Competing interests None.
Provenance and peer review Commissioned; externally peer reviewed.
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Osteomyelitis and septic arthritis in children
Osteomyelitis (OM) is inflammation of the bone accompanied by bone destruction,1 usually due to bacterial infection. It is an acute process, but if not treated effectively, the inflammation can become chronic, leading to the development of sequestra and fistulae.2 OM and septic arthritis (SA) can both be divided into three types according to the source of the infection: haematogenous, secondary to contiguous infection and secondary to direct inoculation. Haematogenous OM can present acutely or as a more indolent, progressive process subacutely, with symptoms present for more than 2 weeks.3 In children, OM most often affects long bones (femur 36%, tibia 33%, humerus 10%, pelvis 2.8%).4 Single site infection is most common, but 5–20% of children have multifocal OM.5 SA is acute infection of synovial joints,6 7 usually secondary to bacteraemia. The infection affects the synovial membrane and the joint space. In younger children, the capsule of the joint often extends to the metaphysis, which when the cortex is damaged can lead to SA secondary to OM and vice versa. The epiphysial growth plate can also be affected, causing growth discrepancies and long term disability or permanent joint destruction if the acute infection is not treated promptly.2
The estimated incidence for both OM and SA arthritis in Western populations is between 5 and 12 cases per 100 000 children per year.2 Half of the children with acute haematogenous OM are under the age of 5.2 7 Boys are 1.2–3.7 times more likely to be affected by osteoarticular infections (OAI) than girls.2 The incidence in Southampton from 1979 to 1997 was between 1.4 and 10.5 cases per 100 000 per year8 and in Newcastle from 1991 to 1999 was 7 per 100 000 for SA and 11 per 100 000 for OM (unpublished data). Recent unpublished national data from England show that the admission rate for OM in children 0–18 years of age has varied between 0.048 and 0.070 per 1000 child years (M Sharland, personal communication, 2008). Subacute OM appears to be increasing over recent years9 and was reported to be found in 5 per 100 000 children in Norway.10 Neonatal infection can occur in preterm or term babies and is associated with a wider range of causative organisms (table 1)11 and potential complications. Neonatal vascular anatomy allows infection within bone to reach the growth plate or joint in 76% of cases.12
The pathogens implicated in paediatric bone and joint infections at different ages are shown in table 1.
Discitis is an infection of the intervertebral disc space, probably arising in one of the contiguous vertebral end plates with secondary disc infection. Discitis forms part of a continuum of spinal infections including vertebral OM and soft tissue collections. Lumbar discitis is most frequent in children <5 years of age,13 probably due to the continuing presence of vascular channels in the cartilaginous region of the disk space that disappear later in life. Early in the course of these disease processes, differentiation between discitis and vertebral OM is often difficult. The pathogens implicated in discitis are similar to those implicated in SA and OM (table 1).
Chronic recurrent multifocal osteomyelitis
Chronic recurrent multifocal osteomyelitis (CRMO) is an inflammatory condition with recurrent, sterile, lytic lesions often in the clavicle, humerus and tubular bones. Lesions may occur recurrently in the same site or at different sites at the same time. Diagnosis is by persistence or recurrence of lesions despite adequate antibiotic treatment, supported by MRI which provides characteristic imaging in established disease.
The diagnosis and management of OAI in children should ideally be multidisciplinary, and involve paediatricians, orthopaedic surgeons, radiologists and microbiologists. The clinical features depend on age and disease type, and are detailed in table 2. The diagnosis of OM or SA is made on the basis of the clinical presentation, laboratory tests, imaging and, where available, microbiology results.
WBC, CRP and ESR
The white blood cell count (WBC) is an unreliable indicator of an OAI as in many cases it remains normal throughout the infection.14 The inflammatory markers erythrocyte sedimentation rate (ESR) and C reactive protein (CRP) are more reliable, although normal values also do not exclude OM.15 CRP levels are most sensitive (elevated in up to 98% of cases)6 7 but not specific for bone or joint infection. Two studies have shown that CRP levels increased and also decreased faster than the ESR, predicting recovery with more sensitivity than the ESR or WBC.15 16 Differences in the causative organism may also cause differences in the acute phase markers. Patients with OM caused by Panton-Valentine leukocidin (PVL)-expressing Staphylococcus aureus isolates had significantly higher mean values for ESR at admission, and higher maximum CRP levels, ESR and absolute neutrophil counts at presentation compared with patients whose isolates were PVL negative.17 Other markers remain unproven. In a small study, procalcitonin has not shown benefit over CRP.18
Imaging is of great importance in the diagnosis of acute OM and discitis, although less so in acute SA. The advantages and disadvantages of currently available imaging modalities are shown in table 3, and suggested use in practice in figures 1 and 2.
Identification of the pathogenic organism by culture should be attempted with samples preferably taken prior to starting treatment, as positive results allow targeted antibiotic therapy. Blood cultures, joint fluid (from aspiration), periosteal pus or bone biopsy can all be used. Samples from the infected bone or joint require an invasive procedure but are more likely to be positive (40–50% positive) than blood cultures (9–22% positive).14 19 In current practice, bone biopsy is infrequently necessary for diagnostic reasons alone. This is one of the reasons why bacterial identification in children with OM is generally low.14
New molecular techniques including PCR and broad-range 16s rDNA PCR20 21 have established the basis for more rapid and sensitive microbiological diagnosis,22 although these methods currently do not provide information on specific organism antibiotic resistance profiles.
Blood cultures (minimum 4 ml aerobic culture sample in older children, 2 ml in a specific neonatal aerobic bottle)23 should therefore be taken, and, where available, samples from infected bone or joint placed in a sterile universal container and sent for culture and sensitivity testing. Older reports suggesting an increase in Kingella kingae recovery from inoculating synovial fluid or bony exudates directly into blood-culture bottles have not been replicated in UK practice.24 K kingae is detectable using new PCR techniques from cultures where conventional direct plating of specimens on solid media has been used.22 25
Surgical drainage in acute OM is indicated if the patient is not responding to antibiotics after 48–72 h (although this may be due to resistance) or if there is radiological evidence of a substantial pus collection.6 Best practice is to immobilise any surgically treated limb or focus of infection.
Occasionally, where a soft tissue or subperiosteal collection is clearly demonstrated by ultrasound or MRI, needle aspiration can be performed prior to starting intravenous antibiotics. When performed, the procedure should be carried out under sterile conditions. If there is bony destruction or pus is aspirated, surgical debridement is usually required. With only early radiographic signs conservative intravenous antibiotic therapy may suffice.
Historically, the role of surgery is poorly defined. Cole26 identified three groups of patients: in the group of patients older than 1 year who presented within 48 h, antibiotic therapy alone was sufficient; in a group aged more than 1 year, patients usually require surgery and sometimes multiple procedures if presentation is delayed 5 days or more from the onset of illness; and in infants less than 1 year old in whom the exact diagnosis was difficult to make, a single operation and antibiotic therapy usually sufficed. In current practice, the relative roles of bacterial virulence and host age and immunity are unclear. More invasive surgery appears more common when bacteria have specific virulence genes, for example PVL.27 While most children recover rapidly with simple medical management, others require repeated debridement. A UK study is currently proposed to undertake a detailed national service evaluation of current medical and surgical practice.
In SA, prompt drainage and washout of the affected joint (either arthroscopic or open) is advocated by some for both diagnostic and therapeutic purposes as the articular cartilage is damaged early.6 The role of surgery in the treatment of SA is in fact poorly defined except in relation to the hip, where prompt surgical drainage is absolutely necessary. Open capsulotomy to allow continuing drainage of septic material is advocated, and if the arthrotomy does not provide turbid material, drilling the femoral neck may decompress a proximal femoral OM. The anterior approach is preferred as this also allows open reduction of any displacement of the femoral head.
The indications for surgical drainage of septic joints other than the hip remain controversial. Where there is a large effusion, drainage is usually advocated, although in some joints arthroscopic irrigation may be appropriate, such as the knee or ankle. However, with arthroscopic treatment joint visualisation is less complete. Overall, for joints other than the hip, aspiration, irrigation and intravenous antibiotic therapy is the preferred first line of treatment. If the patient fails to respond, then the joint should be surgically drained, usually by formal open arthrotomy rather then arthroscopic drainage.
Medical management and antibiotics
OAIs are treated with antibiotics and surgery where clinically required. Immobilisation of the affected limb and traction may also be used.
Intravenous antibiotics are started empirically as soon as the clinical diagnosis of acute OM or SA is made (table 4), as delaying therapy until the bacterium is identified increases the risk of complications. In SA, where urgent surgery is indicated, a widespread pragmatic approach has been to start antibiotics following surgery unless it will take longer than 4 h to get to theatre. As soon as organisms are isolated, antimicrobial treatment should be adjusted and optimised. In subacute OM with no systemic reaction, oral antibiotics can be used from the start.
Although there has not been a definitive randomised controlled trial, a number of observational and retrospective studies in the literature show that several different antibiotic regimes have been effective in treating acute haematogenous OM in children, including the use of β-lactam and macrolide antibiotics.8
The initial antibiotics should always include potent cover against methicillin sensitive S aureus (MSSA) and group A streptococci, and in younger children against K kingae, although the choice will vary according to the age of the child, route of infection and local resistance patterns.7 Activity against Haemophilus influenzae type b is essential in children who have not been fully immunised against it.
In the UK, rational empirical therapy prior to microbiological optimisation or oral switch would therefore be to start monotherapy according to the age of the child (table 4).
Switch to oral antibiotics and total duration of treatment
Currently there is no international and little UK consensus regarding the route or duration for antibiotic treatment of acute OAI in children. Sequential intravenous and oral therapy is usual as it is less inconvenient and painful for the patient, has fewer complications and is cheaper.2 6 7 There is no current evidence to aid the clinical decision of when to switch from intravenous to oral therapy, which is widely accepted and usually occurs when the patient has shown a marked clinical improvement.8 A Canadian systematic review of short (≤7 days) versus long course (>7 days) parenteral antibiotic treatment for acute haematogenous OM in children due primarily to S aureus showed no difference in the overall cure rate after 6 months between short course and long course parenteral antibiotic therapy.28 A recent retrospective cohort study of 1969 children in the USA found that early switch to oral therapy (median 4 days) was as effective as prolonged intravenous treatment,29 a finding also suggested in a smaller retrospective study of 186 children with SA.30 The laboratory or clinical parameters that would determine the decision to switch to oral therapy remain undefined.
Most clinicians continue intravenous antibiotics until the child shows clinical improvement, is afebrile and oral fluids and medication can be established. Additionally, observing a decrease in inflammatory markers such as WBC, CRP and ESR, is thought to be of value.2 Studies have shown that the serum CRP level decreased more rapidly than the ESR in children recovering from acute OM, and that children with a raised CRP level were more likely to have symptoms or extensive radiographic abnormalities.15 31 32 A recent Finnish clinical trial showed apparently good long term results and apparently no failure rates using CRP as the biological marker of infection.33 34
Failure to improve necessitates repeat blood culture, additional imaging for metastatic infection, assessment for deep vein thrombosis, and consideration of unusual pathogens such as PVL S aureus or fusobacterium.
Where the pathogen is known, switch to oral antibiotic monotherapy following local microbiological or clinical infectious diseases advice. A pragmatic guide to oral switch criteria when the pathogen is unknown is presented in table 5.
Total duration of antibiotic therapy
Currently there is no consensus about the route or duration for antibiotic treatment of acute OM in children. The suggested duration for parenteral antibiotic treatment ranges from 3 days up to 6 weeks, based on several, mainly observational studies with a relatively poor level of evidence.8 35 In the past, the overall duration of antibiotic treatment has been considered an important factor to improve outcome and reduce relapse. Several paediatric textbooks recommend at least 4–6 weeks of treatment.2 36
Although there are encouraging data from a recent clinical trial conducted between 1983 and 2005 in Finland33 34 and from other review papers and case series, no recent formal randomised controlled trial has been conducted to show good evidence for shorter courses of parenteral antibiotic treatment. There are a number of reasons why the recent Finnish data may not be directly applicable to practice in the UK or other countries.33 34 First, the characteristics and severity of disease in the subjects studied suggest there may have been a degree of selectivity in the application of the enrolment criteria. The Finnish data exclude ‘culture negative’ cases of OM/SA while reporting culture positivity in 131/183 (72%) cases of acute haematogenous OM34 and in 154/200 (77%) of children with SA,33 which is much higher than reported elsewhere (see above). Second, there may be differences between the reported cases and/or approaches taken towards microbiological diagnosis compared to standard (UK and other European) practice. In the Peltola studies, 89% of OM34 and 40% of SA33 were due to S aureus. As discussed above, recent data suggest that this is not reflective of current molecular epidemiology where 85% of cases are culture negative and other bacteria may be detected by PCR. Finally, there are important differences in surgical management. For cases of SA in the Finnish study,33 “the number of surgical procedures was kept to a minimum”, and where performed was needle aspiration alone. Of 48 hip joint infections over 22 years, hip arthrotomy was carried out only seven times.33 This suggests that the Finnish cohort was less seriously ill than that currently seen in the UK and USA where rates of arthrotomy for hip infections appear to be much higher, due in many cases to lack of response to antibiotics. Despite these differences, the Peltola study is important as it provides some evidence to justify a prospective randomised controlled study in the UK, the feasibility of which is the subject of a proposed national study in 2012. In addition, some historical observational studies showed an association between short duration of antibiotic therapy and a 15–19% rate of poor outcome or relapse with courses of 3 weeks or less.37,–,39
Oral antibiotic choice and dose
This recommendation considers dose reduction and formulation to enhance drug adherence due to flucloxacillin, clindamycin and fusidic acid unpalatability and dose frequency (table 6). Flucloxacillin and clindamycin have good oral bioavailability and excellent tissue penetration but poor taste and drug adherence of suspension in small children. Clindamycin rarely leads to Clostridium difficile disease in children.
Continuation of intravenous antibiotics for more than 2 weeks
Complex disease requiring continuing intravenous therapy poses problems of vascular access, hospitalisation and schooling. Most children will require central or peripherally-inserted central venous long line (CVL/PIC) insertion for long term antibiotic treatment. Delivery of subsequent care at home depends on local services and ability to provide outpatient parenteral antibiotic therapy (OPAT). Treatment at home is facilitated by once daily therapy which may be either ‘pathogen identified and sensitive’ (eg, MSSA, for example treated with intravenous daily teicoplanin or ceftriaxone often combined with twice daily oral rifampicin) or ‘no organism identified’ (for example treated using once daily intravenous ceftriaxone combined with teicoplanin in some centres). These regimes may either be delivered at home by community nursing teams or by once daily return to hospital. Where more complex regimes are needed, treatment at home can only be achieved with good community nursing support, an OPAT service or parental intravenous administration. Central venous lines (CVL) or peripherally-inserted central catheters and OPAT have attendant risks, with a 3–11% rate of CVL associated infection noted in the USA.40 41
Additional or second line antibiotics for complex disease or where resistant pathogens are identified
Where cases are complex, additional antibiotics may be advised by local microbiologists or clinical infectious diseases specialists. Box 1 identifies specific antimicrobial practice points and details current national guidance for PVL positive S aureus infection.
Box 1 Special antibiotic practice points including complex disease
▶ Rifampicin has good oral bioavailability and excellent tissue penetration but must never be given as monotherapy as resistance is rapidly induced.
▶ Teicoplanin has good bone penetration. Levels should be maintained >10 mg/L.
▶ Erythromycin resistant MSSA or MRSA may exhibit dissociated resistance to clindamycin and in these situations clindamycin should not be used alone.
▶ Vancomycin and linezolid for OAI in children should only be prescribed following specialist microbiological or clinical infectious diseases specialist advice.
▶ Where cases are complex, or in PVL positive or MRSA disease, additional antibiotics may be advised by local microbiologists or clinical infectious diseases specialists (suspect PVL disease if it fails to respond to surgical treatment or is recurrent, multifocal or associated with necrotising process). Recent HPA guidelines suggest initial therapy for deep seated PVL positive Staphylococcus aureus infections in children as “intravenous clindamycin plus rifampicin and linezolid. Linezolid should be used for a maximum of 4 weeks due to the risk of development of peripheral neuropathy. For all antibiotics use the maximum dosages listed in the British National Formulary for children (BNFc). As continuation therapy for bone/joint infections use clindamycin plus rifampicin or an alternative combination advised by a specialist in paediatric infectious disease. Maintain vigilance or the occurrence of thromboses”.67
HPA, Health Protection Agency; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin sensitive S aureus; OAI, osteoarticular infections; PVL, Panton-Valentine leukocidin.
Medical treatment of discitis
The appropriate treatment of these lesions has been the subject of controversy, with improvement documented with any of antibiotics, rest, immobilisation or, in fact, no treatment.13 However, antibiotics appear to speed up resolution39 and the same regime as for OM is recommended.42 The length of treatment is tailored to clinical response and normalisation of acute phase reactants, and is usually 4–6 weeks.
Medical treatment of CRMO
The mainstay of treatment is with simple analgesia and non-steroidal anti-inflammatory drugs. In difficult cases, clinicians have used additional agents such as corticosteroids, methotrexate or sulphasalazine.43 Recently, case reports in severe persistent cases have suggested intravenous pamidronate44 to be effective, but bisphosphonates and new biological agents such as the antitumour necrosis factor agent infliximab45 remain to be tested in formal clinical trials. Referral to a paediatric rheumatologist is recommended if these therapies are considered.
Deep venous thrombosis and thromboembolism have been seen in up to 30% of children with OM and are associated with a higher risk of disseminated infection.46 In addition, joint stiffness, limb shortening, dislocation (acutely in neonates) and avascular necrosis of affected epiphysis may occur.
Routine follow-up allows most children with simple disease to be discharged without the need for long term care or further assessment of growth or function.
In the context of clinical audit or clinical trials, outcome measures may include length of stay in hospital, total length of therapy, operative procedures required as well as formal assessment of growth and function.
The authors thank Ivor Byren, Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford for his comments on manuscript drafts.
Competing interests None.
Provenance and peer review Commissioned; externally peer reviewed.
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