Neonatal osteomyelitis: a case series and literature review

Introduction

Neonatal osteomyelitis is a disease that involves the bone and joint of neonates. This happens when bacteria or other pathogens invade and multiply in the bone’s cellular and extracellular structures, typically triggering an inflammatory response. These pathogens can access the bone through the bloodstream (hematogenous spread), direct inoculation (traumatic or procedural), or by contiguous spreading from nearby infected soft tissues or synovial fluid (1-3).

Neonates have a few risk factors that make them susceptible to bone and joint infections. The possible risk factors include the immature anatomy of long bones, exposure to frequent invasive procedures during hospitalization, immature host-defense mechanisms, and maternal complications (4-7).

The reported incidence of neonatal osteomyelitis ranged from 1 to 7 cases for every 1,000 hospital admissions (8-10), and from 1 in 1,500 to 1 in 15,000 for live births (11,12). Since any bone can be affected, the presentation of neonatal osteomyelitis varies from well-localized infection over a single metaphysis with a minimal associated systemic inflammatory response to multifocal infection with septic shock, and multifocal osteomyelitis can occur at any age but is most common in neonates (2). The most common symptoms of bone infection are fever and pain, while pain may only appear as reluctance to bear weight or limited movement of a limb in infants (7,13-17). In addition, the symptoms’ onset of neonatal osteomyelitis can be insidious and atypical (7). If it is not rapidly identified and appropriately treated, it can cause devastating sequelae, such as pathological fractures, growth disturbances and deformity (18).

In the past 30 years, studies that focused on neonatal osteomyelitis are very rare and most of them only involved a small number of cases (7,13-17). To further obtain a more comprehensive understanding of neonatal osteomyelitis, this study aimed to describe the clinical characteristics, etiologies and outcomes of neonatal osteomyelitis in one of the largest neonatal intensive care units (NICU) in China across a 6-year time period and to compare the results with those reported in the latest literature. We present this article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-45/rc).

Methods

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments and approved by the Ethical Review Board of Children’s Hospital of Fudan University [No. (2022) 55]. This is a single center case series study and individual consent for this retrospective analysis was waived. Infants admitted to the NICU for neonatal osteomyelitis from January 1, 2016 to December 31, 2021 were included. Data were collected retrospectively from the clinical records. Neonatal osteomyelitis was diagnosed by medical history, clinical presentation, and by a positive blood culture, the finding of pus at surgery or radiographic changes such as metaphyseal rarefaction or periosteal reaction (14). We excluded term infants with an age at onset of >28 days, and preterm infants with an age at onset of >44 weeks post-menstrual age. All patients were followed up until 31 December, 2021.

Literature searches and evidence eligibility

To obtain the most recent data related to epidemiology, clinical presentation, diagnosis, treatment, and outcome of neonatal osteomyelitis, we compared our results to the large case series reports (>10 cases) on neonatal osteomyelitis in the last 30 years, that is, after 1990.

An electronic literature search for articles published between January 1st, 1990 and March 20th, 2025 was conducted by using the English databases of Ovid MEDLINE(R), Ovid Embase and Chinese databases of Wanfang, China National Knowledge Infrastructure (CNKI) and SinoMed. The search term of (“osteomyelitis”) AND (“newborn infant”) was used.

Inclusion and exclusion criteria

The target population was newborn infant with osteomyelitis. Studies without bacterial culture results, or radiographic imaging were excluded. In accordance with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (19), two authors (H.W. and J.W.) independently reviewed the references of the retrieved publications for any relevant articles (Figure 1).

Figure 1 Flowchart of the screening process used to exclude or retain studies for the review of neonatal osteomyelitis. CNKI, China National Knowledge Infrastructure.

Statistical analysis

Statistical analysis was performed using SPSS software (v. 22.0, SPSS Inc., Chicago, IL, USA). Continuous variables were summarized as mean ± standard deviation (SD), or median and interquartile range (IQR), or range. Categorical data were expressed as number and percentage (%).

Results

Patients’ characteristics

In total, 15 cases were identified, accounting for 0.05% (15/30,518) of total neonatal admissions from 2016 to 2021. The ratio of male to female is 2:1. The median (IQR) gestational age (GA) was 37.9 (IQR, 36.6–39.9) weeks, in which one-third (n=5) were GA <37 weeks. The median (IQR) birth weight was 3,000 (IQR, 2,400–4,000) grams, with 26.7% (n=4) of BW <2,500 g. Twins accounted for 26.7% (n=4).

The median (IQR) age at onset was 7 (IQR, 6–16) days after birth, and the median (IQR) time from symptom onset to confirmed diagnosis was 5 (IQR, 1–10) days.

The most common presenting signs of the infection were fever, local swelling and reduced mobility of the affected segment. Femur was the most frequently affected site, which was involved in 66.7% (n=10) neonates. About 73.3% (n=11) neonates had ≥2 bones involved (Table 1).

Laboratory evaluation and imaging

Elevated C-reactive protein (CRP) (normal range: <8 mg/L) and erythrocyte sedimentation rate (ESR) (normal range: 0–15 mm/h) were seen in 93.3% (n=14) and 73.3% (n=11) neonates, respectively. The median (IQR) of CRP and ESR were 39 (IQR, 13–125) mg/L and 44 (IQR, 15–74) mm/h, respectively.

A sample of blood, urine or material drained from the infected site was sent for bacterial culture in all patients, but tested positive was only in 60.0% (n=9) cases. Staphylococcus aureus is the most common organism identified (n=6), with methicillin-resistant Staphylococcus aureus (MRSA) being isolated from 4 cases.

There were 100% (n=15), 66.7% (n=10), 100% (n=15) and 93.3% (n=14) patients who underwent X-ray, ultrasound, magnetic resonance imaging (MRI) and bone scintigraphy, in which osteolysis or bone resorption and destruction was identified in 100% (n=15), 100% (n=10), 100% (n=15), and 78.6% (n=11), respectively.

Treatment and outcomes

All patients were started with intravenous combined antibiotics after admission to the hospital, which was adjusted later according to patient’s clinical response, and the culture with sensitivity results (when available). There were 60.0% (n=9) patients switched to oral antibiotics when recovery was almost complete. The median (IQR) duration of intravenous and total antibiotic therapy were 29 (IQR, 25–42) and 42 (IQR, 41–42) days, respectively. The most common antibiotics in use was vancomycin (80.0%), followed by third generation cephalosporins (60.0%) and ampicillin-tazobactam (33.3%).

The median (IQR) length of hospital stay was 30 (IQR, 29–42) days. Two patients underwent surgical drainage of the infected site during hospitalization. The patients were followed-up for a median (IQR) time of 9 (IQR, 2–19) months. All patients survived, but 40.0% (n=6) presented with joint deformity during follow-up (Table 2).

Comparison with large case series (>10 cases) in the past 30 years

There were six studies that reported more than 10 cases of neonates with osteomyelitis since 1990 (7,13-17). Table 3 shows the comparison between our report and these studies.

In total, there were 170 neonates with osteomyelitis in the seven reports. Males accounted for 66.2% and 19.4% were preterm infants. The most common presenting signs of the infection was bone swelling (85.8%). Other common clinical presentation included fever, bone pain and reduced active mobility of the affected segment. The most frequently affected site in all patients was femur, followed by humerus and tibia. Patients that had ≥2 bones involved accounted for 42.9%.

Staphylococcus aureus is the most common organism identified, accounted for 37.6% of all patients. However, about 27.1% patients had negative cultures. X-ray was widely used in all reports, and had a high rate of positivity. Except the report by Knudsen et al. (17), ultrasound and MRI had 100% positive rate, but they were only used in 52.5% and 73.5% patients respectively. Bone scintigraphy was only used in our study.

Most patients received antibiotics for over 21 days, and over half of them required surgical intervention. There were 13.4% patients with sequelae during follow-up.

Discussion

We report a single center experience of neonatal osteomyelitis among 15 neonates during a 6-year period and compare our results to the large case series reports (>10 cases) on neonatal osteomyelitis in the last 30 years (7,13-17). As most studies on neonatal osteomyelitis only involved a small number of cases, our study aims to obtain the most recent data related to epidemiology, clinical profile, and outcome of neonatal osteomyelitis.

Neonatal osteomyelitis is a relatively rare disease. Our report showed the incidence of neonatal osteomyelitis was about 1 out of 1,000 hospital admissions, which was in line with previous studies (8-10), but was much higher than the incidence in the overall pediatric population (20,21).

Similar to the previous studies, the most common presenting signs of the infection was bone swelling and femur was the most frequently affected site. To avoid the development of sequelae, neonates with osteomyelitis usually received aggressively and empirically intravenous antimicrobials with broad spectrum before the causative pathogen is cultured and identified, then treatment can be adjusted based on antimicrobial sensitivities (18). Staphylococcus aureus is the most common organism identified, which is a Gram-positive bacterium commonly found on the skin and mucous membranes of humans and various animals. Its prominence as a cause of osteomyelitis stems from two key factors (22). First, about 25% to 30% of the global population is colonized by Staphylococcus aureus, with rates as high as 50% to 70% among healthcare workers and transient carriers. Second, it produces multiple virulence factors, such as adhesins, cytolytic toxins, immune evasion molecules, superantigens, and antioxidant systems, which enhance its pathogenicity (23-26).

Determining the causative organism is pivotal; however, the rate of positive cultures was relatively low, and about 27.1% patients had negative cultures in the seven reports. Peltola et al. also found blood culture is positive in only 40% of the patients with osteomyelitis (27). Overall, culture negative osteomyelitis remains difficult to diagnose and has limited guidance for treatment. In the setting of a negative culture but high clinical suspicion for neonatal osteomyelitis, clinicians can look to biomarkers like white blood cell count, CRP and ESR, along with imaging, to help guide the use of antibiotics. The culture of material derived from the affected sites, which is also the diagnostic gold standard, may increase the positive rate (27), but it is likely not performed when the patient clinical course was uncomplicated (7). In order to confirm the microbiological diagnosis and optimize the spectrum and duration of antimicrobial therapy, the 2021 guideline on diagnosis and management of acute hematogenous osteomyelitis (AHO) in pediatrics (1) recommended performing invasive diagnostic procedures to collect aspirates and/or biopsy specimens of bone and/or associated purulent fluid collections for routine microbiological studies (aerobic bacteriologic culture and Gram stain) rather than only performing noninvasive diagnostic tests (conditional recommendation and moderate certainty of evidence). In addition, metagenomic next-generation sequencing, a new microbial detection technology, has been shown to improve detection of pathogens in culture-negative patients with bone and joint infections, and reduce antibiotic-related complications, shorten hospital stay and antibiotic use duration, and improve treatment success rate in these patients (28). Metagenomic next-generation sequencing ensures a rapid identification of the pathogen. It could be a useful method for neonatal osteomyelitis in the future.

The therapeutic management of neonatal osteomyelitis is still object of controversy. On the one hand, there is a broad debate on the total antibiotics’ duration (intravenous and oral). The mean total length of treatment of children with uncomplicated acute hematogenic osteomyelitis is approximately four weeks, ranging from 3 to 6 weeks (29). We found that patients received antibiotics for over 21 days in 5 reports. In addition, prolonged intravenous antibiotic treatment is associated with longer hospitalization, higher costs, and a central venous catheter placement, with the risk of catheter-related occlusion, rupture, dislocation, infection, thrombosis, etc. However, the indicators for switching from intravenous to oral therapy in the treatment of neonatal osteomyelitis are still debated, the 2017 European Society for Paediatric Infectious Diseases (ESPID) bone and joint infection guidelines made recommendations for children with acute osteomyelitis to switch to oral therapy after 2–4 days of intravenous antibiotics if the child is showing clinical improvement (30), but there is lack of data to support short intravenous therapy with a subsequent switch to oral treatment in infants under 3 months of age. In our report and reports from Roversi et al. (7) and Zhao et al. (16), patients usually received intravenous antibiotics at least 2–3 weeks, and not all the patients switch to oral antibiotics. Unfortunately, all the seven reports didn’t include the clear indicators for switching from intravenous to oral therapy, either. Further research is needed to investigate proper antibiotics’ duration and indicators for switching antibiotics from intravenous to oral therapy for this population, especially for those with negative culture. On the other hand, there is limited evidence from randomized trials regarding surgical intervention. Questions about the timing, extent, and necessity of surgery, beyond biopsy, remain unresolved, though intraosseous abscesses in subacute or chronic cases (e.g., Brodie’s abscesses) often require surgical intervention (18). There were about 1/2 patients underwent surgery in the seven reports in our study, but there was a lack of information on the timing or indication for surgical intervention. According to 2021 guideline on diagnosis and management of AHO in pediatrics (1), for children with AHO presenting with sepsis or rapidly progressing infections, immediate surgical debridement of infected bone and any associated abscesses is strongly recommended over medical therapy alone (strong recommendation, moderate evidence). In clinically stable children with AHO and a significant abscess (>2 cm), debridement is suggested over medical therapy alone (conditional recommendation, very low evidence).

For the seven reports focusing on neonatal osteomyelitis since 1990, X-ray remains the most common initial diagnostic approach, and it is also helpful to rule out a fracture or detect Ewing’s sarcoma or another type of malignant condition. MRI, is the gold standard in the diagnosis of osteomyelitis because of its higher sensitivity and specificity (29), and has been increasingly used during these years. We found MRI was used in 73.5% patients, and the positivity rate was 100%. Ultrasound is another common diagnostic approach to identify acute osteomyelitis, and it was used in about half infants in five reports with the positivity rate 100%. Bone scintigraphy is a complementary method to identify acute osteomyelitis (31), especially helpful in evaluating multifocal infection or identifying infection site; however, it has high sensitivity but low specificity. Bone scintigraphy was only used in our report and the positivity rate was 78.6%. Further studies are needed to evaluate the clinical value of bone scintigraphy in neonatal osteomyelitis.

Notably, although the rate of sequelae differed greatly across the studies, three studies showed that patients had a high rate of sequelae during follow-up, which is much higher than children with osteomyelitis (32), differences in clinical practice and duration of follow-up is likely to have influenced clinical outcomes. The seven reports showed patients continued to follow up for a long time, ranging from 2 to 144 months after the infection. As sequelae may emerge slowly, follow-up for a year or more is justified.

There are limitations in this study. First, our study is limited to its retrospective design and the six reports from the latest literature showed a wide variability, differences in staffing and clinical practice may impact clinical outcomes in these patients. Second, the duration of follow-up for each patient varies greatly in the seven reports. As a result, the rate of sequelae may be underestimated. The information on risk factors for developing bone or joint deformity were also not shown in these reports. Third, the seven reports showed one fourth patients had negative cultures, but there were no clear indicators for switching antibiotics from intravenous to oral therapy in these reports, further research is needed to investigate the therapeutic management of neonatal osteomyelitis, especially for those with negative culture. In addition, about 1/2 patients underwent surgery in the seven reports in our study, but there was a lack of information on the timing or indication for surgical intervention. Further research is needed to investigate the timing, extent, and necessity of surgery in this population.

Conclusions

Neonates with osteomyelitis required a long duration of antibiotics administration and had a high rate of sequelae. The treatment of neonatal osteomyelitis remains challenging, especially for those with negative culture. Further research is needed to investigate the proper duration of antibiotics administration and the indicators for switching antibiotics from intravenous to oral therapy for this population.

Acknowledgments

The article was linguistically revised by assistant Professor Zhiguo Zhou from the University of Central Missouri, USA, whose efforts are sincerely appreciated.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-45/rc

Data Sharing Statement: https://tp.amegroups.com/article/view/10.21037/tp-2025-45/dss

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-45/prf

Funding: The project was supported by Key Development Program of Children’s Hospital of Fudan University (Nos. EK2022ZX02 and EK2022PT06).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-45/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by Ethical Review Board of Children’s Hospital of Fudan University [No. (2022) 55] and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Woods CR, Bradley JS, Chatterjee A, et al. Clinical Practice Guideline by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America: 2021 Guideline on Diagnosis and Management of Acute Hematogenous Osteomyelitis in Pediatrics. J Pediatric Infect Dis Soc 2021;10:801-44. [Crossref] [PubMed]
2. Krogstad P. Osteomyelitis. In: Cherry JD, Harrison GJ, Kaplan SL, et al. editors. Feigin & Cherry’s Textbook of Pediatric Infectious Diseases. 8th edition. Philadelphia, PA: Elsevier; 2014:3.
3. Hong DK, Gutierrez K. Osteomyelitis. In: Long SS, Prober CG, Fischer M. editors. Principles and Practice of Pediatric Infectious Diseases. 5th edition. Philadelphia, PA: Elsevier; 2018:8.
4. Shalabi M, Adel M, Yoon E, et al. Risk of Infection Using Peripherally Inserted Central and Umbilical Catheters in Preterm Neonates. Pediatrics 2015;136:1073-9. [Crossref] [PubMed]
5. McPherson DM. Osteomyelitis in the neonate. Neonatal Netw 2002;21:9-22. [Crossref] [PubMed]
6. Liao SL, Lai SH, Lin TY, et al. Premature rupture of the membranes: a cause for neonatal osteomyelitis? Am J Perinatol 2005;22:63-6. [Crossref] [PubMed]
7. Roversi M, Chiappini E, Toniolo RM, et al. Neonatal osteomyelitis: an Italian multicentre report of 22 cases and comparison with the inherent literature. J Perinatol 2021;41:1293-303. [Crossref] [PubMed]
8. De Boeck H. Osteomyelitis and septic arthritis in children. Acta Orthop Belg 2005;71:505-15. [PubMed]
9. Asmar BI. Osteomyelitis in the neonate. Infect Dis Clin North Am 1992;6:117-32. [Crossref] [PubMed]
10. Berberian G, Firpo V, Soto A, et al. Osteoarthritis in the neonate: risk factors and outcome. Braz J Infect Dis 2010;14:413-8. [Crossref] [PubMed]
11. Narang A, Mukhopadhyay K, Kumar P, et al. Bone and joint infection in neonates. Indian J Pediatr 1998;65:461-4. [Crossref] [PubMed]
12. Fox L, Sprunt K. Neonatal osteomyelitis. Pediatrics 1978;62:535-42. [Crossref] [PubMed]
13. Zhao C, Sun H. Clinical analysis of 56 cases of neonatal osteomyelitis. Chin J Neonatol 2022;37:405-8.
14. Zhan C, Zhou B, Du J, et al. Clinical analysis of 17 cases of neonatal osteomyelitis: A retrospective study. Medicine (Baltimore) 2019;98:e14129. [Crossref] [PubMed]
15. Li L, Su Y, Yang J. Clinical characteristics of 13 cases of neonatal acute osteomyelitis. Chin J Neonatol 2017;32:283-6.
16. Zhao Q, Wei H, Hua Z, et al. Clinical analysis of neonatal acute osteomyelitis in 13 cases. Chinese Journal of Practical Pediatrics 2014;29:600-3.
17. Knudsen CJ, Hoffman EB. Neonatal osteomyelitis. J Bone Joint Surg Br 1990;72:846-51. [Crossref] [PubMed]
18. Peltola H, Pääkkönen M. Acute osteomyelitis in children. N Engl J Med 2014;370:352-60. [Crossref] [PubMed]
19. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372: [PubMed]
20. Mitha A, Boutry N, Nectoux E, et al. Community-acquired bone and joint infections in children: a 1-year prospective epidemiological study. Arch Dis Child 2015;100:126-9. [Crossref] [PubMed]
21. Grammatico-Guillon L, Maakaroun Vermesse Z, Baron S, et al. Paediatric bone and joint infections are more common in boys and toddlers: a national epidemiology study. Acta Paediatr 2013;102:e120-5. [Crossref] [PubMed]
22. Urish KL, Cassat JE. Staphylococcus aureus Osteomyelitis: Bone, Bugs, and Surgery. Infect Immun 2020;88:e00932-19. [Crossref] [PubMed]
23. Wójcik-Bojek U, Różalska B, Sadowska B. Staphylococcus aureus-A Known Opponent against Host Defense Mechanisms and Vaccine Development-Do We Still Have a Chance to Win? Int J Mol Sci 2022;23:948. [Crossref] [PubMed]
24. Laux C, Peschel A, Krismer B. Staphylococcus aureus Colonization of the Human Nose and Interaction with Other Microbiome Members. Microbiol Spectr 2019; [Crossref] [PubMed]
25. Tam K, Torres VJ. Staphylococcus aureus Secreted Toxins and Extracellular Enzymes. Microbiol Spectr 2019; [Crossref] [PubMed]
26. de Jong NWM, van Kessel KPM, van Strijp JAG. Immune Evasion by Staphylococcus aureus. Microbiol Spectr 2019; [Crossref] [PubMed]
27. Peltola H, Pääkkönen M, Kallio P, et al. Short- versus long-term antimicrobial treatment for acute hematogenous osteomyelitis of childhood: prospective, randomized trial on 131 culture-positive cases. Pediatr Infect Dis J 2010;29:1123-8. [Crossref] [PubMed]
28. Hu H, Ding H, Lyu J, et al. Detection of rare microorganisms in bone and joint infections by metagenomic next-generation sequencing. Bone Joint Res 2024;13:401-10. [Crossref] [PubMed]
29. Krzysztofiak A, Chiappini E, Venturini E, et al. Italian consensus on the therapeutic management of uncomplicated acute hematogenous osteomyelitis in children. Ital J Pediatr 2021;47:179. [Crossref] [PubMed]
30. Saavedra-Lozano J, Falup-Pecurariu O, Faust SN, et al. Bone and Joint Infections. Pediatr Infect Dis J 2017;36:788-99. [Crossref] [PubMed]
31. Van den Wyngaert T, Strobel K, Kampen WU, et al. The EANM practice guidelines for bone scintigraphy. Eur J Nucl Med Mol Imaging 2016;43:1723-38. [Crossref] [PubMed]
32. Disch K, Hill DA, Snow H, et al. Clinical outcomes of pediatric osteomyelitis. BMC Pediatr 2023;23:54. [Crossref] [PubMed]