ORIGINAL ARTICLE
Pediatric Acute Hematogenous Osteomyelitis Matthew Street, MBChB,*w Rupesh Puna, MBChB,* Mark Huang, MBChB,* and Haemish Crawford, FRACS*w
Background: Osteomyelitis continues to be a significant problem among the New Zealand pediatric population. We present a large series of acute hematogenous osteomyelitis (AHO) cases, with the aim to identify any changing trends and guide successful management of the disease. Methods: A 10-year retrospective review was performed of clinical records of children with AHO at the 2 children’s orthopaedic departments in the Auckland region. Cases were identified from Starship Children’s Hospital between 1997 and 2007 and Middlemore’s Kidz First Hospital between 1998 and 2008. Results: A total of 813 cases of pediatric AHO were identified. The incidence was 1:4000, which was decreasing over the 10-year period. There was a male predominance and New Zealand (NZ) Maori and Pacific Islanders were overrepresented. The diagnosis was made clinically in 27%, radiographically in 66%, and surgically in 7%. The most common pathogen was Staphylococcus aureus and the incidence of methicillin-resistant S. aureus was low (2%). The average length of antibiotic treatment was 44 days and 44% required surgery. This produced a recurrence rate of only 7% and a 15% treatment-related complication rate. Conclusions: In the New Zealand population, the incidence of AHO remains high with NZ Maori and Pacific Islanders overrepresented. The predominant pathogen remains S. aureus and our population has a very low incidence of methicillin-resistant S. aureus; flucloxacillin remains a good choice for empiric treatment in our population. Our rate of relapse and subsequent chronic osteomyelitis is low. This could be explained by traditionally longer antibiotic courses; however, this may also lead to increased treatment-related complications. Through prompt and accurate diagnosis with the aid of laboratory and radiologic tests and effective treatment with appropriate antibiotics (guided by local pathogen sensitivities) and surgical treatment when indicated, AHO can be well managed with minimal severe complications. Level of Evidence: Level IV—retrospective case series. Key Words: pediatric, infection, osteomyelitis, acute, hematogenous (J Pediatr Orthop 2015;35:634–639)
From the *Starship Children’s Hospital; and wDepartment of Medicine, University of Auckland, Auckland, New Zealand. The authors declare no conflicts of interest. Reprints: Matthew Street, MBChB, Department of Medicine, University of Auckland, 50 Sonia Avenue, Remuera, 1050, Auckland, New Zealand. E-mail: [email protected]. Copyright r 2014 Wolters Kluwer Health, Inc. All rights reserved.
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A
cute hematogenous osteomyelitis (AHO) continues to be a rare but significant problem among the pediatric population. The reported incidence ranges from 1:1000 to 1:20,000 children per year.1 The diagnosis of osteomyelitis involves skilled interpretation of the clinical presentation, blood tests and bacterial cultures, radiologic studies, and in some cases surgical exploration.2 Management of AHO includes antibiotics, immobilization, and surgery when indicated. Morbidity due to delay in diagnosis and inadequate treatment continue to result in permanent sequelae.3 Up-to-date knowledge of AHO and its current trends is important to aid prompt and accurate diagnosis and effective treatment. Gillespie and Mayo4 published the most recent large series from New Zealand in 1981, which included 655 children. We present our 10-year retrospective series of 813 children with AHO; to our knowledge the largest series presented thus far.
METHODS A 10-year retrospective review was performed of clinical records of all cases of pediatric (age: newborn to 15 y) osteomyelitis treated at Auckland’s 2 pediatric orthopaedic departments. The osteomyelitis database was formed by identifying all cases by clinical coding. Patients were included from Starship Children’s Hospital from 1997 to 2007 and Middlemore’s Kidz First Hospital from 1998 to 2008. These patients were provisionally included in the study population. Review of case notes and hospital records was conducted on this provisional group, and from this our study group was identified. We defined AHO based on symptom duration 15 mm/h) in 562 of 719 tested (78%). The average C-reactive protein (CRP) was 86.4 mg/L (range, 5 mg/L) in 495 of 602 tested (82%). A total of 65 (8%) had both a normal ESR and CRP on admission. Of those patients with normal ESR and CRP, the small bones in the foot and hand were more commonly affected (23% and 14%, respectively) and only 1 case was initially blood culture positive. The diagnosis of AHO was made primarily clinically in 27%, radiographically in 66%, and surgically in 7%. Clinical diagnosis was made by the primary treating orthopaedic surgeon or physician. This was based on the clinical presentation and laboratory investigations including inflammatory markers (WCC, ESR, and CRP) and blood cultures, in the absence of an x-ray abnormality. Radiographic diagnosis was made by plain radiograph, magnetic resonance imaging (MRI), bone scintigraphy, and less commonly ultrasound scan and computed tomography. In the final group, the diagnosis was confirmed on surgical exploration, undertaken based on suspicion in the septic child without initial radiographic abnormality. These children were generally more unwell with higher inflammatory markers (average ESR, 57.3 mm/h; average CRP, 111.1 mg/L). Seventy-five percent of these cases yielded positive tissue cultures. We observed a decrease over time of children diagnosed by surgical exploration, with 19 children in the first 2 years compared with 6 children in the last 2 years, which is likely due to MRI Copyright
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Pediatric Acute Hematogenous Osteomyelitis
TABLE 1. Ethnic Group and Sex of Children With AHO n (%) Ethnic Group European (NZ or other) Pacific Island NZ Maori Asian Other Total
Total 285 248 179 48 53 813
(35) (31) (22) (6) (6) (100)
Male 192 162 112 24 27 517
(24) (20) (14) (3) (3) (64)
Female 93 86 67 24 26 296
Incidence
(11) (11) (8) (3) (3) (36)
1:4500 1:2500 1:2500 1:10,000 1:4500 1:4000
AHO indicates acute hematogenous osteomyelitis.
becoming more accessible. The use of MRI as a diagnostic modality increased significantly over the study period, with 22% of diagnoses made based on MRI in the first 2 years, compared with 64% in the last 2 years. The means of diagnosis as well as the specific radiographic modality used to diagnose AHO is shown in Table 2. The most common bone affected was the femur in 267 cases (31%), followed by the tibia in 191 cases (22%). Unusual sites of infection included 12 affecting the clavicle, 2 affecting the skull, 2 affecting the patella, and 1 affecting the ribs. A total of 37 (4.5%) had multifocal osteomyelitis on admission. Sites of infection are summarized in Table 3. A causative pathogen was isolated in 406 children (50%). The most common pathogen was Staphylococcus aureus, isolated in 321 cases (39% of total population or 77% of total pathogens cultured). Methicillin-resistant S. aureus (MRSA) was isolated in only 18 patients (2% of the population or 4% of total pathogens cultured). There were 3 cases with Kingella kingae isolated. There was only a single case of Haemophilus influenzae type B. Pathogens and means of culture are summarized in Table 4. Flucloxacillin was the most common antibiotic used. It was administered as first-line treatment in 482 children (59%), and in 268 (33%) it was the only antibiotic given. Looking at overall use, flucloxacillin was prescribed in 510 (63%) at 1 point in time during the course of their treatment. The next most common antibiotic was amoxicillin clavulanate. This was administered as first-line treatment in 252 (31%) and was the only antibiotic given in 227 (28%). A total of 328 (40%) were prescribed amoxicillin clavulanate at 1 point in time during their treatment. When no pathogen was cultured, amoxicillin clavulanate was most commonly used.
TABLE 2. Means of Diagnosis Means of Diagnosis
No. Cases (%)
Clinically Radiographically (total) MRI Bone scintigraphy Others (CT/USS/XR/combination) Surgically
217 536 387 90 59 60
(27) (66) (48) (11) (7) (7)
CT indicates computed tomography; MRI, magnetic resonance imaging; USS, ultrasound scan; XR, x-ray.
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TABLE 3. Site of Osteomyelitis
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TABLE 5. Complications of AHO (Nontreatment Related)
Location
No. Cases (%)
Lower limb Femur Tibia Fibula Calcaneus Other tarsals Metatarsals Phalanges Patella Upper limb Humerus Radius Ulna Carpals Metacarpals Phalanges Clavicle Scapula Pelvis Spine Skull Ribs
619 267 191 51 60 13 22 13 2 147 56 29 23 3 4 18 12 2 101 8 2 1
(71) (31) (22) (6) (7) (1) (3) (1) (0.2) (17) (6) (3) (3) (0.3) (0.5) (2) (1) (0.2) (12) (1) (0.2) (0.1)
Complications
N (%)
Recurrence Chronic osteomyelitis Pathologic fracture Femur Tibia Growth disturbance Femur Tibia Humerus Radius/ulna Finger phalanx Metatarsal Amputation Below knee amputation Digit amputation Deep vein thrombosis Other Total
55 14 8 6 2 15 4 3 2 2 2 1 2 1 1 3 16 45
(6.8) (1.7) (1) (0.7) (0.2) (1.8) (0.5) (0.4) (0.2) (0.2) (0.2) (0.2) (0.2) (0.1) (0.1) (0.4) (2) (5.5)
AHO indicates acute hematogenous osteomyelitis.
(1.8%) experienced growth-related problems (Table 5). Pathologic fractures occurred in the long bones of the lower limb, in which there was significant disruption of the bony architecture secondary to the infection. Growth disturbance predominantly led to limb length discrepancy; however, there were 3 cases of angular deformity. One was in a metatarsal and 2 in phalanges of the hand. There was also a case of radius/ulna synostosis. Three cases were complicated by deep vein thrombosis (DVT). All 3 had S. aureus septicemia secondary to osteomyelitis of the femur (2) or pelvis (1). One case resulted in a below knee amputation. This was a 15-year-old male with severe tibia/fibula osteomyelitis with pus extending throughout all compartments of the lower leg. During multiple debridements, flexor digitorum longus, tibialis posterior, and flexor hallucis longus were found to be completely necrotic and removed. He developed chronic recurring osteomyelitis with persistent wound problems and minimal function of the affected limb. After below knee amputation he has been free of infection and mobilizing with a prosthesis. A total of 124 patients (15.2%) experienced complications secondary to their treatment. Ninety-five patients (11.7%) had antibiotic reactions, for example, urticaria or neutropenia. Twenty-three (2.8%) had problems related to their peripherally inserted central catheter (PICC) or
Note that the total of 878 sites is >813 patients in the study, given 37 individuals had a multifocal acute hematogenous osteomyelitis.
The average length of combined intravenous (IV) and oral antibiotic treatment was 43.7 days (range, 14 to 336 d). There were no significant changes in antibiotic duration over the course of the study. Average length of IV treatment was 22.3 days (range, 1 to 168 d). Average length of oral antibiotic treatment was 21.4 days (range, 0 to 252 d). A CRP < 5 mg/L and clinical resolution were indications for changing from IV to oral antibiotics and an empiric 6-week antibiotic course was often observed. A total of 361 patients (44%) required surgical intervention. These patients underwent an average of 2 operations (range, 1 to 12). This included drainage of subperiosteal abscess, open biopsy, adjacent joint aspiration and/or washout, and uncommonly drilling of the affected metaphysis. Fifty-five children (6.8%) suffered relapse of osteomyelitis, with average time until relapse of 5.8 months. Relapse was more common in children with multifocal osteomyelitis (19%). Fourteen children (1.7%) subsequently developed chronic osteomyelitis (Table 5). Evaluating other complications, 8 patients (1%) suffered pathologic fracture following discharge and 15
TABLE 4. Organisms Cultured and Means of Culture Pathogens Staphylococcus aureus MRSA Streptococcus pyogenes Other Total
Blood Culture
Tissue Culture
Blood and Tissue Culture
Total
Total Pathogens Cultured (%)
Total Patients (%)
115 1 12 26 154
107 9 14 25 155
99 8 0 1 108
321 18 26 52 417
77 4 6 13 100
39 2 3 6 50
MRSA indicates methicillin-resistant S. aureus.
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other venous access. Six (0.7%) had both antibiotic reactions and PICC-related problems. A total of 119 (14.6%) required readmission to hospital for treatment-related complications. Starship Children’s Hospital and Middlemore’s Kidz First Hospitals cover pediatric orthopaedics for the entire region, thus any complications should present to our institutes. The follow-up period is thus estimated at 5 to 16 years.
DISCUSSION AHO remains a potentially serious disease. Prompt diagnosis and initiation of antibiotic treatment gives the best chance of avoiding surgical intervention and adverse outcomes.3,6–8 Knowledge of current trends in demographics, diagnosis, and treatment is important to aid effective management. The incidence of AHO in our population (1:4000) is higher than that reported by others.4,9–11 For comparison, the annual incidence in the United States is estimated at 1:5000.10 There has been a worldwide fall in the incidence of AHO.11–13 Our series also demonstrates a decline over time with the incidence in the last 2 years (1:4500) lower than that in the first 2 years (1:3500) of the study period. We have also demonstrated a significantly higher incidence in the NZ Maori and Pacific Island populations compared with that in the European population and a much lower incidence in the Asian population. Rosaak and Pitto14 also showed this in their study, in which the incidence of osteomyelitis in non-Polynesian New Zealand children was 11.1:100,000 (or 1:9000), whereas the incidence for Polynesian children (including NZ Maori) was 42.8:100,000 (or 1:2500). Lower socioeconomic status and lower standard of living have been suggested to contribute to this higher rate; however, Blyth et al11 have shown that the incidence of osteomyelitis is similar throughout the social spectrum and locally Finger et al15 have demonstrated no increased risk of cellulitis with lower socioeconomic status. We showed a male predominance of 1.75:1 and the majority of children in our series were aged between 2 and 10 years (51%), which is a similar distribution to that previously reported, with preschool and school-aged children predominating over neonates, infants, and adolescents.7,13,16–18 Craigen et al12 have reported a decreasing incidence of long bone osteomyelitis; however, 69% of our cases still affected the long bones. The femur (31%) and tibia (22%) are the most common sites of AHO, which compares to the reported ranges of 16% to 33% for the femur, and 12% to 31% for the tibia.6,7,13,16–19 Radiology remains an essential tool for diagnosing AHO and should be used in every case of suspected infection.20 The main role of plain radiographs is to rule out other pathologies, such as fracture, as it can take 10 to 14 days before periosteal new bone formation is seen.21 In this study, MRI was the main diagnostic modality, aiding in the diagnosis of 48% of patients. Browne et al22 reported a 98% sensitivity for MRI in diagnosing osteomyelitis; however, the use of MRI was initially limited by Copyright
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cost and access. We observed a significant increase in the use of MRI over the study period, as MRI became more readily accessible. Pa¨a¨kko¨nen et al23 reported the sensitivity of serum markers of inflammation in osteoarticular infection. WCC is normal in 50% to 80% of cases.23,24 ESR and CRP alone provide a sensitivity of 94% and 95%, respectively, whereas together they produce a sensitivity of 98%.23 They are, however, nonspecific, making the high negative predictive value most useful.25 In our study, WCC was abnormal in only 32% of cases, ESR was elevated in 78%, and CRP was elevated in 82%. Eight percent of cases had both normal ESR and CRP. Normal inflammatory markers may be reassuring; however, one must correlate these results with the greater clinical picture and maintain a high level of suspicion for this serious pathology. S. aureus, isolated in 77% of positive cultures, remains the most common causative pathogen. This is in accordance with previous results reporting its occurrence ranging between 48% and 94% in various populations.6,7,11,16–19,26,27 We only had 1 case of H. influenzae type B and attribute this to the introduction of the vaccination, which has essentially led to its eradication, as previously reported.28 The emergence of MRSA over the past few years as a responsible pathogen for musculoskeletal infection has been well described around the world.29–32 SaavedraLozano et al29 reported rates of MRSA acute osteomyelitis approaching 31% in the latter part of their study. In comparison, our series demonstrated a low rate of MRSA AHO, of only 2% of the total cases. Interestingly, Gwynne-Jones and Stott30 reported a 20% incidence of MRSA in musculoskeletal infections (mostly superficial infections) in the same institution in 1996 to 1997. We cannot explain this difference. We identified only 3 cases caused by K. kingae, which most likely reflects inappropriate culture technique and the underuse of polymerase chain reaction in our institutes over the study period. Chometon et al33 reported K. kingae as the most common pathogen in pediatric osteoarticular infections when investigating cases using real-time polymerase chain reaction. The choice of the most effective antibiotics has been well investigated with varying recommendations.17,26,34,35 The antibiotic regimen for the treatment of AHO needs to be tailored for each institution. In Gillespie and Mayo’s4 study, spanning the first 30 years of the “antibiotic era,” penicillin and erythromycin were the main antibiotics used to combat predominantly S. aureus infections. Nowadays, with penicillin-resistant S. aureus as the predominant infecting pathogen, flucloxacillin is accepted as a good first-line treatment.11,35,36 In over half of our population (59%), flucloxacillin was used as the initial antibiotic of choice. In other centers where there is a high incidence of MRSA,29,32 initial treatment may vary and consideration must be given to vancomycin as first-line treatment until a pathogen is cultured and sensitivities are available.32 Our average length of antibiotic treatment was 43.7 days, of which an average of 22.3 days was IV. www.pedorthopaedics.com |
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Controversy over the role of surgical intervention has been well documented with varying opinions both for16,37–40 and against6,7,17,22,34 routine surgical management. The main indications for surgery include failure to respond to antibiotics after 48 to 72 hours, frank pus on aspiration, intra-articular suppuration, or sequestered abscess.6,7,9,41,42 With clinical or radiologic evidence of septic arthritis or abscess formation, we would proceed to surgery immediately. In our institutions drilling of the affected bone is not routine. Forty-four percent required surgical intervention. This is similar to that published in the previous large study in New Zealand by Gillespie and Mayo4 (46%). Our rate of recurrence was 6.8% and development of chronic osteomyelitis was only 1.7%, both of which are comparatively low.4,6,7,11,16,17,26,34 Gillespie and Mayo4 reported a recurrence rate of 17%, most of which occurred within the first year of the initial illness. Other complications of AHO reported include pathologic fracture, growth disturbance, local extension to soft tissues, involvement of an adjacent joint, and occasionally death.3 There were no deaths in our series. Approximately 1.8% of our population experienced growth disturbance and 1% suffered pathologic fracture. Both of these were lower than that reported by Blyth et al11 (2% and 4%, respectively) and Gilmour34 (5% growth disturbance). Pathologic fractures occurred solely in the long bones of the lower limb, in which there was significant disruption of the bony architecture. When this is seen, one should consider a period of prophylactic casting and/or protected weightbearing. DVT and amputation are rare but important complications. The 3 patients who had DVTs all had S. aureus septicemia from osteomyelitis of the femur (2) or pelvis (1). This is an important diagnosis to be aware of when reviewing systemically unwell osteomyelitis patients. Amputation should only be considered once all other reasonable options have failed and there is little or no function to be salvaged from the affected limb. Our rate of treatment-related complications was 15.2% with 14.6% readmitted for these complications. It seems our current regime of treatment is effective; however, Petolta et al’s43 study would suggest a shorter course may be just as effective (in a subset of uncomplicated AHO) and avoid the complications associated with longterm antibiotics and central catheters.44 The high incidence of treatment-related complications (15.2%) has led to a randomized controlled trial at our institutions comparing short-course versus long-course antibiotics, which may lead to a reduction of these complications in the future. In conclusion, from this large series we have found a relatively high incidence of AHO within our population with an increased incidence in the NZ Maori and Pacific Island ethnic groups and a male predominance. The incidence over time, however, is decreasing. The long bones remain most commonly affected. The predominant pathogen is S. aureus and our population had a very low incidence of MRSA. Flucloxacillin remains a good choice for
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empiric treatment in our population. Our rate of relapse and subsequent chronic osteomyelitis remains low. This could be explained by traditionally longer antibiotic courses; however, longer courses may also lead to increased treatment-related complications. Through prompt and accurate diagnosis with the aid of laboratory and radiologic tests and effective treatment with appropriate antibiotics (guided by local pathogen sensitivities) and surgical treatment when indicated, AHO can be well managed with minimal severe complications. REFERENCES 1. Krogstad P, Smith AL. Osteomyelitis and septic arthritis. In: Feigin RD, Cherry JD, eds. Textbook of Paediatric Infectious Diseases. 4th ed. Philadelphia, PA: WB Saunders; 1998:683–704. 2. Gold R. Diagnosis of osteomyelitis. Pediatr Rev. 1991;12:292–297. 3. Nade S. Acute haematogenous osteomyelitis in infancy and childhood. J Bone Joint Surg (Br). 1983;65-B:109–118. 4. Gillespie WJ, Mayo KM. The management of acute haematogenous osteomyelitis in the antibiotic era—a study of the outcome. J Bone Joint Surg (Br). 1981;63-B:126–131. 5. Statistics New Zealand Tatauranga Aotearoa (Census—Statistics New Zealand Web site). 2010 Available at: http://www.stats. govt.nz/Census.aspx. Accessed January 21, 2014. 6. O’Brien T, McManus F, MacAuley PH, et al. Acute haematogenous osteomyelitis. J Bone Joint Surg (Br). 1982;64-B:450–453. 7. Cole WG, Dalziel RE, Leiti S. Treatment of acute osteomyelitis in childhood. J Bone Joint Surg (Br). 1982;64-B:218–223. 8. Mercer W. Acute haematogenous osteomyelitis. Postgrad Med J. 1951;27:327–331. 9. Baker ADL, Macnicol MF. Haematogenous osteomyelitis in children: epidemiology, classification, aetiology and treatment. Paediatr Child Health. 2007;18:75–84. 10. Sonnen GM, Henry NK. Pediatric bone and joint infections: diagnosis and anti-microbial management. Pediatr Clin North Am. 1996;43:933–947. 11. Blyth MJF, Kincaid R, Craigen MAC, et al. The changing epidemiology of acute and subacute haematogenous osteomyelitis in children. J Bone Joint Surg (Br). 2001;83-B:99–102. 12. Craigen MAC, Watters J, Hackett JS. The changing epidemiology of osteomyelitis in children. J Bone Joint Surg (Br). 1992;74-B: 541–545. 13. Goergens ED, McEvoy A, Watson M, et al. Acute osteomyelitis and septic arthritis in children. J Paediatr Child Health. 2005;41:59–62. 14. Rosaak M, Pitto R. Osteomyelitis in Polynesian children. Int Orthop. 2005;29:55–58. 15. Finger F, Rosaak M, Umstaetter R, et al. Skin infections of the limbs of Polynesian children. NZ Med J. 2004;117:U847. 16. Mollan RAB, Pigot J. Acute osteomyelitis in children. J Bone Joint Surg (Br). 1977;59-B:2–7. 17. Blockey NJ, Watson JT. Acute osteomyelitis in children. J Bone Joint Surg (Br). 1970;52-B:77–87. 18. Bonboeffer J, Haeberle B, Schaad UB, et al. Diagnosis of acute haematogenous osteomyelitis and septic arthritis: 20 years experience at the University Children’s Hospital Basel. Swiss Med Wkly. 2001;131:575–581. 19. Nade S. Choice of antibiotics in management of acute osteomyelitis and acute septic arthritis in children. Arch Dis Child. 1977;52: 679–682. 20. Song KM, Sloboda JF. Acute haematogenous osteomyelitis in children. J Am Acad Orthop Surg. 2001;9:166–175. 21. Ranson M. Imaging of pediatric musculoskeletal infection. Semin Musculoskelet Radiol. 2009;13:277–299. 22. Browne LP, Mason EO, Kaplan SL, et al. Optimal imaging strategy for community-acquired Staphylococcus aureus musculoskeletal infections in children. Pediatr Radiol. 2008;38:841–847. 23. Pa¨a¨kko¨nen M, Kallio MJ, Kallio PE, et al. Sensitivity of erythrocyte sedimentation rate and C-reactive protein in childhood bone and joint infections. Clin Orthop Relat Res. 2010;468:861–866.
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24. Khachatourians AG, Patzakis MJ, Roidis N, et al. Laboratory monitoring in pediatric acute osteomyelitis and septic arthritis. Clin Orthop Relat Res. 2003;409:186–194. 25. Unkila-Kallio L, Kallio MJ, Eskola J, et al. Serum C-reactive protein, erythrocyte sedimentation rate, and white cell count in acute hematogenous osteomyelitis in children. Pediatrics. 1994;93:59–62. 26. Blockey NJ, McAllister TA. Antibiotics in acute osteomyelitis in children. J Bone Joint Surg (Br). 1972;54-B:299–309. 27. Maraqa NF, Gomez MM, Rathore MH. Outpatient parenteral antimicrobial therapy in osteoarticular infections in children. J Pediatr Orthop. 2002;22:506–510. 28. Howard AW, Viskontas D, Sabbagh C. Reduction in osteomyelitis and septic arthritis related to Haemophilus influenzae type B vaccination. J Pediatr Orthop. 1999;19:705–709. 29. 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. 30. Gwynne-Jones D, Stott S. Community-acquired methicillin-resistance Staphylococcal aureus: a cause of musculoskeletal sepsis in children. J Pediatr Orthop. 1999;19:413–416. 31. Arnold SR, Elias D, Buckinham SC, et al. Changing patterns of acute haematogenous osteomyelitis and septic arthritis: emergence of community-acquired methicillin-resistant Staphylococcus aureus. J Pediatr Orthop. 2006;26:703–708. 32. Vander Have KL, Karmazyn B, Verma M, et al. Communityassociated methicillin-resistance Staphylococcus aureus in acute musculoskeletal infection in children: a game changer. J Pediatr Orthop. 2009;29:927–931.
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33. Chometon S, Benito Y, Chaker M, et al. Specific real-time polymerase chain reaction places Kingella kingae as the most common cause of osteoarticular infections in young children. Pediatr Infect Dis J. 2007;26:377–381. 34. Gilmour WN. Acute haematogenous osteomyelitis. J Bone Joint Surg (Br). 1962;44-B:841–853. 35. Short Review. Antibiotics for osteomyelitis. Lancet. 1975;1:153–154. 36. Jagodzinski NA, Kanwar R, Graham K, et al. Prospective evaluation of a shortened regimen of treatment for acute osteomyelitis and septic arthritis in children. J Pediatr Orthop. 2009;29: 518–525. 37. Harris NH. The place of surgery in acute osteomyelitis. J Bone Joint Surg (Br). 1962;44-B:219. 38. Merryweather R. Acute osteomyelitis. Br Med J. 1972;4:546–547. 39. Mullick S. Acute osteomyelitis. Br Med J. 1972;4:546–547. 40. Platt H. Special discussion on the treatment of acute osteomyelitis. Proc R Soc Med. 1928;21:1377–1386. 41. LaMont RL, Anderson P, Dajani A, et al. Acute haematogenous osteomyelitis in children. J Pediatr Orthop. 1987;7:579–583. 42. Blundell Jones G. Place of surgery in treatment of acute haematogenous osteomyelitis. Proc R Soc Med. 1971;64:1200–1201. 43. Petolta H, Pa¨a¨kko¨nen M, Kallio P, et al. Short vs. long-term antimicrobial treatment for acute hematogenous osteomyelitis of childhood: prospective, randomized trial on 131 culturepositive cases. Pediatr Infect Dis J. 2010;29:1123–1128. 44. Ceroni D, Regusci M, Pazos JM, et al. Risks and complications of prolonged parenteral antibiotic treatment in children with acute osteoarticular infections. Acta Orthop Belg. 2003;69:400–404.
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639
Pediatric Acute Hematogenous Osteomyelitis Matthew Street, MBChB,*w Rupesh Puna, MBChB,* Mark Huang, MBChB,* and Haemish Crawford, FRACS*w
Background: Osteomyelitis continues to be a significant problem among the New Zealand pediatric population. We present a large series of acute hematogenous osteomyelitis (AHO) cases, with the aim to identify any changing trends and guide successful management of the disease. Methods: A 10-year retrospective review was performed of clinical records of children with AHO at the 2 children’s orthopaedic departments in the Auckland region. Cases were identified from Starship Children’s Hospital between 1997 and 2007 and Middlemore’s Kidz First Hospital between 1998 and 2008. Results: A total of 813 cases of pediatric AHO were identified. The incidence was 1:4000, which was decreasing over the 10-year period. There was a male predominance and New Zealand (NZ) Maori and Pacific Islanders were overrepresented. The diagnosis was made clinically in 27%, radiographically in 66%, and surgically in 7%. The most common pathogen was Staphylococcus aureus and the incidence of methicillin-resistant S. aureus was low (2%). The average length of antibiotic treatment was 44 days and 44% required surgery. This produced a recurrence rate of only 7% and a 15% treatment-related complication rate. Conclusions: In the New Zealand population, the incidence of AHO remains high with NZ Maori and Pacific Islanders overrepresented. The predominant pathogen remains S. aureus and our population has a very low incidence of methicillin-resistant S. aureus; flucloxacillin remains a good choice for empiric treatment in our population. Our rate of relapse and subsequent chronic osteomyelitis is low. This could be explained by traditionally longer antibiotic courses; however, this may also lead to increased treatment-related complications. Through prompt and accurate diagnosis with the aid of laboratory and radiologic tests and effective treatment with appropriate antibiotics (guided by local pathogen sensitivities) and surgical treatment when indicated, AHO can be well managed with minimal severe complications. Level of Evidence: Level IV—retrospective case series. Key Words: pediatric, infection, osteomyelitis, acute, hematogenous (J Pediatr Orthop 2015;35:634–639)
From the *Starship Children’s Hospital; and wDepartment of Medicine, University of Auckland, Auckland, New Zealand. The authors declare no conflicts of interest. Reprints: Matthew Street, MBChB, Department of Medicine, University of Auckland, 50 Sonia Avenue, Remuera, 1050, Auckland, New Zealand. E-mail: [email protected]. Copyright r 2014 Wolters Kluwer Health, Inc. All rights reserved.
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A
cute hematogenous osteomyelitis (AHO) continues to be a rare but significant problem among the pediatric population. The reported incidence ranges from 1:1000 to 1:20,000 children per year.1 The diagnosis of osteomyelitis involves skilled interpretation of the clinical presentation, blood tests and bacterial cultures, radiologic studies, and in some cases surgical exploration.2 Management of AHO includes antibiotics, immobilization, and surgery when indicated. Morbidity due to delay in diagnosis and inadequate treatment continue to result in permanent sequelae.3 Up-to-date knowledge of AHO and its current trends is important to aid prompt and accurate diagnosis and effective treatment. Gillespie and Mayo4 published the most recent large series from New Zealand in 1981, which included 655 children. We present our 10-year retrospective series of 813 children with AHO; to our knowledge the largest series presented thus far.
METHODS A 10-year retrospective review was performed of clinical records of all cases of pediatric (age: newborn to 15 y) osteomyelitis treated at Auckland’s 2 pediatric orthopaedic departments. The osteomyelitis database was formed by identifying all cases by clinical coding. Patients were included from Starship Children’s Hospital from 1997 to 2007 and Middlemore’s Kidz First Hospital from 1998 to 2008. These patients were provisionally included in the study population. Review of case notes and hospital records was conducted on this provisional group, and from this our study group was identified. We defined AHO based on symptom duration 15 mm/h) in 562 of 719 tested (78%). The average C-reactive protein (CRP) was 86.4 mg/L (range, 5 mg/L) in 495 of 602 tested (82%). A total of 65 (8%) had both a normal ESR and CRP on admission. Of those patients with normal ESR and CRP, the small bones in the foot and hand were more commonly affected (23% and 14%, respectively) and only 1 case was initially blood culture positive. The diagnosis of AHO was made primarily clinically in 27%, radiographically in 66%, and surgically in 7%. Clinical diagnosis was made by the primary treating orthopaedic surgeon or physician. This was based on the clinical presentation and laboratory investigations including inflammatory markers (WCC, ESR, and CRP) and blood cultures, in the absence of an x-ray abnormality. Radiographic diagnosis was made by plain radiograph, magnetic resonance imaging (MRI), bone scintigraphy, and less commonly ultrasound scan and computed tomography. In the final group, the diagnosis was confirmed on surgical exploration, undertaken based on suspicion in the septic child without initial radiographic abnormality. These children were generally more unwell with higher inflammatory markers (average ESR, 57.3 mm/h; average CRP, 111.1 mg/L). Seventy-five percent of these cases yielded positive tissue cultures. We observed a decrease over time of children diagnosed by surgical exploration, with 19 children in the first 2 years compared with 6 children in the last 2 years, which is likely due to MRI Copyright
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Pediatric Acute Hematogenous Osteomyelitis
TABLE 1. Ethnic Group and Sex of Children With AHO n (%) Ethnic Group European (NZ or other) Pacific Island NZ Maori Asian Other Total
Total 285 248 179 48 53 813
(35) (31) (22) (6) (6) (100)
Male 192 162 112 24 27 517
(24) (20) (14) (3) (3) (64)
Female 93 86 67 24 26 296
Incidence
(11) (11) (8) (3) (3) (36)
1:4500 1:2500 1:2500 1:10,000 1:4500 1:4000
AHO indicates acute hematogenous osteomyelitis.
becoming more accessible. The use of MRI as a diagnostic modality increased significantly over the study period, with 22% of diagnoses made based on MRI in the first 2 years, compared with 64% in the last 2 years. The means of diagnosis as well as the specific radiographic modality used to diagnose AHO is shown in Table 2. The most common bone affected was the femur in 267 cases (31%), followed by the tibia in 191 cases (22%). Unusual sites of infection included 12 affecting the clavicle, 2 affecting the skull, 2 affecting the patella, and 1 affecting the ribs. A total of 37 (4.5%) had multifocal osteomyelitis on admission. Sites of infection are summarized in Table 3. A causative pathogen was isolated in 406 children (50%). The most common pathogen was Staphylococcus aureus, isolated in 321 cases (39% of total population or 77% of total pathogens cultured). Methicillin-resistant S. aureus (MRSA) was isolated in only 18 patients (2% of the population or 4% of total pathogens cultured). There were 3 cases with Kingella kingae isolated. There was only a single case of Haemophilus influenzae type B. Pathogens and means of culture are summarized in Table 4. Flucloxacillin was the most common antibiotic used. It was administered as first-line treatment in 482 children (59%), and in 268 (33%) it was the only antibiotic given. Looking at overall use, flucloxacillin was prescribed in 510 (63%) at 1 point in time during the course of their treatment. The next most common antibiotic was amoxicillin clavulanate. This was administered as first-line treatment in 252 (31%) and was the only antibiotic given in 227 (28%). A total of 328 (40%) were prescribed amoxicillin clavulanate at 1 point in time during their treatment. When no pathogen was cultured, amoxicillin clavulanate was most commonly used.
TABLE 2. Means of Diagnosis Means of Diagnosis
No. Cases (%)
Clinically Radiographically (total) MRI Bone scintigraphy Others (CT/USS/XR/combination) Surgically
217 536 387 90 59 60
(27) (66) (48) (11) (7) (7)
CT indicates computed tomography; MRI, magnetic resonance imaging; USS, ultrasound scan; XR, x-ray.
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TABLE 3. Site of Osteomyelitis
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TABLE 5. Complications of AHO (Nontreatment Related)
Location
No. Cases (%)
Lower limb Femur Tibia Fibula Calcaneus Other tarsals Metatarsals Phalanges Patella Upper limb Humerus Radius Ulna Carpals Metacarpals Phalanges Clavicle Scapula Pelvis Spine Skull Ribs
619 267 191 51 60 13 22 13 2 147 56 29 23 3 4 18 12 2 101 8 2 1
(71) (31) (22) (6) (7) (1) (3) (1) (0.2) (17) (6) (3) (3) (0.3) (0.5) (2) (1) (0.2) (12) (1) (0.2) (0.1)
Complications
N (%)
Recurrence Chronic osteomyelitis Pathologic fracture Femur Tibia Growth disturbance Femur Tibia Humerus Radius/ulna Finger phalanx Metatarsal Amputation Below knee amputation Digit amputation Deep vein thrombosis Other Total
55 14 8 6 2 15 4 3 2 2 2 1 2 1 1 3 16 45
(6.8) (1.7) (1) (0.7) (0.2) (1.8) (0.5) (0.4) (0.2) (0.2) (0.2) (0.2) (0.2) (0.1) (0.1) (0.4) (2) (5.5)
AHO indicates acute hematogenous osteomyelitis.
(1.8%) experienced growth-related problems (Table 5). Pathologic fractures occurred in the long bones of the lower limb, in which there was significant disruption of the bony architecture secondary to the infection. Growth disturbance predominantly led to limb length discrepancy; however, there were 3 cases of angular deformity. One was in a metatarsal and 2 in phalanges of the hand. There was also a case of radius/ulna synostosis. Three cases were complicated by deep vein thrombosis (DVT). All 3 had S. aureus septicemia secondary to osteomyelitis of the femur (2) or pelvis (1). One case resulted in a below knee amputation. This was a 15-year-old male with severe tibia/fibula osteomyelitis with pus extending throughout all compartments of the lower leg. During multiple debridements, flexor digitorum longus, tibialis posterior, and flexor hallucis longus were found to be completely necrotic and removed. He developed chronic recurring osteomyelitis with persistent wound problems and minimal function of the affected limb. After below knee amputation he has been free of infection and mobilizing with a prosthesis. A total of 124 patients (15.2%) experienced complications secondary to their treatment. Ninety-five patients (11.7%) had antibiotic reactions, for example, urticaria or neutropenia. Twenty-three (2.8%) had problems related to their peripherally inserted central catheter (PICC) or
Note that the total of 878 sites is >813 patients in the study, given 37 individuals had a multifocal acute hematogenous osteomyelitis.
The average length of combined intravenous (IV) and oral antibiotic treatment was 43.7 days (range, 14 to 336 d). There were no significant changes in antibiotic duration over the course of the study. Average length of IV treatment was 22.3 days (range, 1 to 168 d). Average length of oral antibiotic treatment was 21.4 days (range, 0 to 252 d). A CRP < 5 mg/L and clinical resolution were indications for changing from IV to oral antibiotics and an empiric 6-week antibiotic course was often observed. A total of 361 patients (44%) required surgical intervention. These patients underwent an average of 2 operations (range, 1 to 12). This included drainage of subperiosteal abscess, open biopsy, adjacent joint aspiration and/or washout, and uncommonly drilling of the affected metaphysis. Fifty-five children (6.8%) suffered relapse of osteomyelitis, with average time until relapse of 5.8 months. Relapse was more common in children with multifocal osteomyelitis (19%). Fourteen children (1.7%) subsequently developed chronic osteomyelitis (Table 5). Evaluating other complications, 8 patients (1%) suffered pathologic fracture following discharge and 15
TABLE 4. Organisms Cultured and Means of Culture Pathogens Staphylococcus aureus MRSA Streptococcus pyogenes Other Total
Blood Culture
Tissue Culture
Blood and Tissue Culture
Total
Total Pathogens Cultured (%)
Total Patients (%)
115 1 12 26 154
107 9 14 25 155
99 8 0 1 108
321 18 26 52 417
77 4 6 13 100
39 2 3 6 50
MRSA indicates methicillin-resistant S. aureus.
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other venous access. Six (0.7%) had both antibiotic reactions and PICC-related problems. A total of 119 (14.6%) required readmission to hospital for treatment-related complications. Starship Children’s Hospital and Middlemore’s Kidz First Hospitals cover pediatric orthopaedics for the entire region, thus any complications should present to our institutes. The follow-up period is thus estimated at 5 to 16 years.
DISCUSSION AHO remains a potentially serious disease. Prompt diagnosis and initiation of antibiotic treatment gives the best chance of avoiding surgical intervention and adverse outcomes.3,6–8 Knowledge of current trends in demographics, diagnosis, and treatment is important to aid effective management. The incidence of AHO in our population (1:4000) is higher than that reported by others.4,9–11 For comparison, the annual incidence in the United States is estimated at 1:5000.10 There has been a worldwide fall in the incidence of AHO.11–13 Our series also demonstrates a decline over time with the incidence in the last 2 years (1:4500) lower than that in the first 2 years (1:3500) of the study period. We have also demonstrated a significantly higher incidence in the NZ Maori and Pacific Island populations compared with that in the European population and a much lower incidence in the Asian population. Rosaak and Pitto14 also showed this in their study, in which the incidence of osteomyelitis in non-Polynesian New Zealand children was 11.1:100,000 (or 1:9000), whereas the incidence for Polynesian children (including NZ Maori) was 42.8:100,000 (or 1:2500). Lower socioeconomic status and lower standard of living have been suggested to contribute to this higher rate; however, Blyth et al11 have shown that the incidence of osteomyelitis is similar throughout the social spectrum and locally Finger et al15 have demonstrated no increased risk of cellulitis with lower socioeconomic status. We showed a male predominance of 1.75:1 and the majority of children in our series were aged between 2 and 10 years (51%), which is a similar distribution to that previously reported, with preschool and school-aged children predominating over neonates, infants, and adolescents.7,13,16–18 Craigen et al12 have reported a decreasing incidence of long bone osteomyelitis; however, 69% of our cases still affected the long bones. The femur (31%) and tibia (22%) are the most common sites of AHO, which compares to the reported ranges of 16% to 33% for the femur, and 12% to 31% for the tibia.6,7,13,16–19 Radiology remains an essential tool for diagnosing AHO and should be used in every case of suspected infection.20 The main role of plain radiographs is to rule out other pathologies, such as fracture, as it can take 10 to 14 days before periosteal new bone formation is seen.21 In this study, MRI was the main diagnostic modality, aiding in the diagnosis of 48% of patients. Browne et al22 reported a 98% sensitivity for MRI in diagnosing osteomyelitis; however, the use of MRI was initially limited by Copyright
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Pediatric Acute Hematogenous Osteomyelitis
cost and access. We observed a significant increase in the use of MRI over the study period, as MRI became more readily accessible. Pa¨a¨kko¨nen et al23 reported the sensitivity of serum markers of inflammation in osteoarticular infection. WCC is normal in 50% to 80% of cases.23,24 ESR and CRP alone provide a sensitivity of 94% and 95%, respectively, whereas together they produce a sensitivity of 98%.23 They are, however, nonspecific, making the high negative predictive value most useful.25 In our study, WCC was abnormal in only 32% of cases, ESR was elevated in 78%, and CRP was elevated in 82%. Eight percent of cases had both normal ESR and CRP. Normal inflammatory markers may be reassuring; however, one must correlate these results with the greater clinical picture and maintain a high level of suspicion for this serious pathology. S. aureus, isolated in 77% of positive cultures, remains the most common causative pathogen. This is in accordance with previous results reporting its occurrence ranging between 48% and 94% in various populations.6,7,11,16–19,26,27 We only had 1 case of H. influenzae type B and attribute this to the introduction of the vaccination, which has essentially led to its eradication, as previously reported.28 The emergence of MRSA over the past few years as a responsible pathogen for musculoskeletal infection has been well described around the world.29–32 SaavedraLozano et al29 reported rates of MRSA acute osteomyelitis approaching 31% in the latter part of their study. In comparison, our series demonstrated a low rate of MRSA AHO, of only 2% of the total cases. Interestingly, Gwynne-Jones and Stott30 reported a 20% incidence of MRSA in musculoskeletal infections (mostly superficial infections) in the same institution in 1996 to 1997. We cannot explain this difference. We identified only 3 cases caused by K. kingae, which most likely reflects inappropriate culture technique and the underuse of polymerase chain reaction in our institutes over the study period. Chometon et al33 reported K. kingae as the most common pathogen in pediatric osteoarticular infections when investigating cases using real-time polymerase chain reaction. The choice of the most effective antibiotics has been well investigated with varying recommendations.17,26,34,35 The antibiotic regimen for the treatment of AHO needs to be tailored for each institution. In Gillespie and Mayo’s4 study, spanning the first 30 years of the “antibiotic era,” penicillin and erythromycin were the main antibiotics used to combat predominantly S. aureus infections. Nowadays, with penicillin-resistant S. aureus as the predominant infecting pathogen, flucloxacillin is accepted as a good first-line treatment.11,35,36 In over half of our population (59%), flucloxacillin was used as the initial antibiotic of choice. In other centers where there is a high incidence of MRSA,29,32 initial treatment may vary and consideration must be given to vancomycin as first-line treatment until a pathogen is cultured and sensitivities are available.32 Our average length of antibiotic treatment was 43.7 days, of which an average of 22.3 days was IV. www.pedorthopaedics.com |
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Controversy over the role of surgical intervention has been well documented with varying opinions both for16,37–40 and against6,7,17,22,34 routine surgical management. The main indications for surgery include failure to respond to antibiotics after 48 to 72 hours, frank pus on aspiration, intra-articular suppuration, or sequestered abscess.6,7,9,41,42 With clinical or radiologic evidence of septic arthritis or abscess formation, we would proceed to surgery immediately. In our institutions drilling of the affected bone is not routine. Forty-four percent required surgical intervention. This is similar to that published in the previous large study in New Zealand by Gillespie and Mayo4 (46%). Our rate of recurrence was 6.8% and development of chronic osteomyelitis was only 1.7%, both of which are comparatively low.4,6,7,11,16,17,26,34 Gillespie and Mayo4 reported a recurrence rate of 17%, most of which occurred within the first year of the initial illness. Other complications of AHO reported include pathologic fracture, growth disturbance, local extension to soft tissues, involvement of an adjacent joint, and occasionally death.3 There were no deaths in our series. Approximately 1.8% of our population experienced growth disturbance and 1% suffered pathologic fracture. Both of these were lower than that reported by Blyth et al11 (2% and 4%, respectively) and Gilmour34 (5% growth disturbance). Pathologic fractures occurred solely in the long bones of the lower limb, in which there was significant disruption of the bony architecture. When this is seen, one should consider a period of prophylactic casting and/or protected weightbearing. DVT and amputation are rare but important complications. The 3 patients who had DVTs all had S. aureus septicemia from osteomyelitis of the femur (2) or pelvis (1). This is an important diagnosis to be aware of when reviewing systemically unwell osteomyelitis patients. Amputation should only be considered once all other reasonable options have failed and there is little or no function to be salvaged from the affected limb. Our rate of treatment-related complications was 15.2% with 14.6% readmitted for these complications. It seems our current regime of treatment is effective; however, Petolta et al’s43 study would suggest a shorter course may be just as effective (in a subset of uncomplicated AHO) and avoid the complications associated with longterm antibiotics and central catheters.44 The high incidence of treatment-related complications (15.2%) has led to a randomized controlled trial at our institutions comparing short-course versus long-course antibiotics, which may lead to a reduction of these complications in the future. In conclusion, from this large series we have found a relatively high incidence of AHO within our population with an increased incidence in the NZ Maori and Pacific Island ethnic groups and a male predominance. The incidence over time, however, is decreasing. The long bones remain most commonly affected. The predominant pathogen is S. aureus and our population had a very low incidence of MRSA. Flucloxacillin remains a good choice for
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empiric treatment in our population. Our rate of relapse and subsequent chronic osteomyelitis remains low. This could be explained by traditionally longer antibiotic courses; however, longer courses may also lead to increased treatment-related complications. Through prompt and accurate diagnosis with the aid of laboratory and radiologic tests and effective treatment with appropriate antibiotics (guided by local pathogen sensitivities) and surgical treatment when indicated, AHO can be well managed with minimal severe complications. REFERENCES 1. Krogstad P, Smith AL. Osteomyelitis and septic arthritis. In: Feigin RD, Cherry JD, eds. Textbook of Paediatric Infectious Diseases. 4th ed. Philadelphia, PA: WB Saunders; 1998:683–704. 2. Gold R. Diagnosis of osteomyelitis. Pediatr Rev. 1991;12:292–297. 3. Nade S. Acute haematogenous osteomyelitis in infancy and childhood. J Bone Joint Surg (Br). 1983;65-B:109–118. 4. Gillespie WJ, Mayo KM. The management of acute haematogenous osteomyelitis in the antibiotic era—a study of the outcome. J Bone Joint Surg (Br). 1981;63-B:126–131. 5. Statistics New Zealand Tatauranga Aotearoa (Census—Statistics New Zealand Web site). 2010 Available at: http://www.stats. govt.nz/Census.aspx. Accessed January 21, 2014. 6. O’Brien T, McManus F, MacAuley PH, et al. Acute haematogenous osteomyelitis. J Bone Joint Surg (Br). 1982;64-B:450–453. 7. Cole WG, Dalziel RE, Leiti S. Treatment of acute osteomyelitis in childhood. J Bone Joint Surg (Br). 1982;64-B:218–223. 8. Mercer W. Acute haematogenous osteomyelitis. Postgrad Med J. 1951;27:327–331. 9. Baker ADL, Macnicol MF. Haematogenous osteomyelitis in children: epidemiology, classification, aetiology and treatment. Paediatr Child Health. 2007;18:75–84. 10. Sonnen GM, Henry NK. Pediatric bone and joint infections: diagnosis and anti-microbial management. Pediatr Clin North Am. 1996;43:933–947. 11. Blyth MJF, Kincaid R, Craigen MAC, et al. The changing epidemiology of acute and subacute haematogenous osteomyelitis in children. J Bone Joint Surg (Br). 2001;83-B:99–102. 12. Craigen MAC, Watters J, Hackett JS. The changing epidemiology of osteomyelitis in children. J Bone Joint Surg (Br). 1992;74-B: 541–545. 13. Goergens ED, McEvoy A, Watson M, et al. Acute osteomyelitis and septic arthritis in children. J Paediatr Child Health. 2005;41:59–62. 14. Rosaak M, Pitto R. Osteomyelitis in Polynesian children. Int Orthop. 2005;29:55–58. 15. Finger F, Rosaak M, Umstaetter R, et al. Skin infections of the limbs of Polynesian children. NZ Med J. 2004;117:U847. 16. Mollan RAB, Pigot J. Acute osteomyelitis in children. J Bone Joint Surg (Br). 1977;59-B:2–7. 17. Blockey NJ, Watson JT. Acute osteomyelitis in children. J Bone Joint Surg (Br). 1970;52-B:77–87. 18. Bonboeffer J, Haeberle B, Schaad UB, et al. Diagnosis of acute haematogenous osteomyelitis and septic arthritis: 20 years experience at the University Children’s Hospital Basel. Swiss Med Wkly. 2001;131:575–581. 19. Nade S. Choice of antibiotics in management of acute osteomyelitis and acute septic arthritis in children. Arch Dis Child. 1977;52: 679–682. 20. Song KM, Sloboda JF. Acute haematogenous osteomyelitis in children. J Am Acad Orthop Surg. 2001;9:166–175. 21. Ranson M. Imaging of pediatric musculoskeletal infection. Semin Musculoskelet Radiol. 2009;13:277–299. 22. Browne LP, Mason EO, Kaplan SL, et al. Optimal imaging strategy for community-acquired Staphylococcus aureus musculoskeletal infections in children. Pediatr Radiol. 2008;38:841–847. 23. Pa¨a¨kko¨nen M, Kallio MJ, Kallio PE, et al. Sensitivity of erythrocyte sedimentation rate and C-reactive protein in childhood bone and joint infections. Clin Orthop Relat Res. 2010;468:861–866.
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24. Khachatourians AG, Patzakis MJ, Roidis N, et al. Laboratory monitoring in pediatric acute osteomyelitis and septic arthritis. Clin Orthop Relat Res. 2003;409:186–194. 25. Unkila-Kallio L, Kallio MJ, Eskola J, et al. Serum C-reactive protein, erythrocyte sedimentation rate, and white cell count in acute hematogenous osteomyelitis in children. Pediatrics. 1994;93:59–62. 26. Blockey NJ, McAllister TA. Antibiotics in acute osteomyelitis in children. J Bone Joint Surg (Br). 1972;54-B:299–309. 27. Maraqa NF, Gomez MM, Rathore MH. Outpatient parenteral antimicrobial therapy in osteoarticular infections in children. J Pediatr Orthop. 2002;22:506–510. 28. Howard AW, Viskontas D, Sabbagh C. Reduction in osteomyelitis and septic arthritis related to Haemophilus influenzae type B vaccination. J Pediatr Orthop. 1999;19:705–709. 29. 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. 30. Gwynne-Jones D, Stott S. Community-acquired methicillin-resistance Staphylococcal aureus: a cause of musculoskeletal sepsis in children. J Pediatr Orthop. 1999;19:413–416. 31. Arnold SR, Elias D, Buckinham SC, et al. Changing patterns of acute haematogenous osteomyelitis and septic arthritis: emergence of community-acquired methicillin-resistant Staphylococcus aureus. J Pediatr Orthop. 2006;26:703–708. 32. Vander Have KL, Karmazyn B, Verma M, et al. Communityassociated methicillin-resistance Staphylococcus aureus in acute musculoskeletal infection in children: a game changer. J Pediatr Orthop. 2009;29:927–931.
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33. Chometon S, Benito Y, Chaker M, et al. Specific real-time polymerase chain reaction places Kingella kingae as the most common cause of osteoarticular infections in young children. Pediatr Infect Dis J. 2007;26:377–381. 34. Gilmour WN. Acute haematogenous osteomyelitis. J Bone Joint Surg (Br). 1962;44-B:841–853. 35. Short Review. Antibiotics for osteomyelitis. Lancet. 1975;1:153–154. 36. Jagodzinski NA, Kanwar R, Graham K, et al. Prospective evaluation of a shortened regimen of treatment for acute osteomyelitis and septic arthritis in children. J Pediatr Orthop. 2009;29: 518–525. 37. Harris NH. The place of surgery in acute osteomyelitis. J Bone Joint Surg (Br). 1962;44-B:219. 38. Merryweather R. Acute osteomyelitis. Br Med J. 1972;4:546–547. 39. Mullick S. Acute osteomyelitis. Br Med J. 1972;4:546–547. 40. Platt H. Special discussion on the treatment of acute osteomyelitis. Proc R Soc Med. 1928;21:1377–1386. 41. LaMont RL, Anderson P, Dajani A, et al. Acute haematogenous osteomyelitis in children. J Pediatr Orthop. 1987;7:579–583. 42. Blundell Jones G. Place of surgery in treatment of acute haematogenous osteomyelitis. Proc R Soc Med. 1971;64:1200–1201. 43. Petolta H, Pa¨a¨kko¨nen M, Kallio P, et al. Short vs. long-term antimicrobial treatment for acute hematogenous osteomyelitis of childhood: prospective, randomized trial on 131 culturepositive cases. Pediatr Infect Dis J. 2010;29:1123–1128. 44. Ceroni D, Regusci M, Pazos JM, et al. Risks and complications of prolonged parenteral antibiotic treatment in children with acute osteoarticular infections. Acta Orthop Belg. 2003;69:400–404.
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