; 15 of the 17 had MRSA [76]. Risk factors for pathologic fracture included prolonged hospital stay, multiple surgical procedures, large circumferential subperiosteal abscess (ie, maximum circumferential extent of abscess ≥50 percent of bone circumference on magnetic resonance imaging [MRI]), sharp zone of diminished marrow enhancement on MRI, and USA300-0114 pulsotype. We suggest that children known to have these risk factors be managed with protected weight-bearing and activity restriction until inflammatory markers have returned to normal, the involved bone appears normal on radiographs, and the child is pain free.

CHRONIC OSTEOMYELITIS — Chronic osteomyelitis is defined by signs and symptoms of bone inflammation for at least two weeks and radiographic evidence of devitalized bone. Chronic osteomyelitis typically is described in patients with inadequate duration of therapy, but patient-specific etiologic and anatomic factors also play a role [54,84,85]. Chronic osteomyelitis is uncommon with current principles of management of acute hematogenous osteomyelitis.

Diagnosis of chronic osteomyelitis requires bone biopsy for culture and histopathologic confirmation. Bone biopsy also may be necessary to exclude other conditions that may have similar radiographic appearance, including nonbacterial osteomyelitis (eg, chronic recurrent multifocal osteomyelitis), Langerhans cell histiocytosis, large cell lymphoma, or primary bone tumors [86]. (See "Hematogenous osteomyelitis in children: Evaluation and diagnosis", section on 'Differential diagnosis'.)

Treatment of chronic osteomyelitis involves removing devitalized bone and long-term administration of antibiotics [86]. Repeated surgical debridement and bone grafting often are necessary. The importance of adequate surgical debridement and adequate dosing and duration of, and adherence to, antimicrobial therapy cannot be overemphasized.

The choice of antimicrobial agents and the duration of therapy have not been well studied [87], largely because chronic osteomyelitis is so rare in children. Antibiotic regimens that have been successful in small case series of patients with methicillin-susceptible S. aureus (MSSA) include oral cloxacillin (not available in the United States) combined with probenecid and nafcillin combined with oral rifampin [86,88,89]. In a 2010 systematic review, the success rate for treatment of chronic osteomyelitis due to various pathogens (predominantly S. aureus) ranged from 80 to 100 percent with parenteral therapy that ranged from 0.4 to 6 weeks and oral therapy from 0.2 to 4.3 months [87].

We suggest that children with chronic osteomyelitis caused by MSSA be treated with the combination of rifampin and a beta-lactam antibiotic (eg, penicillin or cephalosporin). For methicillin-resistant S. aureus, treatment with clindamycin is preferred (if the organism is susceptible). For culture-negative cases, treatment as for MSSA may be started, with careful clinical monitoring for improvement.

The duration of therapy is determined on a case-by-case basis. We typically obtain radiographs at monthly intervals and discontinue therapy after a four-week interval during which all bony changes are indicative of healing (eg, increased bone density, decrease in the size of lytic areas in bone).

Adjunctive measures, such as local irrigation with antimicrobial solutions with or without detergents and surgical implantation of polymethyl methacrylate bone cement or calcium sulfate beads impregnated with antibiotics, have not been shown conclusively to affect outcome [90-94].

Complications of chronic osteomyelitis include joint stiffness, limb shortening, and pathologic fractures. (See "Hematogenous osteomyelitis in children: Clinical features and complications", section on 'Complications'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Septic arthritis and osteomyelitis in children".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Osteomyelitis in children (The Basics)")

SUMMARY AND RECOMMENDATIONS

Indications for surgery – In children with osteomyelitis, surgical intervention may be required at the time of presentation or during antimicrobial therapy. Indications for surgical intervention include:

Drainage of subperiosteal and soft tissue abscesses and intramedullary purulence

Debridement of contiguous foci of infection

Excision of sequestra (ie, devitalized bone)

Failure to improve after 48 to 72 hours of antimicrobial therapy

Lesions requiring surgical intervention usually are diagnosed with radiography and magnetic resonance imaging (MRI). (See 'Indications for surgery' above.)

Indications for empiric antimicrobial therapy – For most children with clinical features compatible with osteomyelitis (eg, symptoms and signs of bone pain, elevated erythrocyte sedimentation rate [ESR]/C-reactive protein [CRP]), we recommend empiric antimicrobial therapy, even if the initial radiograph is normal (Grade 1B). Characteristic features of osteomyelitis are not usually apparent on radiographs until 10 days after symptom onset, and advanced imaging may not be immediately available or feasible. (See 'Indications' above.)

Choice of empiric regimen – Initial antimicrobial therapy for acute hematogenous osteomyelitis usually is administered parenterally. The empiric regimen is determined by the most likely pathogens and antimicrobial susceptibilities based on epidemiologic factors including the child's age (table 2), clinical features (table 3), and organisms prevalent in the community (algorithm 1 and algorithm 2). (See 'Empiric parenteral therapy' above.)

For infants <3 months of age, we generally use a third-generation cephalosporin (eg, cefotaxime [preferred], ceftazidime, ceftriaxone), plus an antistaphylococcal agent (usually vancomycin or nafcillin/oxacillin). Appropriate regimens vary with the clinical presentation and risk factors for methicillin-resistant Staphylococcus aureus (MRSA) or coagulase-negative staphylococci (algorithm 1). (See 'Children younger than three months' above.)

For children ≥3 months of age, we use cefazolin, nafcillin/oxacillin, clindamycin, or vancomycin, depending upon the local prevalence of community-associated MRSA (CA-MRSA) and the susceptibility of CA-MRSA to clindamycin (algorithm 2). (See 'Children three months and older' above.)

For children ≥3 months of age, it may be necessary to add empiric coverage for pathogens other than S. aureus when clinical or laboratory features suggest a specific pathogen (table 3). (See 'Additional coverage for other pathogens' above.)

Tailoring regimen – The antimicrobial regimen can be tailored to a specific pathogen when culture and susceptibility results are available (table 7). Children whose cultures remain negative and improve with empiric therapy usually are continued on the same parenteral regimen on which they improved, followed by an oral regimen with a similar spectrum. (See 'Pathogen-directed therapy' above and 'Culture-negative osteomyelitis' above.)

Response to therapy – Children receiving appropriate antimicrobial therapy generally demonstrate clinical improvement within three to four days. Clinical improvement is indicated by decreased fever, pain, erythema, swelling, peripheral white blood cell (WBC) count, and CRP. (See 'Expected response' above.)

Lack of improvement or worsening may be due to development of a complication requiring surgical intervention (eg, abscess, sinus tract, sequestra), thromboembolism, ineffective antimicrobial therapy (eg, unusual or resistant pathogen, polymicrobial infection, insufficient dose), or the presence of a condition other than osteomyelitis. Additional evaluation may include ESR/CRP, WBC count, plain radiography, and aggressive attempt to isolate fastidious and unusual pathogens. Adjustments to antimicrobial therapy may be necessary. (See 'Lack of improvement or worsening' above.)

Total duration and switch to oral therapy – We generally administer antimicrobial therapy for a minimum of four weeks; three weeks may be reasonable in children who have a good response to therapy, an identified pathogen, and normalization of inflammatory markers. Before discontinuing antimicrobial therapy, we recheck the CRP and the ESR, and we do not stop therapy if either is abnormal. We also generally obtain a radiograph to make sure there are no new bone lesions (eg, abscess, sequestra), even if there is no clinical evidence of treatment failure. (See 'Total duration' above.)

Oral antibiotics may be used to complete the course of therapy for acute osteomyelitis in children older than one month who have unequivocal improvement (eg, afebrile for ≥48 hours, decreased pain and erythema or swelling, normalization of WBC count, consistent decrease in CRP), provided that (see 'Switch to oral therapy' above):

The child is immune competent and fully immunized against Haemophilus influenzae and Streptococcus pneumoniae for age (table 6)

The child demonstrates ability to swallow, retain, and absorb an appropriate oral medication

The clinical course has been uncomplicated, including no progression of bone disease

If a pathogen is identified, it is susceptible to oral antibiotics

If cultures are negative, the child has responded as expected to empiric parenteral therapy and there is an oral regimen with a spectrum similar to the parenteral regimen

The patient and caregiver are expected to adhere to the medication and follow-up regimen

Follow-up – After hospital discharge, children should be evaluated at one- to two-week intervals for clinical improvement and complications related to antibiotic therapy (table 8). In addition, a radiograph should be performed at the end of treatment for children with complicated infections. (See 'Follow-up' above and 'Drug monitoring' above.)

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Topic 5958 Version 43.0

References

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