In children younger than 12 years, acute hematogenous osteomyelitis or septic arthritis is reported at an annual rate of 1/10,000.1 Currently, Staphylococcus aureus is the leading cause of these musculoskeletal infections at most pediatric hospitals.1 In conjunction, methicillin-resistant S aureus (MRSA) has emerged as an extremely common pathogen in these hospital communities. Each year, pediatric hospitals have seen a steady increase in the percent of staphylococcus infections that are methicillin resistant.2,3 Furthermore, the cases of MRSA cause more local soft-tissue destruction, spread more rapidly, and have a higher mortality rate.3-5 Patients with MRSA have longer hospital stays and more frequently experience complications such as deep vein thrombosis (DVT) and septic pulmonary emboli.3-5 Patients with MRSA also have a higher incidence of abscesses and subperiosteal infections that require surgical intervention.6 Consequently, clinicians and hospital epidemiologists are becoming more aware of the impact of this pathogen and its associated morbidity, and are becoming more vigilant in regard to screening protocols, empiric antibiotic treatment, and prevention of complications.
MRSA initially emerged in the hospital setting within the first year after methicillin was introduced in 1961.7 MRSA was considered a nosocomial infection or healthcare-associated infection for the first 30 years of its existence. Five accepted clonal lineages of hospital-acquired MRSA (HA-MRSA) have been identified,8 and resistance to all known antibiotics has developed within these genotypes.9 HA-MRSA tends to affect patients who have significant risk factors for infections, such as recent hospitalization, surgery, or antimicrobial treatment.10
In the early 2000s, reports of MRSA infection in the community began to occur in patients with no risk factors for HA-MRSA.11-22 Shortly thereafter, community-acquired MRSA (CA-MRSA) was identified as a rapidly emerging pathogen, especially in the orthopaedic community. CA-MRSA is a much more virulent pathogen than HA-MRSA, with rapid tissue necrosis that often requires surgical intervention. CA-MRSA may be differentiated from HA-MRSA in three major ways: first, from the genetic sequence of its mobile genetic elements; second, from the presence of virulent exotoxins; and third, from the absence of multidrug resistance.11-13
Mechanism of Resistance
Staphylococcus achieves its resistance to penicillin through the mecA gene. The mecA gene is acquired in a bacterium from a mobile genetic element called a staphylococcal cassette chromosome (SCC-mecA).23 A mobile genetic element is a sequence of DNA that is found in almost all organisms; it is able to move or transpose to other parts of the genome and move between organisms. Four SCC-mec mobile elements have been identified; the first three SCC-mec mobile elements confer HA-MRSA its resistance to penicillins.14 The type IV SCC-mec element is found in CA-MRSA.
The mecA gene, carried by the type IV mobile element, encodes penicillin-binding protein (PBP) 2a. PBPs are involved in the final stages of the synthesis of peptidoglycan, which is the major component of the bacterial cell wall. Most PBPs have a high affinity for β-lactam antibiotics, allowing the antibiotics to inhibit cell wall synthesis and cause lysis of the bacteria. However, PBP2a has a very low affinity for β-lactam antibiotics; consequently, antibiotics are unable to bind to the cell wall, conferring resistance (Figure 1). Methicillin-sensitive S aureus (MSSA) produces different PBPs that have a high affinity for β-lactam antibiotics; thus, it is susceptible to antibiotics. CA-MRSA is typically resistant only to β-lactam antibiotics, although CA-MRSA strains can be resistant to other classes of antibiotics. Cases of vancomycin-resistant S aureus have been reported several times in the last 10 years.24
Mechanism of Virulence
In addition to its resistance to β-lactam antibiotics, CA-MRSA causes rapid local soft-tissue destruction because of its production of cytotoxin. Panton-Valentine leukocidin (PVL) is a virulence factor found in 66% to 100% of MRSA strains compared with <5% of HA-MRSA strains.18,20,21,25 PVL causes necrotic lesions to develop in the skin or mucosa by forming pores in the membranes of cells. It transforms into S aureus through bacteriophages, which are viruses that insert their DNA into the S aureus genome. CA-MRSA strains that have the PVL gene cause rapid tissue necrosis and likely account for most of the infections that progress to abscess formation.23 Ellis et al21 demonstrated that in a cohort of army soldiers with nasal swabs that were positive for MRSA and the PVL gene, the soldiers had a skin and soft-tissue infection rate of 38% compared with a rate of only 3% in patients with MSSA-positive nasal swabs.
Diagnosis of osteomyelitis or septic arthritis can be challenging in children and especially in young children because of their difficulty in describing symptoms or providing a history of preceding trauma; also, some patients have minimal constitutional symptoms early in the disease process. However, MRSA infection may present with a much more fulminant course. A history of prior trauma is present in 30% of patients, and animal models have shown that bone infection is more likely when bacteremic animals sustain trauma.26 Prior trauma should increase concerns for concomitant infection.
Physical examination may reveal a wide variability of signs and symptoms in bone and joint infections in children depending on the stage of the disease. Examination findings may be subtle in the patient early in the course of the disease, especially in cases of isolated osteomyelitis. The clinician should attempt to determine what part of the extremity is the most painful; this may be challenging in a very young child. Every joint should be tested individually so that diagnostic imaging can be directed to the appropriate site. However, it is not always possible to identify the problematic joint. Physical examination often reveals more notable findings in MRSA infections because PVL expression can cause skin discoloration, skin necrosis, and abscess formation. Patients often have a rapidly worsening pustule if the infection is in a subcutaneous location. Additionally, patients with MRSA initially may have a benign examination that progresses rapidly over the next several hours, resulting in life-threatening illness. Vander Have et al27 retrospectively reviewed 27 patients with MRSA infections over a 5-year period and reported that, at presentation, 17 patients had a temperature >101.3°F (>38.5°C), and 6 had a temperature >104°F (>40°C). In their series, 12 patients required admission to the intensive care unit, and multisystem organ failure developed in four patients.
Laboratory evaluation includes a complete blood count, basic chemistry measurements, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, and blood cultures. Examination of joint fluid often proves to be invaluable in patients with septic arthritis. A white blood cell (WBC) count of >50,000/mm3 indicates infection and warrants surgical intervention.
Methicillin-resistant Staphylococcus aureus Prediction
Multiple studies on MRSA prediction have been conducted, seeking to anticipate early in the course of the disease which patients have MRSA and which patients have MSSA so that appropriate empiric antibiotic treatment can be initiated. In a retrospective review, Hawkshead et al28 tried to identify differences in patients diagnosed with MRSA compared with patients diagnosed with MSSA or a non-staphylococcus bacterium, or patients with negative cultures. In the cohort of 97 patients (14 with MRSA), patients with MRSA had a higher ESR, CRP level, and WBC count compared with patients without MRSA on admission. A study by Saavedra-Lozano et al29 looked at patients diagnosed with MRSA or MSSA osteomyelitis; the authors reported that in their cohort of 36 patients with MRSA and 72 patients with MSSA, the patients with MRSA had a CRP level >4 mg/L, an ESR >40 mm/h, and a lower red blood cell count at presentation compared with patients with MSSA. The authors found no difference between the two groups with regard to duration of symptoms before admission, age, gender, or antibiotic use before admission.
Erdem et al30 retrospectively studied 62 children with MRSA and MSSA (culture-proven) osteomyelitis and found no difference in the duration of illness before admission. However, in the MRSA group, the authors noted a statistically significant higher peak for the patients’ ESR and CRP levels compared with the MSSA group during the admission, although the initial value was not documented. Furthermore, in the MRSA group, the absolute neutrophil count and the WBC count showed an increased peak level, as well as higher levels in the emergency department.
Ju et al31 proposed a clinical predictive algorithm to differentiate between MRSA and MSSA on presentation without waiting for culture results. The authors retrospectively reviewed 129 children with MRSA or MSSA osteomyelitis, all of which were culture proven. The authors identified four significant predictors: a WBC count of >12,000 cells/mm3, a hematocrit value of <34%, a temperature >100.4°F (>38°C), and a CRP level >13 mg/L. The percentage of patients with MRSA and MSSA that satisfied each of these criteria is seen in Figure 2. The probability of MRSA osteomyelitis was 0% for no predictors, 1% for one predictor, 10% for two predictors, 45% for three predictors, and 92% for all four predictors. The authors concluded that they had very good diagnostic performance in distinguishing between MRSA and MSSA osteomyelitis when all four predictors were positive.
At Phoenix Children’s Hospital, Wade Shrader et al32 applied the predictive algorithm to an independent patient population to determine its effectiveness. The authors found that the predictive algorithm had relatively poor performance in the independent patient population. Table 1 shows the results from Phoenix Children’s Hospital compared with those of Boston Children’s Hospital. The authors suggest that racial and cultural profiles of the patient population and/or genetic or phenotypic differences in the MRSA bacterial strain may account for the differences in performance of the algorithm. Further testing of the prediction rule is necessary to document its clinical usefulness in making empiric antibiotic treatment decisions before the return of cultures.
Polymerase Chain Reaction Detection of MRSA
Rapid detection of MRSA with the use of a polymerase chain reaction (PCR) has become a topic of interest. However, PCR cannot be used to detect MRSA until S aureus has been identified. In addition, PCRs are usually run in batches of multiple specimens once a day to curtail costs. Consequently, any specimen in which S aureus is isolated would be delayed until the time of day when the PCR is run. Once S aureus is isolated, current methods of MRSA detection take between 18 and 24 hours for results; therefore, the time benefit of PCR, which takes between 2 to 4 hours, is minimal. Researchers continue to search for rapid, cost-effective means for early MRSA detection and screening.
Plain radiographs should be obtained to rule out fracture or malignancy. Signs of acute infection are often not seen on radiographs for several weeks, unless the infection has been ongoing for >2 weeks. In patients with suspected septic arthritis of the hip, ultrasound may be performed to determine whether the patient has an effusion. If an effusion is present, the radiologist should be prepared to aspirate the joint during the same examination. However, because many institutions do not have this capability, aspiration can be performed in the emergency department or operating room, depending on the surgeon’s preference. When the diagnosis is unclear, MRI is helpful in delineating the absence of or location of infection, septic arthritis, osteomyelitis, subperiosteal abscess, pyomyositis, or any combination of these. Early MRI is beneficial because it informs the surgeon about the entire extent of the infection, thereby minimizing the number of times a patient is sedated. Early MRI also may accelerate appropriate treatment, allowing the entire team to perform more timely and efficient patient care.
Screening MRI of the entire lower extremity is indicated in small children who poorly localize the site of inflammation but clearly have signs of infection on laboratory evaluation; this method allows for acute focusing on the site of infection. Copley4 suggests a daily scheduled MRI slot for musculoskeletal infections as a means to hasten MRI evaluation in cases of suspected serious infection. He notes that MRI is the most useful step in identifying the epicenter and extent of the infection. Figures 3, A and 3, B show the MRIs of a child with acute MRSA osteomyelitis of the tibia with subperiosteal abscess formation. Figures 3, C and 3, D show a radiograph and CT of the same child with central growth disturbance at 7 months and 15 months, respectively.
A multidisciplinary approach is essential in the treatment of patients with suspected MRSA infections, including emergency department physicians, radiologists, interventional radiologists, MRI technicians, pediatricians, infectious disease specialists, anesthesiologists, and orthopaedic surgeons. Communication between team members is necessary to expedite the implementation of treatment decisions. Every effort should be undertaken to obtain cultures early in the course of disease before initiation of antibiotics. Even in cases when the diagnosis of sepsis is clear, blood cultures should be drawn before prophylactic antibiotic administration.
The decision whether to aspirate a joint before MRI is a difficult one. Early aspiration of suspected intra-articular infection allows the team to start early administration of prophylactic antibiotics. However, aspiration may require sedation in a young patient, and if aspiration results are negative, MRI often needs to be obtained, thus requiring a second sedation. In cases of easily accessible joints that are clearly swollen (eg, knee, ankle, elbow, wrist), we prefer to first perform joint aspiration before MRI. If the fluid examination results reveal infection, surgical intervention is warranted. If the diagnosis is unclear, the team should ensure that blood cultures have already been drawn, MRI should be expedited, and prophylactic antibiotics may be initiated depending on the clinical status of the patient.
Patients with suspected CA-MRSA infection should be started on antibiotics with adequate coverage for MRSA. In patients with rapidly spreading soft-tissue infection (ie, necrotizing fasciitis), the patient should also receive antibiotics that cover for group A streptococcus. A clinical practice guideline was published by the Infectious Diseases Society of America regarding the treatment of MRSA in children.33 For patients with acute hematogenous MRSA osteomyelitis and septic arthritis, intravenous (IV) vancomycin is recommended. Data are limited regarding vancomycin dosing in children, but the guidelines recommend a dose of 15 mg/kg every 6 hours for serious or invasive diseases. In addition, the guidelines recommend a target trough concentration of 15 to 20 μg/mL in patients with osteomyelitis, septic arthritis, and necrotizing fasciitis. Pediatric patients with renal dysfunction require close monitoring to maintain the appropriate trough target. If the patient is stable without ongoing bacteremia or intravascular infection, then IV clindamycin at a daily dose of 40 mg/kg (ie, 10 to 13 mg/kg per dose depending on 6-hour or 8-hour dosing) may be used as empiric therapy if the clindamycin resistance rate is low (ie, <10%). Because orthopaedic surgeons treat a large number of patients with MRSA, they should be aware of the antibiotic susceptibilities in their institutions. The patient may then be transitioned to oral therapy if the strain is susceptible. Table 2 summarizes antibiotic therapy in pediatric patients.
The duration of therapy should be individualized according to the response to treatment, but typically a minimum course of 3 to 4 weeks is recommended for septic arthritis and a course of 4 to 6 weeks is recommended for osteomyelitis. Alternatives to vancomycin and clindamycin include daptomycin 6 mg/kg IV once daily or linezolid 600 mg orally or IV twice daily for children older than 12 years and 10 mg/kg every 8 hours for children younger than 12 years. MRSA treatment is similar in neonates with sepsis or bone and joint infections and includes IV vancomycin. The MRSA strain should be analyzed for vancomycin susceptibility because cases of vancomycin-intermediate S aureus or vancomycin-resistant S aureus have been reported.24
Patients with abscess formation or septic arthritis require early surgical management because antibiotic treatment is not able to penetrate large abscesses. However, some small abscesses may be treated with antibiotics alone. Compared to MSSA, MRSA is known to require surgical intervention more frequently and require more procedures to treat the condition.28 MRI is extremely valuable in surgical planning to help ensure that all areas of infection are adequately débrided and decompressed. It is important to address all areas of infection, particularly infected bone; any dead or devitalized tissue must be removed. MRI best detects subperiosteal abscesses and osteomyelitis. Patients with osteomyelitis often require a cortical window to ensure that all infected bone is removed or decompressed. Because infections often involve the metaphysis, fluoroscopy may be helpful in preventing damage to the growth plate. Many surgeons insert drains to allow continued egress of fluid after surgery using a variety of different drainage strategies, although none seems to be more efficacious than another.
MRSA infections are often more invasive and cause more frequent abscess formation than MSSA infections; therefore, aggressive surgical management during the index procedure is paramount to prevent the need for a return to the operating room. However, if the patient has undergone surgery and is not improving on antibiotic therapy, repeat imaging should be obtained, and the clinician should have a low threshold for returning to the operating room for repeat débridement. A study by Vander Have et al27 reported an average of 2.4 visits to the operating room for débridement in patients with MRSA infection. Patients with MRSA infection have longer hospital stays than do patients with MSSA infection,28 likely related to more diagnostic and therapeutic procedures, the increased time required for laboratory values and vital signs to normalize, and the increased time necessary to eradicate the infection. Vander Have et al27 reported that 15 of 27 patients with MRSA infection had stays of >30 days.
Critically Ill Children, Deep Vein Thrombosis, and Septic Emboli
Some children may have a fulminant course of MRSA infection that creates a necrotizing fasciitis-like picture. Vander Have et al27 reported that 12 of 27 patients required admission to the intensive care unit. Multisystem organ failure developed in four patients, necessitating the use of extracorporeal membrane oxygenation; five patients required vasopressor therapy. Patients without signs of sepsis on initial presentation should be monitored closely for any rapid decline in clinical status.
Patients with MRSA bacteremia are at risk for DVT and septic emboli.34 Hollmig et al5 reported that children older than 8 years who have osteomyelitis caused by MRSA, and who have a CRP level >6 mg/L at admission, have a 40% incidence of DVT. In addition, in the authors’ cohort of 212 patients with osteomyelitis, of which 11 patients developed DVT, 8 of the 11 patients were diagnosed with MRSA osteomyelitis. The authors recommend screening for DVT in patients with these risk factors.
Vander Have et al27 reported that 8 of 27 patients (29%) had a DVT in their series, with 7 of the 8 patients having septic pulmonary emboli. Six patients were treated with warfarin for 3 to 6 months, and two patients were treated with an inferior vena cava filter. The authors recommend DVT chemoprophylaxis in all patients hospitalized for CA-MRSA; they also recommend rapid CT of the chest for any patient with respiratory compromise. Gonzalez et al34 reported on seven patients with CA-MRSA osteomyelitis and DVT; this constituted 6% of patients with CA-MRSA osteomyelitis in their series. They reported that all patients had DVT develop in sites adjacent to the infection. Four patients developed septic pulmonary emboli. We recommend DVT ultrasound screening in all patients with MRSA bone or joint infection. If the patient is positive for DVT, has evidence of respiratory compromise, or has evidence of a heart murmur, then CT of the chest and a cardiac echocardiogram should be obtained to exclude valvular disease. Unfortunately, anticoagulation makes curtailing infection much more difficult because it needs to be managed preoperatively and postoperatively. In addition, anticoagulation leads to increased bleeding, often aiding the persistence of MRSA infection because of a decreased hematocrit and a collection of blood at the surgical site.
Patients should be followed at regular intervals after hospital discharge to ensure resolution of the infection. Inflammatory markers should be checked at the completion of treatment to ensure normalization. In addition, because most infections involve the metaphysis, the orthopaedic surgeon must continue to monitor the patient for growth disturbances that may cause limb-length discrepancy or angular deformity.
Precautions to prevent the spread of MRSA in the healthcare setting have been published by the Centers for Disease Control (CDC) in 2007.35 Most importantly, the precautions emphasize hand hygiene for clinicians and use of personal protective equipment when necessary. The CDC also recommends contact precautions when the hospital determines that MRSA is of special clinical and epidemiologic significance. Contact precautions can be cumbersome, especially in children, although the CDC assures us that contact precautions are efficacious in preventing nosocomial spread of infection.
The CDC recommends that children attend school with active MRSA infection. However, if the child has actively draining pus that cannot be covered and contained with a dry bandage, the child must stay home.36 In regard to school notification, each school should have a policy regarding whether they require notification of MRSA infection. The CDC does not feel it necessary to inform the entire school community about a single MRSA infection.
MRSA is spread easily among athletes as a result of repeated skin-to-skin contact. In addition, athletes often get breaks in the skin that allow entry of bacteria. Athletes often share items and surfaces that come into direct skin contact, and they may have poor hygiene practices either as the result of habit or a lack of access to hygiene products. Athletes should not be allowed to participate if a wound cannot be properly protected during participation.37 Proper protection of the wound means that the infected area is covered by a securely attached bandage that allows no leakage and remains attached for the duration of the contest. If the wound can be properly covered and protected, good hand hygiene should be stressed to the athlete and athletic trainers during dressing changes. Athletes with MRSA infections should not use any swimming pools or treatment pools that are not cleaned between treatments; this should remain in effect until the infection is healed. Physicians should stress availability and use of hand sanitizers and barrier creams to athletes, coaches, and athletic trainers, especially in contact sports such as wrestling.
MRSA continues to be a difficult pathogen to treat and prevent in the pediatric population. Prompt evaluation and communication between specialists can expedite the diagnosis of MRSA infection. MRSA prediction rules aim to inform clinicians of a high probability of MRSA infection so that empiric antibiotic coverage against MRSA can begin, although further study is necessary before the rules can be fully adopted. Patients with suspected MRSA infection should undergo early MRI evaluation to delineate the entire extent of the infection so that surgical treatment addresses all infected areas. Inflammatory markers should be monitored to ensure that the patient is responding to therapy appropriately. Patients with risk factors for DVT should be screened with Doppler ultrasound. Culture and sensitivity results should be monitored so that patients can be transitioned to appropriate therapy early in the course of disease to decrease the chances of development of antibiotic resistance.
Patients with MRSA should have appropriate follow-up with orthopaedic surgeons and infectious disease physicians to monitor disease progression and to ensure resolution of the infection. In addition, the orthopaedic surgeon should continue to monitor the patient for growth disturbance if the infection is near the physis. Finally, parents, teachers, and coaches should be educated about MRSA infection and prevention, and they should learn how to prevent the spread of MRSA to other children. Future study is needed to evaluate the MRSA prediction rule at multiple sites. Hospitals should work toward implementing practice guidelines to help standardize and streamline the diagnosis and treatment of this common and serious infection in children.
Evidence-based Medicine: Levels of evidence are described in the table of contents. In this article, reference 13 is a level II study. References 2-5, 8, 12, 17, 21, and 28-33 are level III studies. References 1, 6, 7, 9-11, 14-16, 18, 19, 22, 23, 25-27, and 34 are level IV studies. References 20, 24, and 35-37 are level V expert opinion.
References printed in bold type are those published within the past 5 years.
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28. Hawkshead JJ III, Patel NB, Steele RW, Heinrich SD: Comparative severity of pediatric osteomyelitis attributable to methicillin-resistant versus methicillin-sensitive Staphylococcus aureus. J Pediatr Orthop 2009;29(1):85–90.
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