Acute haematogenous osteomyelitis in the paediatric population: a current concepts review

Acute haematogenous osteomyelitis (AHOM) is a bacterial infection localised in bone that usually occurs after an episode of bacteraemia. This infection is commonly encountered by doctors in low-and middle-income countries (LMICs) and, if not recognised early and managed appropriately, can harbour significant early and late complications, including death. This narrative review aims to summarise the current management of AHOM, highlight the controversies and report on new advances in diagnosis and treatment. AHOM is typically a monomicrobial disease. Staphylococcus aureus remains the most common pathogen globally, accounting for 70–90% of all cases. Diagnostic work-up includes complete blood cell count, serum C-reactive protein, erythrocyte sedimentation rate, imaging and blood culture. Management of AHOM includes empiric intravenous (IV) antibiotics based on the most likely causative agents; source control entailing surgery to drain any abscesses and obtain specimens for microscopy, culture and sensitivity (MCS), as well as debridement of any necrotic bone; and subsequent targeted antibiotic therapy effective against the identified pathogen with the narrowest spectrum. Treatment response is monitored with repeat CRP every 48–72 hours. The decision to switch from IV to oral antibiotics is made if there is clinical improvement and the CRP is < 20 mg/L. The total duration of antibiotics is six weeks. Treatment of paediatric AHOM is multidisciplinary and includes orthopaedic surgeons, paediatricians, infectious diseases specialists, physiotherapists, dieticians, nurses and social workers. AHOM can cause devastating destruction of the bone due to tissue necrosis, leading to late sequelae. These complications are more common in children in LMICs.


Introduction
Acute haematogenous osteomyelitis (AHOM) is a bacterial infection localised in bone that usually occurs after an episode of bacteraemia. 1 Acute haematogenous osteomyelitis is commonly encountered by doctors in low-and middle-income countries (LMICs) and, if not recognised early and managed appropriately, can harbour significant early and late complications, including death.
Premature growth arrest, limb deformity and leg length discrepancy lead to severe disability, especially in this young population. [2][3][4][5][6] Predictors of poor outcome include concomitant septic arthritis, as damage to the joints in these young patients leads to severe degenerative arthritis. 4,[6][7][8][9] Although perhaps not very high, a mortality rate of 1.06% is significant, especially for a treatable condition. 10 This narrative review aims to summarise the current management of AHOM, highlight the controversies and report on new advances in diagnosis and treatment. PubMed, Cochrane and Google Scholar search engines were searched for articles published since 2018 with the keywords 'Acute Haematogenous Osteomyelitis' AND 'Paediatric'. The titles were then screened for relevance. Those included were then read for content. The bibliographies of included articles were also screened for relevant articles. If novel ideas were quoted, the original articles were sought and cited.

Epidemiology
The annual incidence of AHOM in high-income countries is reported as 8 per 100 000, while the incidence in LMICs is as high as 43 to 200 per 100 000. [11][12][13] Munshi et al. speculated that this increased prevalence is due to the warmer tropical climate, low socioeconomic status, use of traditional medicine and predisposing genetic factors. 14 Seasonal variations have been observed, with a peak in late summer and autumn. 15 Lindsay et al. reported that most children were admitted in summer and found a correlation between the severity of illness and the average temperature during the summer season and a correlation with the average humidity change during the winter months. 15 Children under the age of 5 years are generally affected and present three to four days after the onset of symptoms. [2][3][4]7,12,[16][17][18] Some studies have reported a higher median age of presentation of between 6.7 and 11.1 years. 5,8,14,[19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] Males appear to be between 1.2 and 3.6 times more affected than females.

Kingella kingae
Gram-negative bacteria account for between 60% and 82% of cases in children under the age of 4 years. 60,71 K. kingae is a fastidious Gram-negative coccobacillus, extremely difficult to culture, even when inoculating infected bone fluid into blood culture bottles. 65 Olijve et al. reported the increased incidence of K. kingae in young children coincides with the eruption of deciduous teeth. 44 K. kingae infection presents indolently with low fever, moderately elevated inflammatory markers and is most frequently seen in children between 6 months and 5 years. 2,3,7,16,18,42,44,45,48,65,67,68,79,80 Thakolkaran and Shetty reported that less than 15% of children with K. kingae infection had fever on admission, and 39% had normal CRP levels. 2 K. kingae represents 15-31% of all cases of AHOM. 65 The epiphyses and apophyses, normally spared by other organisms, are frequently involved in K. kingae infections. 18,65 Because of the indolent nature, K. kingae infections can often evolve into subacute osteomyelitis, forming a lucent lesion within the bone (Brodie's abscess). 65

Haemophilus influenzae
H. influenzae accounts for 10-15% of AHOM cases in unvaccinated children under three months in low-income countries. 2 This bacteria typically leads to pneumonia and meningitis in infancy. 27 The South African vaccination schedule includes the vaccine against H. influenzae type B and is given at six weeks, ten weeks, 14 weeks and 18 months. 81

Streptococcus pneumoniae
Infections caused by H. influenzae and S. pneumoniae are more common in children under 5 years of age. 27 Unvaccinated children who develop S. pneumoniae AHOM have a higher risk of developing severe disease with resultant bacteraemia, meningitis, pneumonia Enteric Gram-negative organisms and bone and joint infections. 2 It is also worth noting that not all S. pneumoniae sub-types are covered by vaccination, and S. pneumoniae AHOM can still be seen in vaccinated children. 27 The South African vaccination schedule includes the pneumococcal conjugated vaccine (PCV1) given at six weeks, 14 weeks and nine months.

Streptococcus pyogenes
While the incidence of S. pneumoniae has declined due to vaccination, S. pyogenes is still a bacteria implicated in AHOM. 45

Salmonella
Giaccai and Idriss reported that Salmonella (typhi and paratyphoid B) caused AHOM in 0.2-0.85% of all cases. 82 The incidence increases to between 1.5% and 12% in children with sickle cell disease. 83 It is interesting to note that a prior review article by Burnett et al. in 1998 indicated a higher ratio (1.4:1) of Salmonella AHOM compared to S. aureus in patients with sickle cell disease. 84 This ratio was even lower than a report from 1981, which reported that 50 out of 68 positive cultures yielded Salmonella. 85 This seems to indicate a decreasing incidence of Salmonella infection over time.
Multifocal osteomyelitis is common, but the disease is mild with minimal bone destruction. 82 Some authors have speculated that children with sickle cell disease suffer small gastrointestinal tract infarctions, leading to a Salmonella bacteraemia. 86 The increased incidence of bone infarction, combined with the sluggish microcirculation, causes the Salmonella bacteraemia to localise to the metaphysis of bone and present like the typical AHOM. 86 However, Salmonella osteomyelitis has been reported as typically affecting the diaphysis of long bones, particularly the femur and humerus, as well as the vertebrae. 82,83

Negative cultures
Negative cultures are seen in 33-55% of cases. 3,16,48,60,66 This could be due to a low bacteria load, a fastidious organism or an inaccurate microbiology sampling modality preceding antibiotic therapy. 48,65,87 Searns et al. reported that culture-negative infections have a distinct clinical phenotype: they are younger, less febrile and less likely to have an abscess, and postulated that a smaller volume of blood collected, decreased inoculum, and a more difficult surgical approach may all contribute to negative cultures. 87 Nucleic acid amplification methods (real-time polymerase chain reaction [PCR]) have improved the detection of bacteria not cultured by routine methods. 7,42,88 This becomes important in cases of prior antibiotic use and pathogens notoriously difficult to culture such as K. kingae. 3,4,42,45 Supplemental techniques to improve culture yield include inoculation of blood or chocolate agar plates intraoperatively. 3,12,16 When available, culture-negative specimens can be sent for further molecular testing to better identify the underlying causative agent and guide antibiotic therapy. 3,4,87 O'Rouke et al. reported that real-time PCR testing (testing for S. aureus, group A Streptococcus, S. pneumoniae and K. kingae) could play a role in culture-negative cases as a second-line investigation, 80 and this was confirmed by a few authors. 2,7,38,44,66,67,79 16S rRNA PCR utilisation showed no additional yield when compared to target real-time PCR and should be reserved for cases where the culture and targeted PCR remained negative. 80,87 Diagnosis Early diagnosis is the key to successful management and the prevention of long-term sequelae. 7,37,40 A high suspicion index is required to diagnose AHOM, especially in neonates. 7,12,16,48 The differential diagnosis list is given in Table II.
The diagnosis of AHOM can be made using symptoms (present for 14 days or less) together with at least one of the following four criteria: 7,16,19,20,89 • Positive culture or Gram stain of bone • Positive blood culture • Abnormal imaging • An abnormal clinical examination 45,[49][50][51][52][53][54]75 Waldvogel added an additional criterion: surgical findings of an intraosseus pus collection. 38,90,91   The presentation can vary from a well-localised infection to multifocal infection and septic shock. 39 For toddlers, pain can be expressed as failure to bear weight or pseudoparalysis, as seen in neonates. 9,39,41 A 2012 systematic review reported the most common clinical features to be: pain (81%), localised signs/ symptoms (70%), fever (62%), decreased range of motion (50%) and inability to bear weight (49%) 2,11 ( Figure 1). A limp or refusal to walk, along with back pain and fever, may be associated with vertebral osteomyelitis. 2,4,39 Children with pelvic or sacroiliac infections can present nonspecific abdominal, back or flank pain. 4, 16 Morgan and Yates in 1966 reported pelvic osteomyelitis presented with four clinical syndromes: hip joint; abdominal; buttock and sciatic syndrome. 92 The hip joint syndrome presents with clinical features like those of a hip septic arthritis. 92 The abdominal syndrome features are similar to acute appendicitis with iliac fossa pain. 92 Buttock syndrome presents with pain radiating down the thigh to the knee; this differs from sciatic syndrome which presents with pain along the distribution of the sciatic nerve and represents sacroiliac joint arthritis secondary to iliac AHOM. 92 Lack of coordinated care may result in missed or delayed diagnosis, and current level III evidence suggests a multidisciplinary team to streamline the diagnostic work-up, improve efficiency and increase the rate of positive cultures. 88

Special investigations
Diagnostic work-up includes complete blood cell count, serum C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), radiographs and blood culture. 3,4,7,12,16,48,80,88 The blood culture should be drawn on admission, even if the child is apyrexial, and repeated during a temperature spike. 7 It is recommended that 2-4 ml blood be drawn in a child weighing 1-2 kg, 6 ml in a 2-12 kg child, 10-20 ml in a 13-40 kg child and 40 ml in a child weighing > 40 kg. 16 Because the CRP level rises within six hours, has a half-life of 19 hours, and normalises by 7-10 days, it is used to monitor the response to treatment. [2][3][4]11,12,42,48,92 CRP is elevated in 81-98% of patients and up to 100% by day 3 of the disease. 4 The 2021 Pediatric Infectious Diseases Society and the Infectious Diseases Society of America guidelines recommend performing a serum CRP on the initial evaluation because of its sensitivity. 19,39 Although raised inflammatory markers are not specific to AHOM, a normal CRP and ESR are rarely seen in these patients. 48 Van der Merwe et al. found that the CRP on presentation was the most reliable predictor of culture yield, duration of hospital stay and the number of debridements needed. 33 ESR is elevated in 91-95% of children but peaks in three to five days and normalises by three weeks. [2][3][4]7 It has a lower specificity for AHOM. 4 White blood cell count (WBC) is a poor indicator of disease and is only elevated in 35% of patients; it also correlates poorly with response to treatment. 4,7,11 The use of serum procalcitonin (PCT) is not advocated as it has a sensitivity of 85% and specificity of 87% and thus does not outperform CRP. 4

Imaging
Radiographs of the affected limb should be requested to exclude other diagnoses such as fractures and malignancy. [2][3][4]11,12,39,41,46,48 X-rays are often normal in early AHOM as it takes up to two weeks for radiographic changes to appear, because lytic changes in bone require 50% of the bone mineral density to be depleted before becoming evident on X-rays. 3,7,16,37,42,48,94 Ultrasound is a cheap, readily available and non-ionising investigation. 20 Ultrasound can guide diagnostic or therapeutic aspiration of fluid collections, but the sensitivity and specificity are low. 4,7,12,16 Ultrasound is used to screen for possible deep vein thrombosis (DVT). 3 The advantage of ultrasound is that it is non-invasive and does not require sedation but it is operator dependent. 3 The ultrasound criteria needed to diagnose AHOM include any one of the following: 20 • Deep soft tissue fluid collection around the bone • Periosteal thickening or elevation with a thin layer of subperiosteal fluid collection • Increased vascularity within or around the periosteum on Doppler sonography MRI is particularly useful in detecting pelvic osteomyelitis and discitis. 7  The MRI criteria to diagnose AHOM includes: 20,41,96 • Alteration of normal signal intensity (low signal on T1-weighted images and high signal of STIR or T2-weighted images). On fat-suppressed gadolinium-enhanced T1-weighted images, it is seen as increased enhancement relative to the adjacent marrow • Subperiosteal collection The MRI scan details bone and soft tissue involvement and helps with surgical planning. [2][3][4]39,42 (Figure 2). Gadolinium may enhance  clinical efficacy by detecting intramedullary or muscular abscesses and necrosis. 4,7,16,95 Diffusion-weighted imaging (DWI) relates to the composition of tissue and fluid, for example, high cellularity and the viscosity of pus. 95,96 Habre et al. reported that DWI can be used to detect AHOM (restricted diffusion in soft tissue or bone) and could potentially negate the use of contrast. 95 However, one does need an experienced radiologist. 95,96 Contrast-enhanced sequences should be used for young children under 3 years of age, where proximal femoral head involvement is suspected, as the non-contrasted images are less sensitive due to the proximity of the epiphysis. 95,96 Repeat MRI does not have a role in routine surveillance but could be useful if the current treatment fails. 4 End-of-therapy imaging (MRI or X-rays) is only recommended if the physis was involved. 39 MRI does not come without limitations -scan times can potentially be long, and the child needs anaesthesia or deep sedation to prevent movement. 2,4,7,16,42 A diagnostic MRI can be successful in non-sedated infants younger than six months when swaddled and asleep. 96 The cost of MRI can be justified because its use leads to fewer surgeries and days spent in hospital. 22 Where MRI is not possible, contrasted computed tomography (CT) to detect abscess formation, bone scan or scintigraphy and ultrasound have been used. 42,48 CT involves high-dose radiation with decreased sensitivity for marrow and soft tissue pathology but is excellent at defining bony pathology. [2][3][4]20 Technetium radionuclide scan can be used to identify multifocal osseous involvement. 7,16,42 It has high sensitivity but less specificity and can give false positive results in infancy and with virulent bacteria like MRSA. 4,7,11,12,42 Triphasic Technetium scanning includes a flow phase (2-5 seconds after injection), a blood pool phase (5-10 minutes after injection) and a delayed phase (2-4 hours after injection). 7 AHOM leads to focal absorption in the third phase, and the brighter the signal, the more osteoblastic activity. 7 This modality is a functional scan and cannot give information on whether pus collections are present. 4,7 Technetium radionuclide scan involves a significant amount of radiation exposure (200-750 chest X-rays) but could still be faster and more accessible than MRI in some centres. 42

Management
The management for AHOM includes: 3 Figure 3. Proposed management algorithm for AHOM in South Africa * All patients to be started on IV empiric antibiotics until positive blood/tissue culture ** Avoid anteromedial incisions on the tibia; take note of skin bridges between tibia, knee and femur incisions initiation of antibiotics is equivalent to those obtained before the administration of antibiotics. 39,46 Van der Merwe et al. reported that, in matched groups, antibiotic administration before surgery did not decrease surgical culture yield. 33 Some children with AHOM can be severely ill with septicaemia. 5 Septicaemia could lead to acute multiorgan failure, including septic pulmonary emboli and DVT. 60,72 The early course of infection may be complicated by persistent bacteraemia, prolonged fever, sepsis, thrombophlebitis, longer hospital stays and prolonged course of parenteral antibiotics. 5,12 The prolonged bacteraemia may reflect inadequate source control, the establishment of endovascular foci (endocarditis and septic venous thromboembolism) or metastatic infection. 97 Gouveia et al. reported a 30% association with concomitant pyomyositis and a 68% association with septic arthritis. 98 Manz et al. reported that the incidence of concomitant AHOM and septic arthritis was higher than initially thought in children older than 6 years. 37 The incidence of concomitant AHOM and septic arthritis has been reported as 46% below 2 years of age; 28% in 2 to 5 year olds, and for 6 years and older, 40%. 26,37,38 Yi et al. reported that children with concomitant infections have a higher intensive care unit (ICU) admission frequency and significantly longer hospitalisation. 59 Concomitant infection also produced higher inflammatory markers. 59 Primary treatment failure can occur, and if so, the adequacy of the antibiotic treatment should be assessed and the need for surgical intervention evaluated. 39 The rate of complications has been reported at 6-9%, and patient nonadherence to treatment accounted for 43% of treatment failures. 59 Amaro et al. showed a link between the peak level and duration of CRP elevation and the risk of thrombotic complications in children with musculoskeletal infections. 99 The theory is that the prolonged acute phase response due to the infection predisposes to thromboembolism. 99 At the peak CRP of 180 mg/L, the predicted probability of venous thromboembolism was 4.9%, while the risk increased to 50.9% at a peak CRP of 420 mg/L. 99 The risk of DVT and pulmonary embolism increases from 0.4-6% 3,12 to as high as 40% in children older than 8 years old with MRSA infection and a CRP > 60 mg/L. 4,7,100 Some studies suggest that each child with MRSA infection should be screened for a DVT. 42,54,71,74,76,77 Those at particular risk are infections of the femur and tibia. 74 Hester et al. aimed to improve the care of their patients by implementing four quality improvement interventions: 1) infectious disease education, 2) centralisation of admission, 3) communication between orthopaedics and radiology, and 4) application of a management algorithm. 101 They aimed to decrease peripherally inserted central catheter (PICC) use by 50%, reduce the number of sedation episodes, and reduce empirical vancomycin by 50%. 101 The use of PICC lines decreased, but this was already noticed before the improvement intervention was implemented. Sedation episodes decreased as the use of PICC lines decreased. Empiric use of vancomycin did not decrease. 101 Treatment of AHOM is multidisciplinary and includes orthopaedic surgeons, paediatricians, infectious diseases specialists, physiotherapists, dieticians, nurses and social workers. 2,48,71 Figure 3 depicts a proposed treatment algorithm for the South African system. Copley and colleagues established guidelines in the context of a multidisciplinary team. 48,102 This included daily ward rounds by orthopaedic surgeons, paediatricians, infectious disease specialists, nurses and social workers. 48,102 The key to successful treatment included a dedicated MRI slot for children with suspected AHOM, with an immediate transition to the operating room if necessary. 3,48,102 A multidisciplinary approach with interdisciplinary MRI protocols has been shown to decrease time to MRI and surgery and thus decrease days in hospital; MRI has great utility as an initial screening test. 3 Quick et al. reported that involving the paediatric orthopaedic services immediately upon admission improved communication and created a timely diagnosis and treatment plan. 88 The prearranged early morning MRI slot and reserved operating room facilitates the surgeon's availability to perform the relevant surgery following a positive MRI. 88 Griswold et al. reported on this protocol: the MRI is scheduled for 7 am the morning after the admission. The consultant orthopaedic surgeon and radiologist review the MRI in real-time. 22 A scout view was done to scan for any unexpected foci; T1 with or without contrast, T2 fat-suppressed and STIR images in all planes were done. 22, 96 An operating room was kept on hold, and the patient was transported to the operating room for surgery without being awakened. 22 The authors studied the patients treated before and after the implementation of the MRI protocol and found that preoperative MRI significantly reduced the number of surgeries and unplanned returns to the operating room. 22 The duration of hospital stay was reduced, and this was clinically significant. 22 This protocol led to a reduction of after-hours MRI scans and after-hour surgical debridements being done. 22 In 1997, Roine et al. reported on the early detection of sequelae. 24 They used a clinical scoring system tabulated in Table III and the patient's CRP level. The CRP cut-off limits were as follows: day one 190 mg/L, day two 202 mg/L, day three 178 mg/L, day five 86 mg/L. Their research reported that a clinical score of ≥ 1, plus a CRP exceeding the cut-off on the taken day, was statistically significant in predicting sequelae. 24 Copley et al. subsequently created a scoring system to assess the severity of AHOM. 25,48 This scoring system used clinical and laboratory findings (Table IV). 25 Severity was the sum of the parameters, with mild being (0-3), moderate (4-7), and severe (8-10). 3, 25 Copley et al. reported that their clinical experience suggested that the clinical and laboratory response of the child during the first four to five days of treatment served to determine the severity score. 3,25 Disseminated disease included children with meningitis, septic shock, toxic shock, multifocal infection, endocarditis, DVT, septic pulmonary emboli, empyema or pneumonia ( Figure 4). 3,9,25,40,59 It is not clear but assumed that a patient would only need one of these associated symptoms to deem it a disseminated disease. Mignemi et al. also reported a classification system. 25,103 In their study, disseminated infection was defined as AHOM with subperiosteal abscess extension, while local infection was defined as isolated AHOM with no subperiosteal pus formation. 103 These patients with disseminated infection were more likely to have longer hospital stays as well as ICU admissions, more surgeries performed, more positive blood cultures, longer duration of antibiotics, more pyrexial days and more imaging studies. 103 Inflammatory markers were also higher in disseminated infections. 103 No extrapolation was given regarding predictive factors which could be useful on admission to determine prognosis.
Sanchez et al. reported that children with severe severity scores had concomitant endocarditis, thrombophlebitis and septic pulmonary emboli. 97 Children with severe illness underwent more surgical debridement and cultured MRSA as the primary pathogen more frequently. 10,97  Additional surgical drainage after the initial one 1 More than one focus of osteomyelitis or septic shock 1

Empiric antibiotics
Empiric antibiotic therapy is determined by the geographic resistance patterns, age of the child and laboratory results, and targets the most likely causative agent. 1 Antibiotic bioavailability and bone penetration should also be considered. 7 A summarised version of the empiric antibiotics per age group is reported in Table V. First-generation cephalosporins and anti-staphylococcal penicillins such as cloxacillin or clindamycin form the mainstay of antibiotic treatment with additional Gram-negative cover (third-generation cephalosporin) for neonates and young children. 2,4,9,17,18,45,54,56,57,60,68,72,77,105 In Europe, empiric guidelines include clindamycin plus a first-generation cephalosporin. 4,42,48 Cefuroxime 150 mg/kg/day IVI q8h can be used empirically if you suspect H. influenzae in unvaccinated children under 4 years of age. 16 First-generation cephalosporins provide dual cover against K. kingae and S. aureus. It is important to note that the antistaphylococcal penicillins, clindamycin and glycopeptides are ineffective against K. kingae. 18,42,68 In cases of MSSA PVL-positive infections, first-generation cephalosporins plus clindamycin is suitable. 2,18,42 In vitro evidence has shown that clindamycin, linezolid and rifampicin inhibit the production of PVL, and thus, adding these antibiotics will inhibit toxin production. 7,42,56,70 If the MRSA prevalence is > 10%, the Infectious Disease Society of America has recommended the empirical antibiotic choice be vancomycin or clindamycin. 2,4,7,12,18,48,53,68,72,74,76,77,93,100 Clindamycin has excellent bone penetration and is safe, inexpensive and effective against MSSA and MRSA. 2,18,68,100 Other alternatives for MRSA include daptomycin and linezolid in patients who do not respond to vancomycin. 2,18,68,93,100,106 Linezolid has excellent bone penetration. 18   In some European studies, amoxicillin-clavulanate is widely used in low MRSA prevalent areas. 68 Serrano et al. reported using amoxicillin-clavulanic acid in more than 60% of their cases as empirical oral therapy. 17 The epidemiology and pathogen distribution in Serrano et al.'s study was similar to other literature. 17 Other options include nafcillin or oxacillin in conjunction with vancomycin for severely ill children with MSSA, although they are not typically used in South Africa due to lack of availability. 74 Vancomycin-resistant S. aureus (VRSA) infections are emerging. 41 If a VRSA strain is suspected, a paediatric infectious disease specialist should be consulted. 41 In cases of a negative culture, the antibiotic recommendation is a first-generation cephalosporin in MRSA-low regions and clindamycin with or without first-generation cephalosporin in high MRSA regions. 2,4,40,42 The dosages of the empiric antibiotics as well as the susceptible organisms are tabulated in Table VI. These dosages have been advised using the European literature and verified using the South African Medical Formulary. 68,107,108

Biopsy and source control
Nonoperative management with only antibiotics can cure early AHOM in up to 90% of cases. 2,4,11,12,35,40,42,68 There is insufficient literature on indications and techniques for the surgical management of AHOM, and consensus regarding the need for surgery is lacking. 3,4,21,42,98 Bacterial biofilm, abscess formation and bone necrosis impact antibiotic delivery. 48 These factors highlight the importance of surgery to decompress the abscess, decrease disease burden by debriding any necrotic tissue and obtain tissue cultures. 21,48,89 Clinical response to antibiotic therapy, the presence of an abscess, persistent fever or elevated CRP and MRSA or PVLpositive bacterial infections should be considered when deciding on surgical management. [2][3][4]16,21,41,42,48 Woods et al. recommended surgical debridement in patients with sepsis or rapidly progressive infection and stable patients with large abscesses (greater than 2 cm). 11,39,46 Independent predictors of surgical intervention in Upasani et al.'s study were multifocal infection, ambulatory status, elevated CRP on admission and elevated platelet count on admission. 21 Upasani reported that there is marked variability in the surgical management of these patients in centres in the USA, and the overall surgical rate was 62%. 21 The decisions were based primarily on institutional practice or dogma. Secondarily, the clinical presentation did affect the surgery rate in centres that did not frequently use surgical management to treat AHOM. 21 There was more consensus if patients had multifocal disease, and even in institutions where surgery was not the norm, these patients were taken to theatre for debridement. 21 Once AHOM is diagnosed, a biopsy is needed to obtain a culture to guide antibiotic therapy. 7,21,42,46,48 This can be done through a percutaneous biopsy or open debridement. 48 Deep cultures are not influenced by preceding antibiotics if taken within 72 hours of initiating antibiotic therapy. 4,41,45 Interventional radiology-guided All bone, tissue and fluid samples should be placed in sterile containers. 16 The use of pus swabs is discouraged due to low yield. 16 Any fluid should be placed in blood culture bottles. 16 Some samples should be stored for further molecular testing if no bacteria are cultured. 16 The reported rates of surgical management vary widely from 8-80%, primarily due to inconsistencies with the description of the procedure. 4,38 The fundamental principle is source control. 4 A corticotomy can be performed for intraosseous collections, and drains are routinely placed. Bone drilling is required in patients with subperiosteal or intramedullary abscesses. 41 Placing plastic tubing into a drill hole and irrigating the medullary canal has been described 89 ( Figure 5). Montgomery et al. reported that when not drilling the cortex and irrigating the medulla, patients were six times more likely to need a re-debridement and recommended drilling the cortical bone (even if subperiosteal abscess is present) one to three times and flushing the canal. 109 Of those who undergo a surgical debridement, 15-33% need a repeat debridement. 4 Infections with MRSA increase the risk for multiple procedures. 4,10 Indicators of a secondary procedure include persistent pain, clinical deterioration and increasing inflammatory markers, as well as the presence of MRSA. 10 Localised delivery of antibiotics could be advantageous -it leads to a higher drug concentration at the infected site while limiting systemic toxicity. 89 Routine surgical-site antimicrobial agents remain controversial, with little evidence recommending their use. 39 Wang et al. reported on antibiotic-loaded calcium sulphate beads versus conventional surgery (removal of pus, the entire length of the canal debrided to remove the infected debris and endosteal bone) used in the treatment of AHOM. 89 The calcium sulphate beads were impregnated with vancomycin in combination with a negative-pressure dressing. 89 Vancomycin beads were placed in the medulla at the initial surgery and changed with each surgery. 89 The authors found that the vancomycin group needed fewer surgeries, but the complication rates were the same. 89 The vancomycin group had a quicker clinical response with a drop in CRP level seen (4.8 ± 2.5 days versus 13 ± 9.6 days). 89

Targeted antibiotic therapy
Cephalosporins and anti-staphylococcal penicillins are bacteriostatic and bactericidal depending on the serum concentration, and continuous IV infusions can increase the serum concentration to make the antibiotic bactericidal. 45 High-dose cefazolin (100-150 mg/kg/day divided q8h) is well tolerated and has a clinical cure rate above 95% for susceptible bacteria. 16,45 Cefazolin is preferred over nafcillin or oxacillin due to their adverse side effects. 45 S. pyogenes has been exquisitely susceptible to ampicillin and amoxicillin. 45 Ampicillin-sulbactam and amoxicillin-clavulanic acid should be reserved for situations where narrow-spectrum, firstline drugs cannot be administered. 45,68 Serrano et al. reported few cases of recurrence and sequelae (0.9%) when using amoxicillinclavulanic acid. 17 Amoxicillin-clavulanic acid can be used in young children because of its q8h schedule, palatability and seemingly good efficacy in areas with a low prevalence of MRSA. 17,105 Intravenous clindamycin should be considered in patients who do not have ongoing bacteraemia and in hospitals with low clindamycin resistance. However, this is controversial as some clinicians have good outcomes with clindamycin, even in the presence of bacteraemia. 42,48,93 Rifampicin is bactericidal and may prevent S. aureus resistance to other antibiotics, such as fluoroquinolones. 45 Another benefit is the synergism in bacteraemia and its ability to penetrate biofilms, but there is no substantial evidence that this is the case in vitro. 18,45 However, the low rate of adverse effects makes this an attractive adjuvant. 45,105 It is important to note that rifampicin should never be used as monotherapy. 45,105 The rifampicin dose is 10 mg/kg q12h, and the duration should be based on clinical judgement. 45 It has excellent oral bioavailability and is also available in an intravenous preparation. 18,68 Salmonella infection, common in sickle cell anaemia, should be treated with a third-generation cephalosporin or a fluoroquinolone. 2,7,18 Adverse reactions to vancomycin include ototoxicity and nephrotoxicity, so hearing and renal function should be monitored during its use. 29,100 As the half-life of vancomycin may be prolonged, it is important to monitor the trough concentration. 2,18,29 Fosfomycin is a bactericidal antibiotic against Gram-positive and Gram-negative pathogens. 110 It is effective in acidic and low-oxygen environments, like in an abscess. 110 Tsegka et al. investigated the efficacy of fosfomycin against AHOM. 110 Fosfomycin was successful in 82.2% of patients; it has low toxicity and high bone and abscess penetration, making it a drug to consider. 110 Future therapies include dalbavancin, an intravenous concentration-dependent bactericidal drug with a prolonged halflife (202 hours) and thus could potentially be given once daily. 100 The duration of antibiotics should be a minimum of four to six weeks, but there is no consensus on duration. 2,3,11,16,18,37,45,48,89 Oral therapy should be continued for three to four weeks. 94 Shorter durations are recommended in an uncomplicated course where PVL-positive pathogens are not suspected. 39,45,94 Some authors have reported that children with negative cultures or K. kingae had a lower mean treatment duration. 44,65 Some groups report that neonates should receive four weeks of intravenous antibiotics. 18 The European guidelines are shorter, with the total therapy (IV and oral combined) being three to four weeks for AHOM; these children must have CRP levels under 100 mg/L on admission. 4,42,64 Longer therapy (up to six weeks) should be given in children with CRP levels above 100 mg/L; resistant or unusual pathogens; children under the age of three months; slow or poor Figure 5. Intraoperative photo of the feeding tube irrigating the medullary canal proximally, and pus being expressed distally through distal drill holes. This illustrates the extent of pantibial osteitis and the importance of drilling the cortex and irrigating the medulla. Drill holes are present with a feeding tube placed intramedullary and irrigated. Note the periosteal stripping.
Feeding tube placed in a drill hole irrigating the tibia Pus escaping through the distal drill holes Ivory tibia with marked periosteal stripping response to treatment; any complications; pelvic or spinal AHOM; septicaemic children or immunocompromised children. 4,37,42,64 The decision between oral therapy once ready for discharge versus outpatient parenteral antibiotic therapy (OPAT) via a PICC line sways towards a switch to oral therapy. 39,45,88,111 This avoids high costs and harm to the patient. 3,39,45,88,111 However, OPAT is preferred over a prolonged inpatient hospital stay if oral therapy is not feasible. 39 Prolonged intravenous antibiotics are associated with risks, including catheter-associated complications such as thrombophlebitis. 2,4,16,18,45 Oral therapy is contraindicated in cases of poor medication compliance or follow-up, malabsorption or a slow resolution of infection. 16 The timing of the switch to oral therapy is still debated. 7,18,38,68 Some authors recommend at least five to seven days of intravenous treatment. 18 An early oral switch has been used if the child shows clinical improvement. 4 Faust et al. considered an oral switch safe if the CRP value is under 20 mg/L or at least two-thirds of its maximum peak. 7,112 Flucloxacillin is a narrow spectrum, semisynthetic penicillin and can be prescribed for sensitive S. aureus but bear in mind the poor taste of the oral suspension. 7,11,16,111 Flucloxacillin has bactericidal properties but little evidence that, in vitro, there is good bone penetration. 111 Preiss et al. conducted a narrative review on oral flucloxacillin to treat AHOM. 111 The experience of most publications reports good outcomes with oral flucloxacillin, despite the poor bone penetration. 111 Adverse effects include hypersensitivity, gastrointestinal symptoms, nephrotoxicity and myelotoxicity. 111 Drug-drug interactions have been reported with paracetamol and rarely with warfarin and rifampicin. 111 Most clinicians recommend 100 mg/kg/day. 16 Cephalexin is an oral first-generation cephalosporin and has demonstrated positive outcomes in 82-100% of patients. 45 The dosage should be 100-150 mg/kg/day q6h to improve the minimum inhibitory concentration (MIC). 45 The half-life is short (one hour); thus, the six-hour dosing is better than eight hours. 16 For MRSA, oral therapy with clindamycin, trimethoprimsulfamethoxazole or linezolid can be considered with careful monitoring. 16 34 When compared to vancomycin, daptomycin performed as well as vancomycin regarding successful treatment and was better tolerated. 34,100 Daptomycin and linezolid should be considered second-line drugs. 100

Outcomes
The incidence of complications after AHOM is unclear -highincome countries report the incidence to be 27% 113 but it has been reported as high as 48% in South African literature. 114 Risk factors for a more prolonged hospital course and long-term complications include high-virulence organisms (such as MRSA), contiguous septic arthritis, positive cultures, younger children, location of the disease and delay in care and source control. 4,6,10,11,41,89,94,[113][114][115] Osteonecrosis or chondrolysis, seen in 8% of cases, is correlated with the initial illness severity and leads to premature arthritis. 4,6 To protect the hip from dislocation, abduction skin traction can be applied when proximal femur AHOM and hip septic arthritis is diagnosed. 118 The common complications are tabulated in Table VII. AHOM can cause devastating destruction of the bone due to tissue necrosis, leading to late sequelae like chronic osteomyelitis (1.7%) 3 and pathological fractures 5,23,31,36 ( Figure 6). Complications such as these are more common in children in LMICs. 50,54,55 Belthur et al. described the incidence of pathological fracture as 4.6-5%; however, Popsecu et al. reported an incidence of almost 10%. 31,119,120 In addition, on admission, large subperiosteal abscesses extending into the muscle were more likely to fracture within 72 days of presentation. 3,4,7,71,74 The limb segment should be protected in the first six weeks to prevent a pathological fracture. 42 Calvo et al. reported that children with contiguous infections also had the highest incidence of surgery (46%), complications (18%) and sequelae (10%). 56  Delayed source control (three days in hospital) 4 Maximum score 15 The Other complications include avascular necrosis, angular deformities and limb-length discrepancy due to physeal growth arrest or overgrowth. 1,5,6,12,49,50,53,54,57,60,72,76,115,121 These children can also develop joint contractures, chronic pain and gait disturbances. 9,42,76 Sequelae at one-year follow-up are higher in infants under 3 months. 9 Predictors of poor outcome in neonates include hip and shoulder involvement, concomitant septic arthritis with AHOM, bacteraemia and S. aureus infection (especially with MRSA). [7][8][9] The recurrence rate has been reported as between 3% and 6.8%. 3,23,88 McNeil et al. reported that infection with agr III (accessory gene regulator III) S. aureus organism, fever more than four days after admission and delayed source control were associated with significant increase in orthopaedic complications. 31,41 The fracture risk increased significantly with more than three debridements. 31 Alhinai et al. developed an A-SCORE and C-SCORE to predict acute and chronic complications (Table VIII). 5 The negative predictive value of the A-SCORE ≤ 4 was ≥ 91%, and the C-SCORE ≤ 3 was ≥ 95%. 5 Vij et al. found similar results in their study and concluded that the A-SCORE should be used in combination with clinical judgement to determine optimal timing for early care decisions like an oral antibiotic switch. 30 The C-SCORE can be used to consider specific decisions regarding the development of chronic osteomyelitis and the need for prolonged (> 12 weeks) antibiotics, as well as to rule out pathological fractures and avascular necrosis. 30 Rehabilitation is an integral part of management, with prompt mobilisation crucial to prevent contractures. 42 Prolonged orthopaedic follow-up for up to 12 months is recommended in those with infections around the physis and any patient who underwent surgical debridement and even longer if the pelvis, spine or hip were involved. 4,39,42 Hunter and Baker reported on the quality of life of children treated for AHOM. 23 The most common complaints were pain, stiffness (mostly related to sport) and anxiety. 23 There are no validated assessment tools to assess the quality of life after AHOM. 23 The recommendation is for a disease-specific assessment tool to analyse the longer-term outcomes. 23

Conclusions
A multidisciplinary approach to managing acute haematogenous osteomyelitis should be the standard of care. Proactive MRI protocols may improve patient care and should be implemented in centres where MRI is available. Local antibiogram profiles should govern empiric antibiotics, and clindamycin should be considered for its anti-toxin properties in systemically ill children. If an abscess is present, surgical management to decompress the pus and obtain a biopsy is needed. The bone should be drilled even if there is subperiosteal pus. A total of six weeks of antibiotics is key in complicated cases of AHOM. More research from LMICs should be published to guide local treatment algorithms. A proposed management algorithm is proposed for the South African system (Figure 3).