Bacterial resistance has changed approaches to the treatment of infectious diseases worldwide. In his 1945 Nobel Prize acceptance address, Sir Alexander Fleming warned that improper use of penicillin would eventually result in widespread bacterial resistance.1 Unfortunately, he was correct. Clinicians continue to encounter bacterial infections with heightened resistance to standard antibiotic regimens. Such infections are reminiscent of those seen in the preantibiotic era.2 Surprisingly virulent pathogens have complicated the treatment of childhood musculoskeletal infections.3-7 As a result, many pediatric clinicians and surgeons have become more aggressive in treating these conditions, relying on MRI for early diagnosis and using more complex antibiotic regimens and more aggressive surgical debridement than the standard of care 20 years ago.3-6 Treatment methods more commonly used in adults with chronic osteomyelitis—such as repeated surgical debridement or implantation of antibiotic-impregnated beads at infection sites—are now sometimes required for children.3-6 Failure to diagnose childhood musculoskeletal infections can result in serious consequences such as joint destruction, growth disturbance, or death. In the battle against these resistant infections, pediatric primary care providers, including physician assistants (PAs), will find themselves on the front lines, where prompt diagnosis and treatment are essential.
DEFINITION AND PREVALENCE
Acute hematogenous osteomyelitis and septic arthritis are bacterial infections of the bones and joints, respectively. These conditions are uncommon but not rare (about 8 cases per 100,000).8 Osteomyelitis is considered acute if detected within 2 weeks of onset, subacute if detected after 2 weeks, and chronic after several months.3 Although the prevalence of acute hematogenous osteomyelitis and septic arthritis has remained unchanged for the past 20 years, the causative organisms have changed dramatically. The emergence of highly virulent and resistant bacterial strains has made the treatment of these diseases far more challenging.3-6
Acute hematogenous osteomyelitis and septic arthritis develop similarly. In acute hematogenous osteomyelitis, bloodborne bacteria seed into the trabecular network of a child's bone—most commonly near the knee or hip.4-6 The predilection for rapid growth of infection at the metaphyses of the femur and tibia is not fully understood, but may be secondary to a relative dearth of reticuloendothelial cells in these regions or other host or bacterial interactions not fully defined (Figure 1).9
Within minutes to hours of microbial implantation, bacterial adhesion occurs and infection develops. Bacterial cytotoxins and proteolytic enzymes produced by host macrophages result in tissue invasion and destruction. As purulent exudate develops in the confines of the bony trabeculum, pressure from pus produces local ischemia and further necrosis. Microabscesses coalesce to form macroabscesses that in turn cause osteonecrosis (the sequestrum). The inflammation stimulates surrounding healthy periosteum to produce new reactive bone (the involucrum) (Figure 1).10 Eventually the infection may perforate the adjacent joint capsule or cortex and extend into neighboring soft tissues.3,4,10-12
Septic arthritis follows a similar chronologic sequence as bloodborne bacteria seed the synovial lining of a joint. In hours to days, bacteria develop protective mechanisms such as biofilms, making them exceedingly difficult to eradicate. Infections that are not promptly arrested may become chronic.3,10 Long-term sequelae of acute hematogenous osteomyelitis or septic arthritis, such as severe growth disturbance or permanent joint destruction (Figure 2), can be devastating, especially for younger children. These complications are more common with virulent pathogens such as methicillin-resistant Staphylococcus aureus (MRSA).3-5,7,11,12 If unchecked, these infections may lead to septicemia, toxic shock, multiorgan failure, and death.
S. aureus remains the most common cause of acute hematogenous osteomyelitis and septic arthritis in children, followed by group A beta-hemolytic Streptococcus, Streptococcus pneumoniae, and Enterobacter.6 Bacterial resistance has become the alarming issue. Although local experience varies, resistant organisms, especially MRSA, now are more commonly encountered everywhere.3-5,11-13 Both community-acquired and healthcare-associated MRSA can be extremely virulent.3,7 Complications such as deep vein thrombosis, wide extension of abscesses into adjacent muscles and bones, septic emboli, and multiorgan failure may occur.3-5,7,12,13
Thirty years ago, healthcare-associated MRSA infection in children was rare. Today, children commonly may present with pustular “bug bite” skin abscesses caused by community-acquired MRSA (Figure 3).3 Often these patients can be treated with superficial drainage of the abscess and a short course of oral trimethoprim-sulfamethoxazole or clindamycin, but these skin abscesses can produce bacteremia capable of seeding a bone or joint.
Although methicillin-sensitive S. aureus remains the most common pathogen in childhood musculoskeletal infections, only about 50% of proven cases of musculoskeletal infection will yield positive cultures, so many causes remain conjectural.5,10 Viable organisms may not be able to be cultured for various reasons.10 Pathogens may be protected by a glycocalyx or biofilm; they may be fastidious and difficult to grow; or they may persist intracellularly.10 In previous times, children could sometimes overcome osteomyelitis on their own by containing the infection as a chronic Brodie abscess or eradicating it entirely. Others developed classic chronic osteomyelitis, in which a large sequestrum of necrotic bone became safely enveloped in healthy soft tissue and a new bony involucrum was produced.4 With today's hypervirulent and resistant bacterial strains, infections typically extend into surrounding soft tissue, resulting in pyomyositis, abscesses, or septic emboli.4,5,7,11,13
Infectious disease specialists at most medical centers track pathogens carefully. In many hospitals, methicillin-sensitive S. aureus remains the leading cause of serious musculoskeletal infections in children, although facilities frequently encounter children with MRSA skin infections. Some larger tertiary pediatric centers document so many children with resistant musculoskeletal infections that hospital protocols have been modified to treat these cases more aggressively.3-5,11,14 These institutions may serve a more fragile patient population with comorbidities such as immunodeficiencies or endocrinopathies. Infectious disease specialists can help guide the treatment of suspected infections based on local bacterial prevalence, resistance, and other risk factors such as patient age, comorbidities, or history of previous infections. Specialists also may be familiar with less-common pathogens such as Kingella sp. and Salmonella.
Diagnosing acute hematogenous osteomyelitis or septic arthritis centers on observation of the limping child.15 Classic signs of acute hematogenous osteomyelitis or septic arthritis include fever and limited motion of the affected limb with redness, swelling, tenderness, and inability to bear weight. Ambulatory children exhibit an antalgic gait, characterized by a shortened stance phase. This antalgic limp appears the same in patients with hip, knee, or foot problems. Usually, the location of the problem can be determined by the point of maximum tenderness or restricted motion.
Often children with a bona fide acute hematogenous osteomyelitis or septic arthritis will refuse to bear weight. A nonambulatory child with fever and a painful lower extremity should be suspected of having acute hematogenous osteomyelitis or septic arthritis until proven otherwise. The predictive value of laboratory criteria for diagnosing acute hematogenous osteomyelitis and septic arthritis remains controversial. Kocher criteria have generally been helpful in diagnosing acute hematogenous osteomyelitis and septic arthritis but not in identifying MRSA infections.16,17 Kocher criteria are limp (or refusal to walk), fever (>38.5° C [101.3° F]), white blood cell count greater than 12,000 cells/mm3, erythrocyte sedimentation rate (ESR) greater than 40 mm/hour, and C-reactive protein (CRP) level greater than 2 mg/mL. Documentation of four of the five criteria correlates highly with true septic arthritis or acute hematogenous osteomyelitis.
Differentiating MRSA infection from methicillin-sensitive S. aureus has proven more difficult. Because laboratory data have not proven to be consistently reliable, clinical or historical criteria may be superior predictors. A history of purulent skin infection, previous MRSA infection, or a surgical or traumatic wound all correlate reliably with current MRSA musculoskeletal infection.14,17
Tables 1 and 2 list differential diagnoses for limb and hip pain in children.
A good history and physical examination, CBC count, ESR, CRP level, and plain radiographs of the affected limb often suggest the diagnosis of acute hematogenous osteomyelitis or septic arthritis presumptively. The sine qua non is a positive bacterial culture from the affected body tissue. As discussed previously, positive identification of pathogens from known marrow or joint infections is obtained in only 50% of cases.5,10 Blood cultures may be positive although cultures of joint or marrow aspirates are negative. In all suspected bone or joint infections, obtain and send blood for culture before the patient starts antibiotics. If cultures demonstrate no growth and the diagnosis remains presumptive, treatment must be empiric based on local experience with likely pathogens, and consultation with an infectious disease specialist is crucial.
Ultrasonography has repeatedly been shown to be accurate in documenting pediatric hip effusion. Rapid, painless, noninvasive, portable, and inexpensive, ultrasound has demonstrated a sensitivity of 86% and specificity of 89%.3,4,18 Ultrasound remains useful for diagnosis as well as for guiding aspiration of suspected joint effusion or soft-tissue abscesses.4,12
Although plain radiographs can rule out other bony pathology, they usually are nondiagnostic in most cases of acute hematogenous osteomyelitis and septic arthritis. With the emergence of resistant bacterial strains, advanced imaging has become more important in diagnosing acute musculoskeletal infection in children. MRI is the imaging test of choice.3-5,10 Osteomyelitic marrow shows decreased signal on T1 and increased signal on T2. An MRI with gadolinium contrast is the best imaging study for osteomyelitis in children (Figure 4).4
In the future, superparamagnetic iron oxide (SPIRO) may prove to be a superior contrast agent for differentiating neoplastic metastases from inflammatory lesions.4,10 Also of increasing interest is the fluorodeoxyglucose positron emission (FDG-PET) scan, which has shown great diagnostic accuracy for confirming or excluding chronic osteomyelitis.10 However, neither of these methods are available for routine clinical use.
The gold standard for treatment of musculoskeletal infections in children is the appropriate antibiotic given by the proper route at the proper dose for the proper length of time, with concomitant surgical debridement or drainage as needed. Many clinicians choose antibiotic regimens using guidelines such as those published by the Infectious Diseases Society of America. These regimens recognize the increasing prevalence of resistant bacterial strains such as MRSA, and advise more potent antibiotics as first-line therapy.14 Recommendations include IV vancomycin or IV clindamycin for suspected MRSA, and IV ceftriaxone or IV nafcillin for suspected methicillin-sensitive S. aureus.14,17 If infection is diagnosed in the acute phase, surgery may not be necessary. Surgical drainage or debridement may be needed for patients who present subacutely or later, or for patients whose infections do not resolve with antibiotics alone.4,5,12,14
Appropriate antibiotic selection can be challenging. Most facilities rely on standard culture methodology that requires 24 to 48 hours of bacterial growth for definitive identification. With the emergence of more virulent bacteria, rapid identification has become more critical. Techniques such as DNA sequencing, real-time polymerase chain reaction (PCR) assays, and peptide nucleic acid-fluorescent in situ hybridization (PNA-FISH) have reduced turnaround times in the laboratory but are difficult to apply in practice.19 Some mass spectrometry methods appear more promising. Two examples are PCR electrospray ionization mass spectrometry of genetic material (PCR-ESI/MS) and matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF/MS).19 These methods can accurately identify microbial species by studying their molecular constituents and providing positive identification in hours rather than days.19 Because these methods require a dedicated mass spectrometer, few hospitals may be able to afford them. However, several larger institutions and provider networks are already beginning to use mass spectrometers routinely.
SURGICAL DRAINAGE AND DEBRIDEMENT
Although septic arthritis can be treated successfully using serial aspiration, most pediatric orthopedic surgeons still recommend surgical drainage, especially for the hip.20,21 Open drainage and debridement of osteomyelitic abscesses remain the standard of care.4,5,12-14 Surgery should be performed urgently to clear the joint or bone marrow of bacteria, inflammatory cells, and cartilage-destroying enzymes, and to decrease intra-articular pressure that can lead to ischemic necrosis of the femoral head.4,5,12-14 For debridement of the hip, most surgeons favor the classic anterior Smith Peterson approach with fenestration of the capsule and placement of temporary drainage tubes. The femoral neck is not routinely drilled for septic arthritis unless the patient has associated osteomyelitis. Preoperative MRI studies are helpful in alerting the surgeon to the need to drain adjacent extensions or soft-tissue abscesses (Figure 5).4,5,22
EMPIRIC CHOICE OF ANTIBIOTICS
Because treatment of these serious infections is urgent and many true infections yield no growth in laboratory cultures, clinicians often cannot postpone antibiotic treatment until there is definitive bacterial identification. Many infectious disease consultants now advise broader antibiotic coverage for acute hematogenous osteomyelitis and septic arthritis in children.3-6,12-14 The choices should be risk-adjusted to accommodate the patient's comorbidities and, if possible, the local experience with pathogens. Recommendations for initial empiric therapy for septic arthritis and acute hematogenous osteomyelitis include clindamycin or vancomycin in addition to nafcillin or ceftriaxone.3-6,12-14 These combinations are less toxic for children and assure good coverage for most methicillin-sensitive S. aureus, MRSA, Kingella, pneumococcus, Haemophilus influenzae, and Neisseria gonorrheae. Initial antibiotic therapy should be modified according to culture results and with consultation from an infectious disease specialist.
THE PRIMARY CARE PROVIDER'S ROLE
Successful treatment of serious childhood musculoskeletal infections requires carefully coordinated collaboration among healthcare providers, including primary care providers such as PAs. Although the goal is early recognition and prompt referral, much of the initial clinical investigation (CBC count, ESR, CRP level, and imaging studies) can be started by the primary care provider. PAs, pediatricians, infectious disease specialists, radiologists, orthopedic surgeons, nurses, therapists, and technicians from various ancillary services are all critically important. Musculoskeletal infections in children are neither medical nor surgical diseases. They are infectious diseases with many potential complications and sequelae.
The emergence of highly virulent and resistant bacterial strains has made the management of infections considerably more challenging. Many reports have stressed the urgency of early diagnosis and treatment of childhood musculoskeletal infections, especially in younger and more vulnerable patients.3-6,12-14,17,22,23 Important measures include assuring that the child remains fasting in case surgery is required, obtaining baseline laboratory tests and imaging studies, and contacting consultants as soon as possible. Children who appear gravely ill should be hospitalized immediately.3-5 By understanding the seriousness of these infections, primary care providers can ensure that patients receive prompt, appropriate care to improve their chances for a good outcome.
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