ORIGINAL ARTICLE
Community-acquired Methicillin-resistant Staphylococcus aureus Musculoskeletal Infections: Emerging Trends Over the Past Decade Eric J. Sarkissian, MD,* Itai Gans, MD,w Melissa A. Gunderson, BA,z Stuart H. Myers, MD,y David A. Spiegel, MD,z and John M. Flynn, MDz
Background: The emergence of community-acquired methicillinresistant Staphylococcus aureus (MRSA) has altered the management of pediatric musculoskeletal infections. Yet, institution-to-institution differences in MRSA virulence may exist, suggesting a need to carefully examine local epidemiological characteristics. The purpose of this study was to compare MRSA and methicillin-sensitive S. aureus (MSSA) musculoskeletal infections with respect to prevalence and complexity of clinical care over the past decade at a single children’s hospital. Methods: We retrospectively reviewed a series of patients presenting to The Children’s Hospital of Philadelphia with a diagnosis of osteomyelitis, septic arthritis, or both over a 10-year period. Inclusion criteria were S. aureus (SA) infections proven by positive culture of blood, bone, or joint aspirate. Exclusion criteria were non-SA infectious etiologies. Hospital-acquired infections were also not included to exclusively evaluate acute, communityacquired cases. Data related to hospital course, laboratory values, and number of surgical interventions were collected and compared between MRSA and MSSA cohorts. Results: In our series of pediatric patients, we identified 148 cases of acute, community-acquired musculoskeletal SA infections (MRSA, n = 37 and MSSA, n = 111). The prevalence of MRSA musculoskeletal infections increased from 11.8% in 2001 to 2002 to 34.8% in 2009 to 2010. Compared with MSSA, MRSA infections resulted in higher presenting C-reactive protein levels (10.4 vs. 7.8 mg/L, P = 0.04), longer inpatient stays (10 vs. 5 d, P < 0.01), multiple surgical procedures (n > 1) (38% vs. 14%, P < 0.01), increased sequelae (27% vs. 6%, P < 0.01), and more frequent admissions to the intensive care unit (16% vs. 3%, P < 0.01). Conclusions: At our institution over the past decade, we found an approximate 3-fold rise in community-acquired pediatric MRSA musculoskeletal infections accompanied by an elevated risk for complications during inpatient management. Awareness
From the *Department of Orthopaedic Surgery, Stanford University Medical Center, Palo Alto, CA; wDepartment of Orthopaedic Surgery, Johns Hopkins Hospital, Baltimore, MD; zDivision of Orthopaedic Surgery, The Children’s Hospital of Philadelphia, Philadelphia, PA; and yColorado Orthopedic Consultants, Aurora, CO. Sources of support of funding: None. The authors declare no conflicts of interest. Reprints: John M. Flynn, MD, The Children’s Hospital of Philadelphia Wood Building, 2nd Floor, 34th Street, Civic Center Boulevard, Philadelphia, PA 19104. E-mail: fl[email protected]. Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
J Pediatr Orthop
Volume 36, Number 3, April/May 2016
of the epidemiological trends of MRSA within the local community may guide parental counseling and facilitate timely and accurate clinical diagnosis and treatment. Level of Evidence: Level II—prognostic retrospective study. Key Words: infection, MRSA, pediatric (J Pediatr Orthop 2016;36:323–327)
S
ince the beginning of the 21st century the rise of methicillin-resistant Staphylococcus aureus (MRSA) has altered the management of pediatric infections. Once primarily hospital-acquired, MRSA acquired in the community has been steadily increasing as the source of skin, soft tissue, and invasive infections in children and adolescents.1 The organism’s heightened resistance to b-lactam antibiotics is attributed to the mecA gene cassette.2,3 In addition, Panton-Valentine leukocidin genes enable MRSA isolates to produce powerful tissue cytotoxins, leading to increased tissue destruction and invasion.2–4 S. aureus (SA) remains the most common etiologic agent for osteomyelitis and septic arthritis in children and adolescents. Various reports from urban pediatric centers across the United States have documented not only a rise in community-acquired MRSA musculoskeletal infections but also an increase in the extent of tissue injury, resulting in longer hospitalizations, more frequent surgical procedures, severe complications, and residual morbidities.5–8 However, MRSA musculoskeletal pathogenicity may vary geographically,8,9 which highlights the importance of understanding the epidemiological trends of the infection at our institution in Philadelphia, which has not been previously described. Our objectives were to identify the prevalence and clinical characteristics of community-acquired MRSA musculoskeletal infections and compare them to those of methicillin-sensitive S. aureus (MSSA) musculoskeletal infections at The Children’s Hospital of Philadelphia over the past decade.
METHODS After obtaining approval from our institutional review board, a retrospective chart review was performed at our tertiary-care children’s hospital to identify all inpatient cases of children and adolescents below 19 years of age with www.pedorthopaedics.com |
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
323
J Pediatr Orthop
Sarkissian et al
musculoskeletal infections (osteomyelitis, septic arthritis, or both) between January 2001 and June 2010. Patient identification occurred initially by utilizing ICD-9 billing codes for diagnoses of osteomyelitis and septic arthritis. Musculoskeletal infection diagnoses were made on the basis of overall clinical impression, laboratory results, culture results, imaging studies, and intraoperative findings. Patients with concomitant infections of soft tissue, including myositis, pyomyositis, bone abscesses, fasciitis, and cellulitis, were also included. Only SA infections confirmed by positive cultures of blood, bone, or joint aspirate were isolated for data analysis. Other infectious etiologies or cases without a positive culture were excluded from review. Infections were classified as being hospital-acquired if they were due to a hospitalization or operation within the 6 months before admission. All hospital-acquired infections were not included to allow exclusive analysis of previously healthy pediatric patients with acute, community-acquired SA musculoskeletal infections. The medical records of patients meeting inclusion and exclusion criteria were then obtained. Clinical data gathered for each patient included age, sex, musculoskeletal infection type and location, dates of admission and discharge, magnetic resonance imaging study results, C-reactive protein (CRP) level at presentation, number of surgical procedures performed, antibiotic treatment regimen, and complications. Length of inpatient treatment was governed by clinical examination and laboratory values. All patients were divided into 2 cohorts for data analysis: culture-positive MRSA or culture-positive MSSA. The prevalence of MRSA and MSSA infections during the 10-year period was documented by grouping consecutive years (ie, 2001 to 2002, 2003 to 2004, etc.) to allow comparison of a similar total number of cases in each time period and minimize skewing of data. Continuous variables that followed a normal distribution were analyzed by using a 2-sample Student’s t test and reported as means and SDs. The CRP level and duration of hospitalization followed non-normal distributions and, therefore, were analyzed by use of the Mann-Whitney U
Volume 36, Number 3, April/May 2016
test and reported as medians and interquartile ranges. The Pearson w2 test was used to compare both cohorts with respect to categorical data. A 2-tailed P-value of < 0.05 was considered significant.
RESULTS From 2001 to 2010, 148 children and adolescents with acute, community-acquired SA musculoskeletal infections were identified at The Children’s Hospital of Philadelphia. The mean age was 9 years (range, 2 mo to 17 y), and 63% (n = 93) of the patients were male. Of all infections, 25% (n = 37) were caused by MRSA and 75% (n = 111) were due to MSSA. Demographic characteristics and clinical parameters of infection type and location were similar in both groups (Table 1). In our study population, the absolute number of SA cases increased up to the mid-portion of the decade, then plateaued for the next several years before declining at the end of the decade (Fig. 1). An analysis of the prevalence of MRSA musculoskeletal infections revealed a marked increase during the 10-year period (Fig. 2). In the beginning of the decade (2001 to 2002), 11.8% of SA musculoskeletal infections were attributed to MRSA. However, by the end of the decade (2009 to 2010), MRSA was the causative agent in 34.8%, representing an increase of approximately 3 times. The rising prevalence of MRSA was steady throughout the decade, with the exception of a slight decline from 29.3% in 2005 to 2006 to 24.4% in 2007 to 2008. Our evaluation of clinical course revealed that the MRSA group had more complications than the MSSA group (Table 2). At presentation, MRSA-infected patients had significantly higher CRP levels. No differences were noted in frequency of magnetic resonance imaging studies obtained for each cohort. Despite implementation of empiric antibiotic therapy in all patients, the MRSA cohort required twice the length of inpatient treatment compared with the MSSA cohort. Of the 148 patients, 71 received vancomycin therapy (38% of MSSA patients and 78% of MRSA patients). The remaining 77 patients were primarily treated with a combination of clindamycin, oxacillin, or a cephalosporin. Patients with MRSA also more frequently required >1 surgical intervention. Typically, an incision and drainage
TABLE 1. Demographic and Clinical Characteristics of MRSA and MSSA Musculoskeletal Infections Age (y)* Sex [n (%)] Male Female Type [n (%)] Osteomyelitis Septic arthritis Both Location [n (%)] Upper extremity Lower extremity Spine
MSSA (N = 111)
MRSA (N = 37)
P
9.0 ± 4.6
7.7 ± 4.7
0.16 0.92
70 (63) 41 (37)
23 (62) 14 (38)
66 (59) 34 (31) 11 (10)
25 (68) 6 (16) 6 (16)
0.38 0.09 0.30
23 (21) 86 (77) 2 (2)
8 (22) 29 (78) 0 (0)
0.91 0.91 0.41
*Values are reported as mean and SD. MRSA indicates methicillin-resistant Staphylococcus aureus; MSSA, methicillin-sensitive S. aureus.
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FIGURE 1. The absolute number of culture-positive methicillinsensitive Staphylococcus aureus (MSSA) and communityacquired methicillin-resistant S. aureus (MRSA) musculoskeletal infections at The Children’s Hospital of Philadelphia over the past decade. Copyright
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Volume 36, Number 3, April/May 2016
FIGURE 2. The percentage of community-acquired methicillin-resistant Staphylococcus aureus (MRSA) cases of all S. aureus musculoskeletal infections at The Children’s Hospital of Philadelphia over the past decade.
was performed in the operating room. In addition, 19% (7/ 37) of the MRSA cohort required 3 or more surgeries compared with 5% (6/111) of the MSSA cohort. During hospitalization, patients with MRSA more commonly had sequelae from their musculoskeletal infections, often requiring admission to the intensive care unit (ICU). Thromboemboli or septic shock occurred in 22% (8/37) of the MRSA group. Transfer to the ICU for management of impending circulatory failure was necessary in 6 of these patients. In the MSSA group, 3% (3/111) of patients required admission to the ICU for treatment of septic emboli or septic shock. All patients with sequelae except for 1 were diagnosed with osteomyelitis, either alone or in conjunction with septic arthritis. After discharge, residual morbidities, such as recurrence of infection or avascular necrosis, developed in 14% (5/37) of the MRSA cohort compared with 4% (5/111) of the MSSA cohort.
DISCUSSION Mounting evidence indicates that MRSA musculoskeletal infections acquired in the community in normal, healthy pediatric patients are increasing. At an institution in Memphis, a 10-fold increase (4% to 40%) was seen in acute MRSA osteomyelitis and septic arthritis between 2000 and 2004.5 A report from a center in Boston commented on the prevalence of MRSA infections among children with osteomyelitis over a decade.8 During the first half of the study
Community-acquired MRSA
period (2000 to 2004), 5.5% of osteomyelitis cases were due to MRSA, but this percentage more than doubled to 12.1% in the second half of the decade (2005 to 2009). The findings from our series follow a similar pattern. We found an approximate 3-fold increase (11.8% to 34.8%) of osteomyelitis and septic arthritis caused by culture-positive MRSA at our institution in Philadelphia over the past decade (2001 to 2010). Several reports have also documented that pediatric musculoskeletal infections produced by community-acquired MRSA are more virulent and deeply invasive than those produced by MSSA. The results from our decadelong comparison of MRSA and MSSA osteomyelitis, septic arthritis, or both support the findings in these prior studies. In the Memphis report, a retrospective comparison of 47 MRSA and 21 MSSA musculoskeletal infections revealed an increased risk of subperiosteal abscesses requiring surgical treatment in patients with MRSA.5 Subperiosteal abscesses have also been associated with an increased risk of pathologic fractures in children with MRSA osteomyelitis.10 At a children’s hospital in New Orleans, MRSA osteomyelitis (n = 11) was compared with osteomyelitis due to MSSA, other pathogens, and culture-negative cases in a total of 74 patients.11 In accordance with our results from The Children’s Hospital of Philadelphia, MRSA osteomyelitis was associated with a significant increase in CRP level at admission, length of hospital stay, and number of surgical interventions. Similar results were reported in a comparison of patients with MSSA osteomyelitis (n = 72) and MRSA osteomyelitis (n = 36) at a children’s center in Dallas.6 No significant differences in demographics were evident, as in our study. The authors did report that a significantly greater percentage of patients with MRSA osteomyelitis had complications, including bone abscesses, deep venous thromboses, extensive local disease, and disseminated disease. We also found a notable risk for thromboemboli and septic shock in our series of patients with MRSA compared with patients with MSSA. Another retrospective case series of 27 patients with MRSA has illustrated the significant potential for longterm morbidity.12 Of the 27 patients, 12 required admission to the ICU (of which, 4 developed acute multisystem failure) and 7 developed deep venous thrombosis and septic pulmonary emboli. We similarly found that
TABLE 2. Clinical Course Characteristics of MRSA and MSSA Musculoskeletal Infections MSSA (N = 111) MRI evaluation [n (%)] Presenting CRP* (mg/L)w Days as inpatientw > 1 Surgery [n (%)] Sequelae [n (%)]z ICU admission [n (%)]
80 7.8 5 16 7 3
(72) (3.0-14.8) (4-9) (14) (6) (3)
P
MRSA (N = 37) 27 10.4 10 14 10 6
(73) (4.9-23.5) (7-17) (38) (27) (16)
0.92 0.04 < 0.001 0.002 < 0.001 0.003
*CRP indicates C-reactive protein (data for 107 MSSA patients and 35 MRSA patients were available). wValues are reported as the median, with the interquartile range in parentheses. zSequelae include thromboemboli, septic shock, avascular necrosis, and recurrent infection. ICU indicates intensive care unit; MSSA, methicillin-sensitive Staphylococcus aureus; MRSA, methicillin-resistant S. aureus; MRI, magnetic resonance imaging.
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compared with patients with MSSA infection, MRSAinfected patients had a significantly higher risk for admission to the ICU for circulatory compromise and for residual morbidities, including recurrent infection and avascular necrosis. The changing pattern of musculoskeletal infections has prompted investigators to develop novel diagnostic tools to facilitate timely evaluation and accurate treatment of pediatric patients with the disease. Gafur et al7 proposed a hierarchy of musculoskeletal infection according to the primary tissue categories involved (osteomyelitis > septic arthritis > pyomyositis > abscess). The results of our study similarly show that patients with osteomyelitis, either in isolation or paired with septic arthritis, experience more severe disease and require greater amount of resources than patients with septic arthritis alone. Another study created a clinical prediction algorithm to differentiate between MSSA and MRSA osteomyelitis on patient presentation.8 Evidence-based prediction models have previously been informative in guiding clinical care, such as in differentiating between septic arthritis and transient synovitis of the hip in children.13,14 In the retrospective review of 129 children (MRSA, n = 11 and MSSA, n = 118) at a single institution in Boston, 4 independent multivariate predictors of MRSA infection were identified: temperature > 381C, hematocrit < 34%, white blood cell count > 12,000 cells/ mL, and CRP > 13 mg/L.8 The predicted probability of MRSA osteomyelitis was 92% with all 4 findings, 45% with 3, 10% with 2, 1% with 1, and 0% with 0. Despite the morbidity of MRSA musculoskeletal infections observed globally,5–8,15 more recent evidence indicates regional variations may exist in MRSA pathogenicity. A clinical algorithm developed at 1 institution to differentiate between MRSA from MSSA osteomyelitis has performed poorly when applied to the patient population of other pediatric centers.8,9 Differences in environment, racial, and cultural profiles of patients, and genetic variations of MRSA bacterial strain may be responsible for region-to-region changes in MRSA infection severity.9 As differences in MRSA virulence may exist geographically, a complete understanding of the institutional or regional epidemiology may be important to enhance clinical evaluation in establishing a prompt diagnosis and to provide effective early treatment of musculoskeletal infections.16–18 There are important limitations to our study, aside from its retrospective design. First, our study was conducted at a single institution and our findings may not be an appropriate representation of community-acquired MRSA at other institutions or geographic regions, including Philadelphia. Second, the current prevalence of MRSA musculoskeletal infections at our institution may have increased, plateaued, or even declined since the time period during which this study was conducted (2001 to 2010). Third, our clinical data are not exhaustive that hinders a thorough understanding of the perceived association between MRSA infection and a poor clinical course, and lacks a multivariate analysis to evaluate
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potential predictors of MRSA infection, like CRP. Finally, by not reviewing etiologies other than MSSA and MRSA, we were unable to determine the total cases of all musculoskeletal infections over the 10-year period of our study to provide a platform for our findings. Non-SA sources are becoming increasingly common and may be altering the entire spectrum of pediatric musculoskeletal infections.19 In conclusion, the trends of community-acquired MRSA musculoskeletal infections over the past decade at The Children’s Hospital of Philadelphia reveal a 3-fold increase in prevalence and an increase in associated risk for complications and sequelae. These findings raise awareness of MRSA musculoskeletal infections in pediatric patients within our region and provide a scaffold to counsel patients and family members about the possibility for multiple surgical interventions and complications. REFERENCES 1. Gutierrez K, Halpern MS, Sarnquist C, et al. Staphylococcal infections in children, California, USA, 1985-2009. Emerg Infect Dis. 2013;19:10–20, quiz 185. 2. Martinez-Aguilar G, Avalos-Mishaan A, Hulten K, et al. Community-acquired, methicillin-resistant and methicillin-susceptible Staphylococcus aureus musculoskeletal infections in children. Pediatr Infect Dis J. 2004;23:701–706. 3. Bocchini CE, Hulten KG, Mason EO Jr, et al. PantonValentine leukocidin genes are associated with enhanced inflammatory response and local disease in acute hematogenous Staphylococcus aureus osteomyelitis in children. Pediatrics. 2006;117: 433–440. 4. Boyle-Vavra S, Daum RS. Community-acquired methicillin-resistant Staphylococcus aureus: the role of Panton-Valentine leukocidin. Lab Invest. 2007;87:3–9. 5. Arnold SR, Elias D, Buckingham SC, et al. Changing patterns of acute hematogenous osteomyelitis and septic arthritis: emergence of community-associated methicillin-resistant Staphylococcus aureus. J Pediatr Orthop. 2006;26:703–708. 6. Saavedra-Lozano J, Mejias A, Ahmad N, et al. Changing trends in acute osteomyelitis in children: impact of methicillin-resistant Staphylococcus aureus infections. J Pediatr Orthop. 2008;28: 569–575. 7. Gafur OA, Copley LA, Hollmig ST, et al. The impact of the current epidemiology of pediatric musculoskeletal infection on evaluation and treatment guidelines. J Pediatr Orthop. 2008;28:777–785. 8. Ju KL, Zurakowski D, Kocher MS. Differentiating between methicillin-resistant and methicillin-sensitive Staphylococcus aureus osteomyelitis in children: an evidence-based clinical prediction algorithm. J Bone Joint Surg Am. 2011;93:1693–1701. 9. Wade Shrader M, Nowlin M, Segal LS. Independent analysis of a clinical predictive algorithm to identify methicillin-resistant Staphylococcus aureus osteomyelitis in children. J Pediatr Orthop. 2013;33: 759–762. 10. Belthur MV, Birchansky SB, Verdugo AA, et al. Pathologic fractures in children with acute Staphylococcus aureus osteomyelitis. J Bone Joint Surg Am. 2012;94:34–42. 11. Hawkshead JJ 3rd, Patel NB, Steele RW, et al. Comparative severity of pediatric osteomyelitis attributable to methicillin-resistant versus methicillin-sensitive Staphylococcus aureus.. J Pediatr Orthop. 2009; 29:85–90. 12. Vander Have KL, Karmazyn B, Verma M, et al. Communityassociated methicillin-resistant Staphylococcus aureus in acute musculoskeletal infection in children: a game changer. J Pediatr Orthop. 2009;29:927–931. 13. Kocher MS, Zurakowski D, Kasser JR. Differentiating between septic arthritis and transient synovitis of the hip in children: an
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Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
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evidence-based clinical prediction algorithm. J Bone Joint Surg Am. 1999;81:1662–1670. 14. Kocher MS, Mandiga R, Zurakowski D, et al. Validation of a clinical prediction rule for the differentiation between septic arthritis and transient synovitis of the hip in children. J Bone Joint Surg Am. 2004;86-A:1629–1635. 15. Kini AR, Shetty V, Kumar AM, et al. Community-associated, methicillin-susceptible, and methicillin-resistant Staphylococcus aureus bone and joint infections in children: experience from India. J Pediatr Orthop B. 2013;22:158–166. 16. Copley LA, Kinsler MA, Gheen T, et al. The impact of evidencebased clinical practice guidelines applied by a multidisciplinary team
Copyright
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2015 Wolters Kluwer Health, Inc. All rights reserved.
Community-acquired MRSA
for the care of children with osteomyelitis. J Bone Joint Surg Am. 2013;95:686–693. 17. Copley LA. Pediatric musculoskeletal infection: trends and antibiotic recommendations. J Am Acad Orthop Surg. 2009;17: 618–626. 18. Morrison MJ, Herman MJ. Hip septic arthritis and other pediatric musculoskeletal infections in the era of methicillin-resistant Staphylococcus aureus. Instr Course Lect. 2013;62:405–414. 19. Chometon S, Benito Y, Chaker M, et al. Specific real-time plymerase chain reaction places Kingella kingae as the most common cause of osteoarticular infections in oyung children. Pediatr Infect Dis J. 2007;26:377–381.
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327
Community-acquired Methicillin-resistant Staphylococcus aureus Musculoskeletal Infections: Emerging Trends Over the Past Decade Eric J. Sarkissian, MD,* Itai Gans, MD,w Melissa A. Gunderson, BA,z Stuart H. Myers, MD,y David A. Spiegel, MD,z and John M. Flynn, MDz
Background: The emergence of community-acquired methicillinresistant Staphylococcus aureus (MRSA) has altered the management of pediatric musculoskeletal infections. Yet, institution-to-institution differences in MRSA virulence may exist, suggesting a need to carefully examine local epidemiological characteristics. The purpose of this study was to compare MRSA and methicillin-sensitive S. aureus (MSSA) musculoskeletal infections with respect to prevalence and complexity of clinical care over the past decade at a single children’s hospital. Methods: We retrospectively reviewed a series of patients presenting to The Children’s Hospital of Philadelphia with a diagnosis of osteomyelitis, septic arthritis, or both over a 10-year period. Inclusion criteria were S. aureus (SA) infections proven by positive culture of blood, bone, or joint aspirate. Exclusion criteria were non-SA infectious etiologies. Hospital-acquired infections were also not included to exclusively evaluate acute, communityacquired cases. Data related to hospital course, laboratory values, and number of surgical interventions were collected and compared between MRSA and MSSA cohorts. Results: In our series of pediatric patients, we identified 148 cases of acute, community-acquired musculoskeletal SA infections (MRSA, n = 37 and MSSA, n = 111). The prevalence of MRSA musculoskeletal infections increased from 11.8% in 2001 to 2002 to 34.8% in 2009 to 2010. Compared with MSSA, MRSA infections resulted in higher presenting C-reactive protein levels (10.4 vs. 7.8 mg/L, P = 0.04), longer inpatient stays (10 vs. 5 d, P < 0.01), multiple surgical procedures (n > 1) (38% vs. 14%, P < 0.01), increased sequelae (27% vs. 6%, P < 0.01), and more frequent admissions to the intensive care unit (16% vs. 3%, P < 0.01). Conclusions: At our institution over the past decade, we found an approximate 3-fold rise in community-acquired pediatric MRSA musculoskeletal infections accompanied by an elevated risk for complications during inpatient management. Awareness
From the *Department of Orthopaedic Surgery, Stanford University Medical Center, Palo Alto, CA; wDepartment of Orthopaedic Surgery, Johns Hopkins Hospital, Baltimore, MD; zDivision of Orthopaedic Surgery, The Children’s Hospital of Philadelphia, Philadelphia, PA; and yColorado Orthopedic Consultants, Aurora, CO. Sources of support of funding: None. The authors declare no conflicts of interest. Reprints: John M. Flynn, MD, The Children’s Hospital of Philadelphia Wood Building, 2nd Floor, 34th Street, Civic Center Boulevard, Philadelphia, PA 19104. E-mail: fl[email protected]. Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
J Pediatr Orthop
Volume 36, Number 3, April/May 2016
of the epidemiological trends of MRSA within the local community may guide parental counseling and facilitate timely and accurate clinical diagnosis and treatment. Level of Evidence: Level II—prognostic retrospective study. Key Words: infection, MRSA, pediatric (J Pediatr Orthop 2016;36:323–327)
S
ince the beginning of the 21st century the rise of methicillin-resistant Staphylococcus aureus (MRSA) has altered the management of pediatric infections. Once primarily hospital-acquired, MRSA acquired in the community has been steadily increasing as the source of skin, soft tissue, and invasive infections in children and adolescents.1 The organism’s heightened resistance to b-lactam antibiotics is attributed to the mecA gene cassette.2,3 In addition, Panton-Valentine leukocidin genes enable MRSA isolates to produce powerful tissue cytotoxins, leading to increased tissue destruction and invasion.2–4 S. aureus (SA) remains the most common etiologic agent for osteomyelitis and septic arthritis in children and adolescents. Various reports from urban pediatric centers across the United States have documented not only a rise in community-acquired MRSA musculoskeletal infections but also an increase in the extent of tissue injury, resulting in longer hospitalizations, more frequent surgical procedures, severe complications, and residual morbidities.5–8 However, MRSA musculoskeletal pathogenicity may vary geographically,8,9 which highlights the importance of understanding the epidemiological trends of the infection at our institution in Philadelphia, which has not been previously described. Our objectives were to identify the prevalence and clinical characteristics of community-acquired MRSA musculoskeletal infections and compare them to those of methicillin-sensitive S. aureus (MSSA) musculoskeletal infections at The Children’s Hospital of Philadelphia over the past decade.
METHODS After obtaining approval from our institutional review board, a retrospective chart review was performed at our tertiary-care children’s hospital to identify all inpatient cases of children and adolescents below 19 years of age with www.pedorthopaedics.com |
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
323
J Pediatr Orthop
Sarkissian et al
musculoskeletal infections (osteomyelitis, septic arthritis, or both) between January 2001 and June 2010. Patient identification occurred initially by utilizing ICD-9 billing codes for diagnoses of osteomyelitis and septic arthritis. Musculoskeletal infection diagnoses were made on the basis of overall clinical impression, laboratory results, culture results, imaging studies, and intraoperative findings. Patients with concomitant infections of soft tissue, including myositis, pyomyositis, bone abscesses, fasciitis, and cellulitis, were also included. Only SA infections confirmed by positive cultures of blood, bone, or joint aspirate were isolated for data analysis. Other infectious etiologies or cases without a positive culture were excluded from review. Infections were classified as being hospital-acquired if they were due to a hospitalization or operation within the 6 months before admission. All hospital-acquired infections were not included to allow exclusive analysis of previously healthy pediatric patients with acute, community-acquired SA musculoskeletal infections. The medical records of patients meeting inclusion and exclusion criteria were then obtained. Clinical data gathered for each patient included age, sex, musculoskeletal infection type and location, dates of admission and discharge, magnetic resonance imaging study results, C-reactive protein (CRP) level at presentation, number of surgical procedures performed, antibiotic treatment regimen, and complications. Length of inpatient treatment was governed by clinical examination and laboratory values. All patients were divided into 2 cohorts for data analysis: culture-positive MRSA or culture-positive MSSA. The prevalence of MRSA and MSSA infections during the 10-year period was documented by grouping consecutive years (ie, 2001 to 2002, 2003 to 2004, etc.) to allow comparison of a similar total number of cases in each time period and minimize skewing of data. Continuous variables that followed a normal distribution were analyzed by using a 2-sample Student’s t test and reported as means and SDs. The CRP level and duration of hospitalization followed non-normal distributions and, therefore, were analyzed by use of the Mann-Whitney U
Volume 36, Number 3, April/May 2016
test and reported as medians and interquartile ranges. The Pearson w2 test was used to compare both cohorts with respect to categorical data. A 2-tailed P-value of < 0.05 was considered significant.
RESULTS From 2001 to 2010, 148 children and adolescents with acute, community-acquired SA musculoskeletal infections were identified at The Children’s Hospital of Philadelphia. The mean age was 9 years (range, 2 mo to 17 y), and 63% (n = 93) of the patients were male. Of all infections, 25% (n = 37) were caused by MRSA and 75% (n = 111) were due to MSSA. Demographic characteristics and clinical parameters of infection type and location were similar in both groups (Table 1). In our study population, the absolute number of SA cases increased up to the mid-portion of the decade, then plateaued for the next several years before declining at the end of the decade (Fig. 1). An analysis of the prevalence of MRSA musculoskeletal infections revealed a marked increase during the 10-year period (Fig. 2). In the beginning of the decade (2001 to 2002), 11.8% of SA musculoskeletal infections were attributed to MRSA. However, by the end of the decade (2009 to 2010), MRSA was the causative agent in 34.8%, representing an increase of approximately 3 times. The rising prevalence of MRSA was steady throughout the decade, with the exception of a slight decline from 29.3% in 2005 to 2006 to 24.4% in 2007 to 2008. Our evaluation of clinical course revealed that the MRSA group had more complications than the MSSA group (Table 2). At presentation, MRSA-infected patients had significantly higher CRP levels. No differences were noted in frequency of magnetic resonance imaging studies obtained for each cohort. Despite implementation of empiric antibiotic therapy in all patients, the MRSA cohort required twice the length of inpatient treatment compared with the MSSA cohort. Of the 148 patients, 71 received vancomycin therapy (38% of MSSA patients and 78% of MRSA patients). The remaining 77 patients were primarily treated with a combination of clindamycin, oxacillin, or a cephalosporin. Patients with MRSA also more frequently required >1 surgical intervention. Typically, an incision and drainage
TABLE 1. Demographic and Clinical Characteristics of MRSA and MSSA Musculoskeletal Infections Age (y)* Sex [n (%)] Male Female Type [n (%)] Osteomyelitis Septic arthritis Both Location [n (%)] Upper extremity Lower extremity Spine
MSSA (N = 111)
MRSA (N = 37)
P
9.0 ± 4.6
7.7 ± 4.7
0.16 0.92
70 (63) 41 (37)
23 (62) 14 (38)
66 (59) 34 (31) 11 (10)
25 (68) 6 (16) 6 (16)
0.38 0.09 0.30
23 (21) 86 (77) 2 (2)
8 (22) 29 (78) 0 (0)
0.91 0.91 0.41
*Values are reported as mean and SD. MRSA indicates methicillin-resistant Staphylococcus aureus; MSSA, methicillin-sensitive S. aureus.
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FIGURE 1. The absolute number of culture-positive methicillinsensitive Staphylococcus aureus (MSSA) and communityacquired methicillin-resistant S. aureus (MRSA) musculoskeletal infections at The Children’s Hospital of Philadelphia over the past decade. Copyright
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FIGURE 2. The percentage of community-acquired methicillin-resistant Staphylococcus aureus (MRSA) cases of all S. aureus musculoskeletal infections at The Children’s Hospital of Philadelphia over the past decade.
was performed in the operating room. In addition, 19% (7/ 37) of the MRSA cohort required 3 or more surgeries compared with 5% (6/111) of the MSSA cohort. During hospitalization, patients with MRSA more commonly had sequelae from their musculoskeletal infections, often requiring admission to the intensive care unit (ICU). Thromboemboli or septic shock occurred in 22% (8/37) of the MRSA group. Transfer to the ICU for management of impending circulatory failure was necessary in 6 of these patients. In the MSSA group, 3% (3/111) of patients required admission to the ICU for treatment of septic emboli or septic shock. All patients with sequelae except for 1 were diagnosed with osteomyelitis, either alone or in conjunction with septic arthritis. After discharge, residual morbidities, such as recurrence of infection or avascular necrosis, developed in 14% (5/37) of the MRSA cohort compared with 4% (5/111) of the MSSA cohort.
DISCUSSION Mounting evidence indicates that MRSA musculoskeletal infections acquired in the community in normal, healthy pediatric patients are increasing. At an institution in Memphis, a 10-fold increase (4% to 40%) was seen in acute MRSA osteomyelitis and septic arthritis between 2000 and 2004.5 A report from a center in Boston commented on the prevalence of MRSA infections among children with osteomyelitis over a decade.8 During the first half of the study
Community-acquired MRSA
period (2000 to 2004), 5.5% of osteomyelitis cases were due to MRSA, but this percentage more than doubled to 12.1% in the second half of the decade (2005 to 2009). The findings from our series follow a similar pattern. We found an approximate 3-fold increase (11.8% to 34.8%) of osteomyelitis and septic arthritis caused by culture-positive MRSA at our institution in Philadelphia over the past decade (2001 to 2010). Several reports have also documented that pediatric musculoskeletal infections produced by community-acquired MRSA are more virulent and deeply invasive than those produced by MSSA. The results from our decadelong comparison of MRSA and MSSA osteomyelitis, septic arthritis, or both support the findings in these prior studies. In the Memphis report, a retrospective comparison of 47 MRSA and 21 MSSA musculoskeletal infections revealed an increased risk of subperiosteal abscesses requiring surgical treatment in patients with MRSA.5 Subperiosteal abscesses have also been associated with an increased risk of pathologic fractures in children with MRSA osteomyelitis.10 At a children’s hospital in New Orleans, MRSA osteomyelitis (n = 11) was compared with osteomyelitis due to MSSA, other pathogens, and culture-negative cases in a total of 74 patients.11 In accordance with our results from The Children’s Hospital of Philadelphia, MRSA osteomyelitis was associated with a significant increase in CRP level at admission, length of hospital stay, and number of surgical interventions. Similar results were reported in a comparison of patients with MSSA osteomyelitis (n = 72) and MRSA osteomyelitis (n = 36) at a children’s center in Dallas.6 No significant differences in demographics were evident, as in our study. The authors did report that a significantly greater percentage of patients with MRSA osteomyelitis had complications, including bone abscesses, deep venous thromboses, extensive local disease, and disseminated disease. We also found a notable risk for thromboemboli and septic shock in our series of patients with MRSA compared with patients with MSSA. Another retrospective case series of 27 patients with MRSA has illustrated the significant potential for longterm morbidity.12 Of the 27 patients, 12 required admission to the ICU (of which, 4 developed acute multisystem failure) and 7 developed deep venous thrombosis and septic pulmonary emboli. We similarly found that
TABLE 2. Clinical Course Characteristics of MRSA and MSSA Musculoskeletal Infections MSSA (N = 111) MRI evaluation [n (%)] Presenting CRP* (mg/L)w Days as inpatientw > 1 Surgery [n (%)] Sequelae [n (%)]z ICU admission [n (%)]
80 7.8 5 16 7 3
(72) (3.0-14.8) (4-9) (14) (6) (3)
P
MRSA (N = 37) 27 10.4 10 14 10 6
(73) (4.9-23.5) (7-17) (38) (27) (16)
0.92 0.04 < 0.001 0.002 < 0.001 0.003
*CRP indicates C-reactive protein (data for 107 MSSA patients and 35 MRSA patients were available). wValues are reported as the median, with the interquartile range in parentheses. zSequelae include thromboemboli, septic shock, avascular necrosis, and recurrent infection. ICU indicates intensive care unit; MSSA, methicillin-sensitive Staphylococcus aureus; MRSA, methicillin-resistant S. aureus; MRI, magnetic resonance imaging.
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Sarkissian et al
compared with patients with MSSA infection, MRSAinfected patients had a significantly higher risk for admission to the ICU for circulatory compromise and for residual morbidities, including recurrent infection and avascular necrosis. The changing pattern of musculoskeletal infections has prompted investigators to develop novel diagnostic tools to facilitate timely evaluation and accurate treatment of pediatric patients with the disease. Gafur et al7 proposed a hierarchy of musculoskeletal infection according to the primary tissue categories involved (osteomyelitis > septic arthritis > pyomyositis > abscess). The results of our study similarly show that patients with osteomyelitis, either in isolation or paired with septic arthritis, experience more severe disease and require greater amount of resources than patients with septic arthritis alone. Another study created a clinical prediction algorithm to differentiate between MSSA and MRSA osteomyelitis on patient presentation.8 Evidence-based prediction models have previously been informative in guiding clinical care, such as in differentiating between septic arthritis and transient synovitis of the hip in children.13,14 In the retrospective review of 129 children (MRSA, n = 11 and MSSA, n = 118) at a single institution in Boston, 4 independent multivariate predictors of MRSA infection were identified: temperature > 381C, hematocrit < 34%, white blood cell count > 12,000 cells/ mL, and CRP > 13 mg/L.8 The predicted probability of MRSA osteomyelitis was 92% with all 4 findings, 45% with 3, 10% with 2, 1% with 1, and 0% with 0. Despite the morbidity of MRSA musculoskeletal infections observed globally,5–8,15 more recent evidence indicates regional variations may exist in MRSA pathogenicity. A clinical algorithm developed at 1 institution to differentiate between MRSA from MSSA osteomyelitis has performed poorly when applied to the patient population of other pediatric centers.8,9 Differences in environment, racial, and cultural profiles of patients, and genetic variations of MRSA bacterial strain may be responsible for region-to-region changes in MRSA infection severity.9 As differences in MRSA virulence may exist geographically, a complete understanding of the institutional or regional epidemiology may be important to enhance clinical evaluation in establishing a prompt diagnosis and to provide effective early treatment of musculoskeletal infections.16–18 There are important limitations to our study, aside from its retrospective design. First, our study was conducted at a single institution and our findings may not be an appropriate representation of community-acquired MRSA at other institutions or geographic regions, including Philadelphia. Second, the current prevalence of MRSA musculoskeletal infections at our institution may have increased, plateaued, or even declined since the time period during which this study was conducted (2001 to 2010). Third, our clinical data are not exhaustive that hinders a thorough understanding of the perceived association between MRSA infection and a poor clinical course, and lacks a multivariate analysis to evaluate
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potential predictors of MRSA infection, like CRP. Finally, by not reviewing etiologies other than MSSA and MRSA, we were unable to determine the total cases of all musculoskeletal infections over the 10-year period of our study to provide a platform for our findings. Non-SA sources are becoming increasingly common and may be altering the entire spectrum of pediatric musculoskeletal infections.19 In conclusion, the trends of community-acquired MRSA musculoskeletal infections over the past decade at The Children’s Hospital of Philadelphia reveal a 3-fold increase in prevalence and an increase in associated risk for complications and sequelae. These findings raise awareness of MRSA musculoskeletal infections in pediatric patients within our region and provide a scaffold to counsel patients and family members about the possibility for multiple surgical interventions and complications. REFERENCES 1. Gutierrez K, Halpern MS, Sarnquist C, et al. Staphylococcal infections in children, California, USA, 1985-2009. Emerg Infect Dis. 2013;19:10–20, quiz 185. 2. Martinez-Aguilar G, Avalos-Mishaan A, Hulten K, et al. Community-acquired, methicillin-resistant and methicillin-susceptible Staphylococcus aureus musculoskeletal infections in children. Pediatr Infect Dis J. 2004;23:701–706. 3. Bocchini CE, Hulten KG, Mason EO Jr, et al. PantonValentine leukocidin genes are associated with enhanced inflammatory response and local disease in acute hematogenous Staphylococcus aureus osteomyelitis in children. Pediatrics. 2006;117: 433–440. 4. Boyle-Vavra S, Daum RS. Community-acquired methicillin-resistant Staphylococcus aureus: the role of Panton-Valentine leukocidin. Lab Invest. 2007;87:3–9. 5. Arnold SR, Elias D, Buckingham SC, et al. Changing patterns of acute hematogenous osteomyelitis and septic arthritis: emergence of community-associated methicillin-resistant Staphylococcus aureus. J Pediatr Orthop. 2006;26:703–708. 6. Saavedra-Lozano J, Mejias A, Ahmad N, et al. Changing trends in acute osteomyelitis in children: impact of methicillin-resistant Staphylococcus aureus infections. J Pediatr Orthop. 2008;28: 569–575. 7. Gafur OA, Copley LA, Hollmig ST, et al. The impact of the current epidemiology of pediatric musculoskeletal infection on evaluation and treatment guidelines. J Pediatr Orthop. 2008;28:777–785. 8. Ju KL, Zurakowski D, Kocher MS. Differentiating between methicillin-resistant and methicillin-sensitive Staphylococcus aureus osteomyelitis in children: an evidence-based clinical prediction algorithm. J Bone Joint Surg Am. 2011;93:1693–1701. 9. Wade Shrader M, Nowlin M, Segal LS. Independent analysis of a clinical predictive algorithm to identify methicillin-resistant Staphylococcus aureus osteomyelitis in children. J Pediatr Orthop. 2013;33: 759–762. 10. Belthur MV, Birchansky SB, Verdugo AA, et al. Pathologic fractures in children with acute Staphylococcus aureus osteomyelitis. J Bone Joint Surg Am. 2012;94:34–42. 11. Hawkshead JJ 3rd, Patel NB, Steele RW, et al. Comparative severity of pediatric osteomyelitis attributable to methicillin-resistant versus methicillin-sensitive Staphylococcus aureus.. J Pediatr Orthop. 2009; 29:85–90. 12. Vander Have KL, Karmazyn B, Verma M, et al. Communityassociated methicillin-resistant Staphylococcus aureus in acute musculoskeletal infection in children: a game changer. J Pediatr Orthop. 2009;29:927–931. 13. Kocher MS, Zurakowski D, Kasser JR. Differentiating between septic arthritis and transient synovitis of the hip in children: an
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evidence-based clinical prediction algorithm. J Bone Joint Surg Am. 1999;81:1662–1670. 14. Kocher MS, Mandiga R, Zurakowski D, et al. Validation of a clinical prediction rule for the differentiation between septic arthritis and transient synovitis of the hip in children. J Bone Joint Surg Am. 2004;86-A:1629–1635. 15. Kini AR, Shetty V, Kumar AM, et al. Community-associated, methicillin-susceptible, and methicillin-resistant Staphylococcus aureus bone and joint infections in children: experience from India. J Pediatr Orthop B. 2013;22:158–166. 16. Copley LA, Kinsler MA, Gheen T, et al. The impact of evidencebased clinical practice guidelines applied by a multidisciplinary team
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Community-acquired MRSA
for the care of children with osteomyelitis. J Bone Joint Surg Am. 2013;95:686–693. 17. Copley LA. Pediatric musculoskeletal infection: trends and antibiotic recommendations. J Am Acad Orthop Surg. 2009;17: 618–626. 18. Morrison MJ, Herman MJ. Hip septic arthritis and other pediatric musculoskeletal infections in the era of methicillin-resistant Staphylococcus aureus. Instr Course Lect. 2013;62:405–414. 19. Chometon S, Benito Y, Chaker M, et al. Specific real-time plymerase chain reaction places Kingella kingae as the most common cause of osteoarticular infections in oyung children. Pediatr Infect Dis J. 2007;26:377–381.
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