Oral Antibiotics for Children and Adolescents With Uncomplicated Bone and Joint Infections

Bone and joint infections (BJIs) in children and adolescents have traditionally required intravenous (IV) antibiotic treatment and hospitalization, which have implications for the patients, their families, health resources and antimicrobial stewardship.1 Historically, the treatment has involved extended IV therapy of 1–6 weeks, primarily based on expert opinions and retrospective studies.2,3 However, in many settings, the recommended treatment changed during the 2010s to a short individualized IV phase of 2–4 days, followed by oral antibiotics for 1–2 weeks for joint infections and 3 weeks for bone infections.4–8 These changes were primarily based on 2 randomized controlled trials (RCTs) from Finland.9,10 In both trials, the initial IV phase was individualized and tailored to the treatment response, lasting 2–4 days, and followed by oral antibiotics.9,10 The total median treatment duration of 10 days for joint infections9 and 20 days for bone infections10 was noninferior to 30 days for both conditions. Several cohort studies have subsequently confirmed the safety of a short IV phase followed by oral antibiotics.11–15 Most recently, emerging evidence has supported the effectiveness of oral antibiotics for the entire treatment course in uncomplicated BJI, in settings with low risk of methicillin-resistant Staphylococcus aureus (MRSA).16–19 Here, we review the literature on oral-only antibiotics for children and adolescents with BJI, and discuss its implementation in clinical practice. Initial Oral Therapy In a PubMed search of literature from 2000 to 2025, we identified 1 RCT and 5 observational studies evaluating initial oral antibiotic treatment for children with uncomplicated BJI (Table 1).16–20 A nationwide Danish RCT by Bybeck Nielsen et al, published in 2024, evaluated initial oral versus initial IV antibiotics in 192 children with uncomplicated BJI. Initial oral antibiotic therapy was noninferior to IV antibiotics regarding clinical sequelae at 6 months, and with no difference in clinical or radiological sequelae at 12 months.16,21 Excluded patients were those with features of sepsis, substantial soft tissue involvement, expected need for major surgery, previous BJI, prosthetic material, resistant pathogen, and severe comorbidities.16 The children who received initial oral therapy had a median age of 2.4 years (IQR: 1.3–6.7) (Table 1). The rate of antibiotic switch due to suspected treatment failure was low and similar in patients receiving initial oral or IV treatment. Three important conditions regarding this trial should be noted. First, it was conducted in a setting with only 2% MRSA, and only 16 (16%) of 101 children receiving initial oral therapy had proven S. aureus infection, all methicillin-sensitive (MSSA) except one. Second, during the initial phase of the treatment, equivalent to the standard IV phase, the oral dosage was doubled to rapidly achieve high serum levels as with IV therapy. Third, 10% of children were switched to IV treatment due to nonadherence to the oral therapy, arising from issues such as vomiting, nausea, or the refusal to take oral medication. TABLE 1. - Studies on Initial Oral Antibiotics for Children With Uncomplicated Bone and Joint Infections Author Year Country Study Type Inclusion Criteria Patients Pathogen Oral Antibiotic Treatment Clinical Sequelae Number Median Age in Years (IQR) Median CRP in mg/L (IQR) Roul-Levy 2016 France Retrospective Bone infections* 19 2 (1–2) 7 (1–12) 19 NI Amoxicillin-clavulanate (1:4) 80/20 mg/kg/day None Calvo 2016 Spain Retrospective BJI 34 NA NA NA Cefuroxime, cefadroxil None Alcobendas 2018 Spain Retrospective Kingella kingae joint infections 12 <2 NA 12 K. kingae Cefuroxime, amoxicillin-clavulanate None Alcobendas 2022 Spain Prospective BJI† 64 2 (1–3) 16 (7–30) 18 K. kingae, 2 MSSA, 42 NI Cefuroxime 60 mg/kg/day, cefadroxil 60 mg/kg/day, amoxicillin-clavulanate (1:4) 80/20 mg/kg/day None Udaondo 2024 Spain Retrospective BJI† 27 NA NA 7 K. kingae, 2 MSSA Cefuroxime, cefadroxil, amoxicillin-clavulanate None Bybeck Nielsen 2024 Denmark Randomized controlled trial BJI‡ 101 2 (1–7) 48 (16–94) 15 MSSA, 5 K. kingae, 4 S. pyogenes, 1 MRSA, 76 NI Initial high-dose phase: Amoxicillin-clavulanate (1:8), 100/12.5 mg/kg/day (<5 years) or dicloxacillin, 200 mg/kg/day (≥5 years)Maintenance phase: Amoxicillin-clavulanate (1:4), 50/12.5 mg/kg/day (<5 years) or dicloxacillin, 100 mg/kg/day (≥5 years) None§ BJI indicates bone and joint infections; CRP, C-reactive protein; IQR, interquartile range; MRSA, methicillin-resistant S. aureus; MSSA, methicillin-sensitive S. aureus; NA, data not available from the publication; NI, not identified.*Exclusion criteria: CRP >50 mg/L, fever >38.5°C or septic shock signs, subperiosteal abscess, multifocal localizations, and severe immunodepression, including sickle cell disease.†Inclusion criteria: Good general condition, no underlying disease, 6 months to 3 years old, appropriate oral tolerance, C-reactive protein <80 mg/L, erythrocyte sedimentation rate/C-reactive protein ratio ≥0.67, no skin injury, no recent surgery, no cervical spondylodiscitis, and no local complications at onset.‡Exclusion criteria: Features of sepsis, substantial soft tissue involvement, expected need for major surgery, previous BJI, prosthetic material, resistant pathogen, and severe comorbidities.§Clinical sequelae at 6 months demonstrated noninferiority with a 5% risk difference margin, a one-sided 97.5% confidence interval, and a corresponding one-sided pnoninferiority=0·012.16,21 Sequelae after 6 months were not observed in either treatment group. After 12 months, clinical sequelae were identified in 1 (1.1%) of 92 and 2 (2.4%) of 83 who received initial oral and IV therapy, respectively (risk difference: −1.3%, 95% CI: −7.7 to 3.9).16,21 Five retrospective cohort studies have evaluated initial oral antibiotic treatment in children with uncomplicated BJI (Table 1).17–20,22 Four studies from the Spanish Network of Osteoarticular Infection assessed a combined total of 137 children from Madrid from 2008 to 2024.17–19,22 All recovered without clinical sequelae. The children were aged below 3 years and selected for oral treatment if they were in good general health, tolerated oral medication, and could be followed closely as outpatients. Only 4 had S. aureus infection, all MSSA (Table 1). In a study from France, Roul-Levy et al20 described 19 children aged 1–11 years with osteomyelitis diagnosed by technetium-99m bone scan in 2011–2012 and treated with oral antibiotics only. After 6 months, none had clinical sequelae or radiological signs of complications. The findings from these studies highlight that initial oral antibiotic therapy appears to be safe and effective for children with uncomplicated BJI if close monitoring of treatment response is ensured, local resistance patterns are considered, and the initial oral dosage is appropriately adjusted to achieve high serum levels, resembling the initial IV phase. Empirical Oral Antibiotics in Settings With Low MRSA The selection of oral antibiotics for empirical initial treatment of uncomplicated BJI may be guided by the recommended empirical oral antibiotic therapy that follows initial IV treatment, which typically depends on age.4 In children aged 3 months to 5 years, first- or second-generation cephalosporins or amoxicillin with clavulanic acid are the recommended antibiotics.4 They have appropriate coverage against MSSA and Kingella kingae, the most common pathogens in this age group, and they also cover less common pathogens, such as Streptococcus pneumoniae, Streptococcus pyogenes and Haemophilus influenzae. Due to the high risk of K. kingae resistance, clindamycin and antistaphylococcal penicillin (eg, flucloxacillin or dicloxacillin) are inappropriate for children below 5 years.23,24 In children above 5 years, antistaphylococcal penicillin, first- or second-generation cephalosporins, or clindamycin are the recommended oral antibiotics as they cover MSSA, the most common pathogen in this age group, and also S. pyogenes and S. pneumoniae.4,6,7 In the Danish RCT comparing initial oral versus IV antibiotics, high-dose amoxicillin-clavulanate (8:1 ratio; 100/12.5 mg/kg/day in 3 doses) was used in children below 5 years, with dose reduction (4:1 ratio; 50/12.5 mg/kg/day in 3 doses) after clinical improvement.16 For children aged 5 years and above, high-dose dicloxacillin (200 mg/kg/day in 4 doses) was used initially, with dose reduction (100 mg/kg/day in 4 doses) after clinical improvement.16 In Spain, oral treatment has been reported to be safe with cefuroxime (60 mg/kg/day in 3 doses), cefadroxil (60 mg/kg/day in 3 doses), and amoxicillin-clavulanate (4:1 ratio; 80/20 mg/kg/day in 3 doses), with no dose changes during the treatment period.17 Similarly, the French cohort received oral antibiotics with amoxicillin-clavulanate (4:1 ratio; 80/20 mg/kg/day in 3 doses) throughout the treatment period and recovered without sequelae.20 Treatment Duration of Oral-only Antibiotics Studies investigating initial oral antibiotics have used treatment durations according to the standard guidelines for children with BJI.4 In the Danish RCT comparing initial oral versus initial IV antibiotics in uncomplicated BJI, the median treatment duration for patients receiving oral antibiotics was 13 days for joint infections, 26 days for bone infections, and 32 days for spondylodiscitis.16 This treatment duration included the initial individualized high-dose oral phase until clinical improvement (median 4 days, IQR: 3–7) and the subsequent standard-dose oral phase of 1 week for joint infections, 3 weeks for bone infections and 4 weeks for spondylodiscitis.16 In the 2 cohort studies from France and Spain, good outcomes of oral treatment were reported with a median treatment duration of 25 and 43 days.17,20 Thus, treatment with oral-only antibiotics may follow the standard recommended treatment duration. DISCUSSION Solid evidence has demonstrated the safety of short initial IV antibiotics of 2–4 days followed by oral antibiotics in children with BJI.9–15 This suggests that oral therapy, administered for most of the treatment period, effectively controls the infection by achieving adequate serum levels to penetrate bone and joints, likely aided by the high vascularization in children.25 In settings with a low prevalence of MRSA, growing evidence suggests that initial oral antibiotics may be a viable alternative to the initial IV therapy in children with uncomplicated BJI.16–18,20 Still, to date, only 1 RCT has evaluated this approach.16 When to Implement Initial Oral Antibiotics in Clinical Practice? The optimal timing for implementing new recommendations, allowing for initial oral antibiotics, is challenging. It requires a careful balance between ensuring sufficient evidence confirming safety, that is, avoiding an increased risk of relapse and sequelae, while also taking responsibility for minimizing the burden of overtreatment, such as unnecessary invasive IV therapy and hospitalization.26 In general, it is challenging to deimplement IV therapy, even when its use is based on weak evidence or anecdotal experience of complicated cases several decades ago.3 While some settings have implemented initial oral antibiotics in selected children with BJI, such as in Madrid17,18,22 and Denmark,27 others may await further studies to substantiate the safety of oral-only antibiotics before adopting such treatment into guidelines.28 Selecting Patients for Oral-only Antibiotic Therapy A critical knowledge gap for implementing initial oral antibiotics is identifying those who may not achieve sufficient serum levels on oral antibiotics for initial infection control. We identified no studies investigating this aspect. Until such studies are available, selecting patients for oral antibiotics may rely on the published studies demonstrating the effectiveness of oral-only treatment. In Madrid, the safety of oral antibiotics has been demonstrated for children with good general condition, age 6 months–3 years, no underlying disease, appropriate oral tolerance, C-reactive protein (CRP) below 80 mg/L, erythrocyte sedimentation rate/CRP ratio above 0.67, no skin injury, no recent surgery, no cervical spondylodiscitis, no local complications at onset, and with the possibility of close outpatient follow-up.17–19,22 In the Danish RCT, the safety of oral antibiotics was demonstrated for children aged 3 months–17 years, excluding those with features of sepsis, substantial soft tissue involvement, expected need for major surgery, previous BJI, prosthetic material, resistant pathogen (such as MRSA), and severe comorbidities.27 It was also found to be safe to initiate oral antibiotics before the diagnosis was confirmed, for example, via magnetic resonance imaging, which was the case in 27 (51%) of 53 patients with bone infections, including spondylodiscitis. The risk of complications and sequelae should also be considered, with initial IV treatment being appropriate for patients with a high risk of sequelae. Several cohort studies from Europe and the USA have investigated factors associated with an increased risk of complications and sequelae. Identified risk factors include features of sepsis (tachycardia and tachypnea), disseminated disease, bone abscess, hip involvement, MRSA, higher age and a high CRP level.19,29–33 However, a high CRP level by itself does not predict an inability to achieve sufficient antibiotic serum levels with oral antibiotics for effective infection control. In the Danish RCT exploring the safety of initial oral antibiotics, 22 of 101 (22%) children had CRP levels above 100 mg/L, all with favorable responses to initial high-dose oral antibiotics.16 Oral treatment has also proven sufficient in children with high CRP levels caused by other infectious diseases, such as pneumonia and pyelonephritis.34,35 Concerning higher age, the risk of sequelae may not be impacted by initial oral antibiotics, as older children generally absorb oral antibiotics effectively. In the Danish RCT, 35 (35%) of 101 allocated to initial oral antibiotics were above 5 years old and had a favorable outcome.16 Therefore, a high CRP or an older age alone may not be an exclusion criterion for initial oral antibiotics, but they may direct attention to other high-risk conditions, such as disseminated disease, substantial soft tissue involvement, sepsis or rapid progression, where rapid high serum concentrations are required for effective infection control.32,33 One European study has identified MSSA as a risk factor for sequelae.33 Since only initial IV therapy has been proven safe for BJI with MSSA bacteremia,9,10 the safety of initial oral treatment remains uncertain. In the Danish RCT, 14 children with confirmed S. aureus bacteremia were treated with initial oral therapy.16 Four switched to IV, 1 due to MRSA, 1 due to extensive soft tissue involvement, and 2 due to nonadherence to oral medication. All recovered without sequelae at 6 and 12 months.16,21 Thus, in children with uncomplicated BJI and MSSA bacteriemia responding well to initial oral antibiotics, treatment may continue orally if close follow-up confirms adequate treatment response. K. kingae has been associated with a low risk of sequelae.18,33K. kingae and other pathogens causing BJI can now be identified within 1 hour using novel point-of-care multiplex PCR assays, including resistance genes, on bone or synovial fluid samples, aiding oral versus IV treatment decisions.22,30 Ongoing Trials Investigating Oral-only Antibiotic Treatment We identified 2 ongoing trials investigating the safety of oral treatment of BJI in children and adolescents. One RCT from Australia and New Zealand, initiated in 2021, investigates whether initial high-dose oral cefalexin (150 mg/kg/day in 4 doses) is noninferior to initial standard IV treatment in children and adolescents aged 1–17 years.36 Exclusion criteria include features of sepsis, subperiosteal abscesses more than 3 mm, severe concomitant soft tissue infections, prosthetic material, prior BJI and comorbidities. The second trial is a real-world evidence study prospectively enrolling all children and adolescents with BJI aged 3 months–17 years in 2024–2026 across all 18 pediatric departments in Denmark, where national guidelines implemented in 2024 allow initial oral antibiotics for uncomplicated infections.37 Such ongoing studies may further delineate which children and adolescents can safely be treated with oral therapy. In addition, trials from settings with a high risk of MRSA are awaited before initial oral therapy can safely be implemented in such settings. CONCLUSION Initial empirical oral antibiotics seem safe for selected children and adolescents with BJI in settings with a low risk of MRSA, suggesting that the route of administration for initial antibiotics may be individualized according to oral absorption and risk of complications. Initial oral antibiotics may be appropriate for children and adolescents who (i) have no risk factors for complications, such as sepsis or substantial soft tissue involvement, (ii) can tolerate oral medication, and (iii) can be closely monitored to ensure sufficient treatment response. A treatment approach for children and adolescents with BJI, which includes initial oral antibiotics, will facilitate outpatient therapy for selected patients, improve patient and family convenience, reduce healthcare costs, support antimicrobial stewardship and align with the “Choosing Wisely” and “Less is More” initiatives. Acknowledgments The authors greatly appreciate Professor Dr. Cristina Calvo, a pediatric infectious disease specialist and consultant at La Paz University Hospital, Madrid, Spain, for her valuable contributions to the manuscript.