Therapeutic Approaches in Children with Invasive Meningococcal Disease (IMD) in Greece.

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Panagiotis Poulikakos, Dimitrios Kapnisis, Despοina Gkentzi, Maria Tsolia, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7714619/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 6 You are reading this latest preprint version Abstract Background Invasive meningococcal disease (IMD) is an acute, severe infection that continues to pose a significant public health challenge worldwide because of its potential for mortality and long-term sequelae. Objectives This study aimed to assess therapeutic approaches focused on the use of first-line antibiotics as well as practices for dexamethasone treatment in patients with meningococcal meningitis in Greece. Methods A retrospective analysis was conducted on pediatric patients aged up to 16 years identified through laboratory records from the Hellenic National Meningitis Reference Laboratory (HNML) between 2010 and 2020. The data collected included age, treatment regimens, antibiotic susceptibility, and clinical outcomes. Results A total of 161 patients admitted to 9 hospitals across Greece were identified. The medical records of 91 (56.5%) patients were retrieved. The median age was 36 months. All the meningococcal isolates were susceptible to third-generation cephalosporins (ceftriaxone, cefotaxime), which are empirical treatments for 97.7% of the cases, whereas penicillin resistance was recorded in 15.2% of the isolates. The case fatality rate was 5.5% (5 cases). The administration of dexamethasone to 31 patients (34%) with meningococcal meningitis was associated with a nonsignificant reduction in adverse outcomes (12.9% vs. 29%). One fatal case occurred in the nondexamethasone group. Conclusion Third-generation cephalosporins are confirmed as effective empirical treatments for IMD in Greece. Owing to the small size of our cohort, the use of adjunctive dexamethasone was not significantly associated with improved outcomes in this cohort. Invasive meningococcal disease Antibiotic treatment Dexamethasone Introduction Invasive meningococcal disease (IMD) is an acute, severe bacterial infection attributable to Neisseria meningitidis , manifesting as meningitis and/or septicemia. As a notifiable disease, IMD has an overall average incidence of 0.3/100,000, which is elevated among infants and young children but progressively declines with increasing age [ 1 ]. The disease frequently presents with an abrupt onset and rapid progression, with a case fatality rate ranging from 4.1–20% [ 2 ]. The sequelae, documented in 4.3–25% of survivors, may be severe and permanent [ 3 – 5 ], encompassing physical, neurological, and psychological-behavioural disorders [ 3 , 5 , 6 ]. Survivors may experience permanent sequelae that include physical effects, such as severe skin necrosis, scarring requiring skin grafts and limb amputation, as well as neurological outcomes, such as nerve palsy, hearing loss, seizures, or a vegetative state. Psychological and behavioral disorders, including anxiety and neurodevelopmental disorders, can also occur [ 10 ]. A recent Greek study in a paediatric population revealed that 16.9% of the patients developed either neurological or physical sequelae. Neurological sequelae (balance impairment, paralysis, seizures, communication disorders (speech difficulties), and hearing loss) were observed in 13.3% of the patients, whereas physical sequelae (skin necrosis, amputation, and skin scarring) were observed in 6% of the patients. {5}. To avoid IMD complications, therapeutic management is highly important. Antibiotics such as third-generation cephalosporins constitute the first-line empirical approach, which may be de-escalated to penicillin upon confirmation of susceptibility [ 7 , 8 ]. Adjunctive dexamethasone administration in community-acquired bacterial meningitis may mitigate sequelae, particularly hearing impairment, and potentially mortality. The administration of corticosteroids confers a direct benefit in reducing the incidence of hearing loss, most notably in children on cephalosporin regimens, and of neurologic sequelae, particularly in cases involving low-dose corticosteroid treatment [ 9 ]. Nevertheless, existing evidence does not preclude a beneficial effect in meningococcal disease [ 10 , 11 ]. Current guidelines advocate for the use of dexamethasone in meningitis caused by Haemophilus influenzae in children and Streptococcus pneumoniae in adults in high-income countries [ 12 ]; consequently, it is often incorporated into empirical antibiotic regimens before pathogen identification. Numerous patients with meningococcal meningitis receive dexamethasone before the final microbiological diagnosis is made, permitting a retrospective analysis of its effects. In Greece, data concerning IMD therapeutic practices remain limited. A recently published study reported epidemiological characteristics, including sequelae and risk factors for adverse outcomes, in the pediatric population [ 5 ]. The present study aims to collect and analyse data on therapeutic practices, focusing on the use of antibiotics and dexamethasone treatment of IMD in the Greek pediatric population. Materials and methods IMD surveillance is compulsory in Greece; all cases must be reported to the National Public Health Organization (EODY). Nationwide, hospitals refer suspected or confirmed cases to the National Meningitis Reference Laboratory (NMRL) for identification and typing [ 5 ]. Study population and data collection Laboratory-confirmed IMD cases were retrospectively identified from the NMRL database for an 11-year time period (2010–2020). Medical records were collected from ten hospitals and departments included in the study. The institutions consisted of three pediatric hospitals located in the Athens metropolitan area (“Aghia Sophia” Children’s Hospital (AS), “P. & A. Kyriakou” Children’s Hospital (AK), and “Pentelis” Children’s Hospital (PP)), as well as nine pediatric departments within six general hospitals: University General Hospital “ATTIKON” (UGHA), University General Hospital of Alexandroupolis, Thrace (UHA), Hippokration University Hospital (Thessaloniki), “St Loukas” private hospital (Thessaloniki), Infectious Diseases Hospital (Thessaloniki), and University General Hospital of Patras, Peloponnese (UHP). Patient records were reviewed to document clinical features such as meningitis or septicaemia, length of hospital stay, discharge outcomes, age, and sex. Meningitis was diagnosed when N. meningitidis was detected in the cerebrospinal fluid, and septicemia was diagnosed when N. meningitidis was isolated from the blood. Pathogens were identified via culture and/or PCR assays on clinical samples (cerebrospinal fluid and/or blood). Standard reference values were utilized for conventional hematological and biochemical analyses [ 13 ]. Treatment data were extracted from medical records. Antibiotic therapy is classified as empirical when it is initiated before pathogen identification or antimicrobial susceptibility results are available and as targeted following microbiological confirmation and appropriate regimen modification [ 14 ]. N. meningitidis identification and antibiotic susceptibility testing Specimens from patients, such as cerebrospinal fluid (CSF), blood, and meningococcal isolates, were sent to NMRL for identification and molecular typing by admitting hospitals nationwide. Among these cases, 161 cases of IMD were confirmed in individuals aged 16 years or younger. Meningococcal isolates were cultured on chocolate Columbia agar (OXOID Ltd., Basingstoke, UK) and incubated at 37°C with 5–10% carbon dioxide for 24 hours. The Minimum Inhibitory Concentration (MIC) for penicillin and third-generation cephalosporins (cefotaxime and ceftriaxone) were ascertained via the E-test method (LIOFILCHEM S.r.l., Italy), which uses Mueller‒Hinton agar containing 5% sheep blood (OXOID Ltd., Basingstoke, UK) followed by incubation at 37°C under 5‒10% carbon dioxide for 24 hours according to the manufacturer’s protocol. The EUCAST guidelines (v13.0; 2023-01-01) were applied to establish the susceptibility breakpoints. In accordance with these criteria, meningococcal isolates demonstrating an MIC value of 0.25 mg/L or greater for penicillin were designated ‘resistant (R)’ [ 16 ]. Statistical analysis The sample size was determined on the basis of the study’s primary outcome, which was the incidence of sequelae. The calculation was performed via OpenEpi software version 3.01. For statistical analysis, Fisher's exact test and the Mann‒Whitney-Wilcoxon test were used as appropriate. The significance level was set at 0.05. Ethical considerations The study was approved by the ethics committees of all the participating hospitals. Results Among the 161 confirmed IMD cases identified in the paediatric cohort, medical records were retrieved for 91 patients (56.5%). The median interval from symptom onset to the ER visit was 24 hours (range: 1.5–480 hours). The median patient age was 36 months (range: 22 days to 16 years). Meningitis was identified in 73.6% of the patients (67/91; 95% CI: 63.3–82.3%), and 36.2% exhibited concurrent septicemia (33/91; 95% CI: 26.4–47.0%). Isolated septicaemia was reported in 26.4% of the patients (24/91; 95% CI: 17.7–36.7%). The majority of the patients presented elevated serum inflammatory markers, including leukocytes (median = 15,140/µL, range: 1,509–43,900) and C-reactive protein (median = 92.96 mg/L, range: 0–515) [ 5 ]. Among the 87 patients whose data were available, the median hospitalization duration was 9.5 days (range: 7–120 days), whereas 34 (39.1%; 34/87; 95% CI: 28.8–50.1%) patients required ICU admission, with a median ICU stay of two days (range: 1–60 days). A coagulation disorder necessitating fresh frozen plasma administration was evident in 27.1% (23/85; 95% CI: 18.0–37.8%) of the patients; two patients were excluded because of incomplete medical records. Cranial imaging (ultrasound, CT, and MRI) was performed on 28 patients. Abnormalities were identified in 7 patients. Brain edema was detected in 5 patients via MRI (n = 3) and CT (n = 2); brain hemorrhage was also observed in 3 of those patients. For the remaining 2 patients, meningoencephalitis and mastoiditis were identified on MRI and CT imaging, respectively. Empirical approach to antibiotic treatment Among the 91 patients, antibiotic treatment data were available for 87 (95.6%; 87/91) (Table 1 ). Empirical treatment with third-generation cephalosporins (ceftriaxone or cefotaxime) was administered to 85 patients either as monotherapy (64.7%; 55/85; 95% CI: 53.6–74.8%) or in combination with other antibiotics (35.3%; 30/85; 95% CI: 25.2–46.4%) (Table 1 ). When susceptibility testing was available, N. meningitidis was sensitive to at least one empirical antibiotic. In one case, a patient empirically treated with ampicillin (the isolate was penicillin resistant; ampicillin susceptibility was unavailable) received a third-generation cephalosporin on the fourth day of hospitalization and had an uncomplicated course. Targeted treatment data were available for 82 of the 87 patients; one was transferred to another hospital on the second day of hospitalization and was missing follow-up data, and 4 patients died between the first and third days of hospitalization. Empirical therapy was altered for 28 patients (34.1%; 28/82). This involved decreasing the number of antibiotics in 26 patients, including 4 who changed to new antibiotic monotherapy; two others had their monotherapy substituted ( Table 1 ). The median targeted treatment duration was 8 days (7–15 days). Table 1 Empirical and targeted antibiotic treatment in children with IMD in Greece, 2010–2020. (The 95% confidence interval (CI) is not presented for cells with a frequency of 1 or 2 due to the small sample size). Antibiotic Treatment Empirical Treatment n = 87 Targeted treatment n = 82 Cef 55 (63.2%, 95% CI: 52.2–73.3%) 75 (91.5%, 95% CI: 83.1–96.5%) Cef + Glycopeptide 22 (25.3%, 95% CI: 16.6–35.7%) 1 Cef + Ampicillin 2 1 Cef + Aminoglycoside 1 1 Cef + Ampicillin + Aminoglycoside 2 Cef + Glycopeptide + Aminoglycoside 1 Cef + Glycopeptide + Moxifloxacin 1 Cef + Glycopeptide + metronidazole 1 1 Ampicillin 1 Ampicillin + Aminoglycoside 1 Penicillin 2 Carbapenem 1 Cef = Ceftriaxone or Cefotaxime (3rd -generation cephalosporins) Antibiotic susceptibility testing Among the 91 confirmed cases, N. meningitidis was identified by culture in 37 cases (37/91; 40,6%), whereas the remaining 54 cases (54/91; 59.4%) were confirmed only by PCR performed directly either in the cerebrospinal fluid (CSF) or in blood samples. All 37 isolates demonstrated susceptibility to third-generation cephalosporins, specifically cefotaxime and/or ceftriaxone. Penicillin resistance (MIC > 0.25 µg/ml) was identified in 15.2% (5/33; 95% CI: 5.1–31.9%) of the cases. Dexamethasone treatment Among the 91 patients, further subpopulation analysis was carried out in 62 patients who either received (n = 31) or did not receive (n = 31) dexamethasone (Table 2 ). Twenty-nine patients were excluded from the analysis (6 patients were less than two months old, 16 were diagnosed with septicemia without meningitis symptoms, 4 had incomplete medical records, and 3 patients had no recorded hospital discharge status). Among the 31 patients with meningococcal meningitis aged two months and above for whom dexamethasone was administered, the median duration was two days (range: 1–18 days). All the children except one received dexamethasone for less than four days, as the dexamethasone regimen was initiated alongside the first antibiotic dose, which was discontinued after N. meningitidis identification. Only one patient with coexistent brain edema received an 18-day course. Septicaemia was less common in the dexamethasone arm (58% vs. 35.5%, p = 0.1261); however, this difference was not statistically significant. Furthermore, hospital length of stay, ICU admission, and sequelae did not significantly differ between patients who received dexamethasone and those who did not. Further data analysis on unfavourable outcomes (specifically, neurological sequelae or death) among children receiving dexamethasone revealed that all 4 patients suffered from a single neurological sequela (balance impingement (2 patients) seizures (1 patient)). Although there was no significant difference between the two groups with respect to the occurrence of sequelae or neurological sequelae in particular, multiple neurological sequelae were observed only in the nondexamethasone arm. Specifically, among the 8 patients who did not receive dexamethasone treatment, only 2 patients were found to have a single sequela (seizures (n = 1) and speech difficulties (n = 1)), while the remaining 3 patients were found to present multiple sequelae (1 patient suffered from five sequelae (cranial nerve pulsy, muscle weakness, balance impairment, mobility problems and seizures), 1 patient suffered four sequelae (paralysis, seizures, visual impairment and hearing loss), and 1 patient suffered 2 sequelae (cranial nerve pulsy, balance impairment)). Notably, no fatal cases were reported in the dexamethasone arm; however, a nonsignificant trend toward fewer composite unfavourable outcomes (sequelae or death) occurred among children receiving dexamethasone (12.9% vs. 29%, p = 0.21). Table 2 Characteristics of 62 patients aged 2 months or older with meningococcal meningitis who either received dexamethasone adjunctive treatment or not. Dexamethasone (n = 31) No dexamethasone (n = 31) p- value Age (months) of patients with meningitis 36 (8-180) 36 (3-162) 0.0703 No. of patients with Concomitant septicemia 11 (35.5%) 18 (58%) 0.1261 No. of patients with ICU admission 12 (38.7%) 12 (38.7%) 1 Length of Hospital stay (median, days) 10 (7–34) 8 (3-120) 0.453 No. of patients with sequelae 4 (12.9%) 8 (25%) 0.3354 No. of patients with neurological sequelae 4 (12.9%) 5 (16.1%) 1 Death 0 1 (3.2%) 1 No. of patients with composite unfavourable outcomes (sequelae or death) 4 (12.9%) 9 (29%) 0.21 ¥ Fisher’s Exact Test was used for nominal data and Mann‒Whitney U Test for ordinal data Discussion This is the first study that analyses data on therapeutic approaches in relation to outcomes in children with IMD in Greece. Although previous studies reported IMD incidence, serogroup distribution, antibiotic susceptibility, the case fatality ratio [ 17 , 18 ], and sequelae [ 5 ] in Greece, the therapeutic approach was not investigated. Antibiotic resistance is still a challenge for the treatment of IMD, as it is gradually increasing with respect to first-line antibiotics and can be a potential threat for the control and management of N. meningitidis in the future. Recently, susceptibility studies on ceftriaxone, one of the 3rd generation cephalosporins currently recommended as the first-choice antibiotic for empirical treatment, have shown that the prevalence of resistance to ceftriaxone and cefotaxime is approximately 2% globally, which is quite low and is mostly related to African countries [ 20 ]. In the present study, according to the susceptibility testing results, all the isolates were sensitive to 3rd -generation cephalosporins, which are used as empirical first-line treatments in Greece (97.7% of cases), in contrast with emerging resistance reports [ 19 , 21 ]. The use of 3rd –generation cephalosporins as empirical and targeted therapy adheres to local and international recommendations. On the other hand, penicillin is not recommended for empirical use, as evidence suggests an increasing trend in reduced penicillin susceptibility rates since 1985 across several countries, including the UK, Spain, Italy, Greece, Israel, and the USA [ 22 ], whereas high resistance rates have recently been reported in Asia (55%) and Africa (38%) [ 20 ]. In the present study, 15.2% (5/33) of the isolates were resistant to penicillin. Dexamethasone is not currently recommended for the treatment of meningococcal meningitis [ 12 ]. In the present study, dexamethasone use was not significantly associated with decreased sequelae among meningococcal meningitis survivors. However, this might be due to the small cohort size; both sequelae and composite unfavourable outcomes were more common in the group that did not receive dexamethasone. Although guidelines [ 12 ] strongly recommend empirical dexamethasone treatment for all suspected cases of acute bacterial meningitis, it is intended mainly for Haemophilus influenzae (in infants and children, with the exception of neonates) or Streptococcus pneumoniae (in adults) to reduce neurological sequelae [ 23 ]. Dexamethasone should be initiated immediately (10–20 min) before or along with the first antibiotic dose and be administered for four days. The ESCMID guideline committee [ 12 ] concluded that dexamethasone should be withdrawn if meningitis is not caused by either Haemophilus influenzae or Streptococcus pneumoniae . However, the committee acknowledges that some experts favour continuing dexamethasone treatment regardless of the causative microorganism. In the present study, a trend toward fewer complications and fewer composite unfavourable outcomes (sequelae or death) occurred in dexamethasone-treated meningococcal meningitis patients. No fatal cases were recorded in this specific patient group. The only fatal case was in the nondexamethasone arm, although this arm had more patients (58% vs. 35.5%, p = 0.1261) with concomitant septicemia, a known fatality risk factor [ 24 ]. With respect to complications, there was a trend favouring dexamethasone use, although the study’s limited sample size was not able to lead to statistically significant differences. Notably, dexamethasone was discontinued in most cases once N. meningitidis was identified (median treatment duration: two days) without completing the recommended four-day course. This may also explain why no beneficial effect was observed, despite data suggesting that a two-day regimen might be sufficient [ 25 ]. The main strength of the present study is the nationwide collection of therapeutic data from pediatric patients with IMD in Greece. Limitations of the study include its retrospective nature and the absence of standardized care protocols. Additionally, other therapeutic practices, such as the treatment of acute medical and neurosurgical complications, were not mentioned in the present study because of insufficient data. Furthermore, owing to a lack of electronic medical records, only 56.5% of the pertinent medical records and files were retrieved and included in the analysis. Records that are saved only as paper prints without digital backups can be easily destroyed or even lost, causing valuable data loss [ 26 ]. Nonetheless, the calculated 5.6% fatality rate for the whole 161-patient population is in agreement with the 5.5% fatality rate of the 91 children analysed in the present study, indicating that our sample was likely representative. Conclusion In the present study, all the isolates demonstrated susceptibility to 3rd -generation cephalosporins, the empirical treatment used in 97.7% of the cases per the guidelines, whereas 15.2% exhibited penicillin resistance. As recent evidence currently suggests low rates of resistance to ceftriaxone and an increasing trend in penicillin resistance rates for N. meningitidis , there is a critical need for ongoing global surveillance of antibiotic susceptibility patterns to improve the prevention and therapy of IMD. While adjunctive dexamethasone administration in meningococcal meningitis patients did not significantly improve sequelae among survivors, extended prospective studies are warranted to definitively assess the impact of dexamethasone on clinical outcomes and establish optimized treatment protocols. Declarations Author Contributions: Conceptualization, P.P., G.T.; methodology, P.P., M.T., A.M., and G.T.; formal analysis, P.P., and G.T.; statistical analysis, T.S.; investigation, P.P., M.T., A.M., E.M., V.P., A.I., S.K., Ε.F., and G.T.; resources, G.T.; data curation, M.T., A.M., E.M., V.P., A.I., D.G., D.K., S.K., E.F., S.K., and G.T.; writing—original draft preparation, P.P., GT. ; writing—review and editing, M.T., A.M., E.M., V.P., A.I., D.G., D.K., S.K., E.F., T.S. and G.T.; supervision, G.T.; project administration, G.T. All the authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Data availability statement: All data are available within the article. Institutional Review Board Statement: Ethical approval for conducting this study was obtained from the corresponding ethical committees of the participating hospitals (approval numbers: 13255 (15/07/2020), 697 (29/12/2020), 29427 (30/12/2021), 26936 (28/09/2023), 221 (22/05/2024), 26164 (10/06/2024), 9156 (28/08/2024), 51294 (08/08/2024), 14(05/11/2024), and 1220 (10/01/2025)). Informed Consent Statement: Patient consent was waived because of the retrospective, descriptive nature of the study, and the anonymity of patients was retained throughout the study through the use of laboratory coding. Clinical trial number : NA Conflicts of interest: The authors declare that they have no conflicts of interest. References European Centre for Disease Prevention and Control. Meningococcal disease. Available at: https://www.ecdc.europa.eu/en/meningococcal-disease (accessed on 20/03/2025). Wang B, Santoreneos R, Giles L, Afzali HHA, Marshall H. 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Technology adoption of electronic medical records in developing economies: A systematic review on physicians' perspective. Digit Health. 2024;10:20552076231224605. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 04 Dec, 2025 Reviewers invited by journal 27 Nov, 2025 Editor invited by journal 29 Sep, 2025 Submission checks completed at journal 27 Sep, 2025 Editor assigned by journal 27 Sep, 2025 First submitted to journal 25 Sep, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7714619","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":552707917,"identity":"25375e12-f424-440e-86ef-d72ae184bdab","order_by":0,"name":"Panagiotis Poulikakos","email":"","orcid":"","institution":"University of West Attica","correspondingAuthor":false,"prefix":"","firstName":"Panagiotis","middleName":"","lastName":"Poulikakos","suffix":""},{"id":552707918,"identity":"559619cb-3741-42ff-a8b7-ada583341940","order_by":1,"name":"Dimitrios Kapnisis","email":"","orcid":"","institution":"University General Hospital of Patras","correspondingAuthor":false,"prefix":"","firstName":"Dimitrios","middleName":"","lastName":"Kapnisis","suffix":""},{"id":552707919,"identity":"3c150e29-221e-4c00-b586-ec87449d8ec3","order_by":2,"name":"Despοina Gkentzi","email":"","orcid":"","institution":"University General Hospital of Patras","correspondingAuthor":false,"prefix":"","firstName":"Despοina","middleName":"","lastName":"Gkentzi","suffix":""},{"id":552707920,"identity":"b91b0bb8-b526-4d25-a67a-b77a4b5e6c96","order_by":3,"name":"Maria Tsolia","email":"","orcid":"","institution":"National and Kapodistrian University of Athens, “P \u0026 A Kyriakou” Children’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"","lastName":"Tsolia","suffix":""},{"id":552707921,"identity":"048ca202-3e16-4bdf-a0e0-b86bed3908da","order_by":4,"name":"Athanasios Michos","email":"","orcid":"","institution":"National and Kapodistrian University of Athens, “Aghia Sophia” Children’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Athanasios","middleName":"","lastName":"Michos","suffix":""},{"id":552707922,"identity":"b03654dd-97f1-44db-9cb1-781ec976ada6","order_by":5,"name":"Elpis Mantadakis","email":"","orcid":"","institution":"University General Hospital of Alexandroupolis, Democritus University","correspondingAuthor":false,"prefix":"","firstName":"Elpis","middleName":"","lastName":"Mantadakis","suffix":""},{"id":552707923,"identity":"f8c7ca81-27c7-4771-92ef-88f7e3311532","order_by":6,"name":"Vassiliki Papaevagelou","email":"","orcid":"","institution":"National and Kapodistrian University of Athens, University General Hospital “ATTIKON”","correspondingAuthor":false,"prefix":"","firstName":"Vassiliki","middleName":"","lastName":"Papaevagelou","suffix":""},{"id":552707924,"identity":"1d1458ee-0bec-42a9-8445-49698d27ce8e","order_by":7,"name":"Andreas Iliadis","email":"","orcid":"","institution":"University General Hospital of Patras","correspondingAuthor":false,"prefix":"","firstName":"Andreas","middleName":"","lastName":"Iliadis","suffix":""},{"id":552707925,"identity":"14c38ad4-b565-4327-b4ca-737bcaba83e5","order_by":8,"name":"Stavroula Kostaridou","email":"","orcid":"","institution":"“Pentelis” Children’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Stavroula","middleName":"","lastName":"Kostaridou","suffix":""},{"id":552707926,"identity":"4b6ed8e2-081c-4fcb-9acb-5f18dc26277a","order_by":9,"name":"Evangelia Farmaki","email":"","orcid":"","institution":"Aristotle University of Thessaloniki, Hippokration General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Evangelia","middleName":"","lastName":"Farmaki","suffix":""},{"id":552707927,"identity":"9d876f87-840f-4066-946f-194e661b5f51","order_by":10,"name":"Theodoros N. Sergentanis","email":"","orcid":"","institution":"University of West Attica","correspondingAuthor":false,"prefix":"","firstName":"Theodoros","middleName":"N.","lastName":"Sergentanis","suffix":""},{"id":552707929,"identity":"f17dbff8-d7b3-46bb-9696-39eab83dc1ef","order_by":11,"name":"Georgina Tzanakaki","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA30lEQVRIiWNgGAWjYPCCBAYJZuYDDAwGxChmg2thSyBVCwMPUeoZGOTj2x9+LqhJk5ds5/kmXVBwWJ6Bf+0DvFoMjzEkS884lmM4m5l3m/QMg8OGDRLP8Vtn2MZwQJqHrYJxHkgLj8FtxgaJY/gdZtjG2Pyb51+F/TxmnmcgLfYEtcizMbNJ87blJM5m5mEDaUls4G/Dr8WALY3NmrcvLXlmM5uxNY/B/+Q2CTYCtjQff3yb51uy7Yzzhx/e5vmTZtvPT8BhBgfQRdgkEgjY0oAhxI9hyigYBaNgFIxwAADiYj0VzlJIGgAAAABJRU5ErkJggg==","orcid":"","institution":"University of West Attica","correspondingAuthor":true,"prefix":"","firstName":"Georgina","middleName":"","lastName":"Tzanakaki","suffix":""}],"badges":[],"createdAt":"2025-09-25 15:38:49","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7714619/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7714619/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":97112460,"identity":"c31a7819-8e96-4e47-ab1f-a27982931586","added_by":"auto","created_at":"2025-12-01 06:51:17","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":49742,"visible":true,"origin":"","legend":"","description":"","filename":"PoulikakosetalmaindocFINALreviewd.docx","url":"https://assets-eu.researchsquare.com/files/rs-7714619/v1/24cac33ae14e421cf95f6871.docx"},{"id":97112461,"identity":"2ebcfd33-8f4f-4666-84a2-8bcb778239b2","added_by":"auto","created_at":"2025-12-01 06:51:17","extension":"json","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":12181,"visible":true,"origin":"","legend":"","description":"","filename":"c2120b8f3f9042d78f6a011af6728c96.json","url":"https://assets-eu.researchsquare.com/files/rs-7714619/v1/91fbe5a1d9571be115eb96d2.json"},{"id":97112465,"identity":"9e55dac0-2587-402f-a55d-ee49d833d8fc","added_by":"auto","created_at":"2025-12-01 06:51:18","extension":"xml","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":85110,"visible":true,"origin":"","legend":"","description":"","filename":"c2120b8f3f9042d78f6a011af6728c961enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-7714619/v1/e7ecb4affc12949e0de51f5f.xml"},{"id":97112464,"identity":"ceecf8de-160e-4131-b6ca-8cbd6cb17e21","added_by":"auto","created_at":"2025-12-01 06:51:18","extension":"xml","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":84642,"visible":true,"origin":"","legend":"","description":"","filename":"c2120b8f3f9042d78f6a011af6728c961structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7714619/v1/ad794bd2634d0bd7269e52a3.xml"},{"id":97112462,"identity":"c17665ea-a3d1-4bc9-8102-e03e1cdb5378","added_by":"auto","created_at":"2025-12-01 06:51:18","extension":"html","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":96543,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7714619/v1/9b49025fd16eec5d02ecf214.html"},{"id":97142831,"identity":"382a8a8f-a0c5-4177-82b3-39727f637b49","added_by":"auto","created_at":"2025-12-01 10:07:58","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":831485,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7714619/v1/e3249512-4da6-454e-afe3-f4b8be131dfd.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Therapeutic Approaches in Children with Invasive Meningococcal Disease (IMD) in Greece.","fulltext":[{"header":"Introduction","content":"\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eInvasive meningococcal disease (IMD) is an acute, severe bacterial infection attributable to \u003cem\u003eNeisseria meningitidis\u003c/em\u003e, manifesting as meningitis and/or septicemia. As a notifiable disease, IMD has an overall average incidence of 0.3/100,000, which is elevated among infants and young children but progressively declines with increasing age [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The disease frequently presents with an abrupt onset and rapid progression, with a case fatality rate ranging from 4.1\u0026ndash;20% [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The sequelae, documented in 4.3\u0026ndash;25% of survivors, may be severe and permanent [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], encompassing physical, neurological, and psychological-behavioural disorders [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eSurvivors may experience permanent sequelae that include physical effects, such as severe skin necrosis, scarring requiring skin grafts and limb amputation, as well as neurological outcomes, such as nerve palsy, hearing loss, seizures, or a vegetative state. Psychological and behavioral disorders, including anxiety and neurodevelopmental disorders, can also occur [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. A recent Greek study in a paediatric population revealed that 16.9% of the patients developed either neurological or physical sequelae. Neurological sequelae (balance impairment, paralysis, seizures, communication disorders (speech difficulties), and hearing loss) were observed in 13.3% of the patients, whereas physical sequelae (skin necrosis, amputation, and skin scarring) were observed in 6% of the patients. {5}.\u003c/p\u003e\u003cp\u003eTo avoid IMD complications, therapeutic management is highly important. Antibiotics such as third-generation cephalosporins constitute the first-line empirical approach, which may be de-escalated to penicillin upon confirmation of susceptibility [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Adjunctive dexamethasone administration in community-acquired bacterial meningitis may mitigate sequelae, particularly hearing impairment, and potentially mortality. The administration of corticosteroids confers a direct benefit in reducing the incidence of hearing loss, most notably in children on cephalosporin regimens, and of neurologic sequelae, particularly in cases involving low-dose corticosteroid treatment [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Nevertheless, existing evidence does not preclude a beneficial effect in meningococcal disease [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Current guidelines advocate for the use of dexamethasone in meningitis caused by \u003cem\u003eHaemophilus influenzae\u003c/em\u003e in children and \u003cem\u003eStreptococcus pneumoniae\u003c/em\u003e in adults in high-income countries [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]; consequently, it is often incorporated into empirical antibiotic regimens before pathogen identification. Numerous patients with meningococcal meningitis receive dexamethasone before the final microbiological diagnosis is made, permitting a retrospective analysis of its effects.\u003c/p\u003e\u003cp\u003eIn Greece, data concerning IMD therapeutic practices remain limited. A recently published study reported epidemiological characteristics, including sequelae and risk factors for adverse outcomes, in the pediatric population [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The present study aims to collect and analyse data on therapeutic practices, focusing on the use of antibiotics and dexamethasone treatment of IMD in the Greek pediatric population.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eIMD surveillance is compulsory in Greece; all cases must be reported to the National Public Health Organization (EODY). Nationwide, hospitals refer suspected or confirmed cases to the National Meningitis Reference Laboratory (NMRL) for identification and typing [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy population and data collection\u003c/h2\u003e\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eLaboratory-confirmed IMD cases were retrospectively identified from the NMRL database for an 11-year time period (2010\u0026ndash;2020). Medical records were collected from ten hospitals and departments included in the study. The institutions consisted of three pediatric hospitals located in the Athens metropolitan area (\u0026ldquo;Aghia Sophia\u0026rdquo; Children\u0026rsquo;s Hospital (AS), \u0026ldquo;P. \u0026amp; A. Kyriakou\u0026rdquo; Children\u0026rsquo;s Hospital (AK), and \u0026ldquo;Pentelis\u0026rdquo; Children\u0026rsquo;s Hospital (PP)), as well as nine pediatric departments within six general hospitals: University General Hospital \u0026ldquo;ATTIKON\u0026rdquo; (UGHA), University General Hospital of Alexandroupolis, Thrace (UHA), Hippokration University Hospital (Thessaloniki), \u0026ldquo;St Loukas\u0026rdquo; private hospital (Thessaloniki), Infectious Diseases Hospital (Thessaloniki), and University General Hospital of Patras, Peloponnese (UHP).\u003c/p\u003e\u003cp\u003ePatient records were reviewed to document clinical features such as meningitis or septicaemia, length of hospital stay, discharge outcomes, age, and sex. Meningitis was diagnosed when \u003cem\u003eN. meningitidis\u003c/em\u003e was detected in the cerebrospinal fluid, and septicemia was diagnosed when \u003cem\u003eN. meningitidis\u003c/em\u003e was isolated from the blood. Pathogens were identified via culture and/or PCR assays on clinical samples (cerebrospinal fluid and/or blood).\u003c/p\u003e\u003cp\u003eStandard reference values were utilized for conventional hematological and biochemical analyses [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eTreatment data were extracted from medical records. Antibiotic therapy is classified as empirical when it is initiated before pathogen identification or antimicrobial susceptibility results are available and as targeted following microbiological confirmation and appropriate regimen modification [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cb\u003eN. meningitidis\u003c/b\u003e\u003cb\u003eidentification and antibiotic susceptibility testing\u003c/b\u003e\u003c/p\u003e\u003cp\u003eSpecimens from patients, such as cerebrospinal fluid (CSF), blood, and meningococcal isolates, were sent to NMRL for identification and molecular typing by admitting hospitals nationwide. Among these cases, 161 cases of IMD were confirmed in individuals aged 16 years or younger.\u003c/p\u003e\u003cp\u003eMeningococcal isolates were cultured on chocolate Columbia agar (OXOID Ltd., Basingstoke, UK) and incubated at 37\u0026deg;C with 5\u0026ndash;10% carbon dioxide for 24 hours. The Minimum Inhibitory Concentration (MIC) for penicillin and third-generation cephalosporins (cefotaxime and ceftriaxone) were ascertained via the E-test method (LIOFILCHEM S.r.l., Italy), which uses Mueller‒Hinton agar containing 5% sheep blood (OXOID Ltd., Basingstoke, UK) followed by incubation at 37\u0026deg;C under 5‒10% carbon dioxide for 24 hours according to the manufacturer\u0026rsquo;s protocol. The EUCAST guidelines (v13.0; 2023-01-01) were applied to establish the susceptibility breakpoints. In accordance with these criteria, meningococcal isolates demonstrating an MIC value of 0.25 mg/L or greater for penicillin were designated \u0026lsquo;resistant (R)\u0026rsquo; [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eThe sample size was determined on the basis of the study\u0026rsquo;s primary outcome, which was the incidence of sequelae. The calculation was performed via OpenEpi software version 3.01. For statistical analysis, Fisher's exact test and the Mann‒Whitney-Wilcoxon test were used as appropriate. The significance level was set at 0.05.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eEthical considerations\u003c/h3\u003e\n\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003e The study was approved by the ethics committees of all the participating hospitals.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eAmong the 161 confirmed IMD cases identified in the paediatric cohort, medical records were retrieved for 91 patients (56.5%). The median interval from symptom onset to the ER visit was 24 hours (range: 1.5\u0026ndash;480 hours). The median patient age was 36 months (range: 22 days to 16 years). Meningitis was identified in 73.6% of the patients (67/91; 95% CI: 63.3\u0026ndash;82.3%), and 36.2% exhibited concurrent septicemia (33/91; 95% CI: 26.4\u0026ndash;47.0%). Isolated septicaemia was reported in 26.4% of the patients (24/91; 95% CI: 17.7\u0026ndash;36.7%). The majority of the patients presented elevated serum inflammatory markers, including leukocytes (median\u0026thinsp;=\u0026thinsp;15,140/\u0026micro;L, range: 1,509\u0026ndash;43,900) and C-reactive protein (median\u0026thinsp;=\u0026thinsp;92.96 mg/L, range: 0\u0026ndash;515) [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAmong the 87 patients whose data were available, the median hospitalization duration was 9.5 days (range: 7\u0026ndash;120 days), whereas 34 (39.1%; 34/87; 95% CI: 28.8\u0026ndash;50.1%) patients required ICU admission, with a median ICU stay of two days (range: 1\u0026ndash;60 days). A coagulation disorder necessitating fresh frozen plasma administration was evident in 27.1% (23/85; 95% CI: 18.0\u0026ndash;37.8%) of the patients; two patients were excluded because of incomplete medical records.\u003c/p\u003e\u003cp\u003eCranial imaging (ultrasound, CT, and MRI) was performed on 28 patients. Abnormalities were identified in 7 patients. Brain edema was detected in 5 patients via MRI (n\u0026thinsp;=\u0026thinsp;3) and CT (n\u0026thinsp;=\u0026thinsp;2); brain hemorrhage was also observed in 3 of those patients. For the remaining 2 patients, meningoencephalitis and mastoiditis were identified on MRI and CT imaging, respectively.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\n\u003ch3\u003eEmpirical approach to antibiotic treatment\u003c/h3\u003e\n\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eAmong the 91 patients, antibiotic treatment data were available for 87 (95.6%; 87/91) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Empirical treatment with third-generation cephalosporins (ceftriaxone or cefotaxime) was administered to 85 patients either as monotherapy (64.7%; 55/85; 95% CI: 53.6\u0026ndash;74.8%) or in combination with other antibiotics (35.3%; 30/85; 95% CI: 25.2\u0026ndash;46.4%) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). When susceptibility testing was available, \u003cem\u003eN. meningitidis\u003c/em\u003e was sensitive to at least one empirical antibiotic. In one case, a patient empirically treated with ampicillin (the isolate was penicillin resistant; ampicillin susceptibility was unavailable) received a third-generation cephalosporin on the fourth day of hospitalization and had an uncomplicated course.\u003c/p\u003e\u003cp\u003eTargeted treatment data were available for 82 of the 87 patients; one was transferred to another hospital on the second day of hospitalization and was missing follow-up data, and 4 patients died between the first and third days of hospitalization.\u003c/p\u003e\u003cp\u003eEmpirical therapy was altered for 28 patients (34.1%; 28/82). This involved decreasing the number of antibiotics in 26 patients, including 4 who changed to new antibiotic monotherapy; two others had their monotherapy substituted \u003cb\u003e(\u003c/b\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cb\u003e).\u003c/b\u003e The median targeted treatment duration was 8 days (7\u0026ndash;15 days).\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eEmpirical and targeted antibiotic treatment in children with IMD in Greece, 2010\u0026ndash;2020. (The 95% confidence interval (CI) is not presented for cells with a frequency of 1 or 2 due to the small sample size).\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAntibiotic Treatment\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEmpirical Treatment n\u0026thinsp;=\u0026thinsp;87\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTargeted treatment n\u0026thinsp;=\u0026thinsp;82\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCef\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e55 (63.2%, 95% CI: 52.2\u0026ndash;73.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e75 (91.5%, 95% CI: 83.1\u0026ndash;96.5%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCef\u0026thinsp;+\u0026thinsp;Glycopeptide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e22 (25.3%, 95% CI: 16.6\u0026ndash;35.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCef\u0026thinsp;+\u0026thinsp;Ampicillin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCef\u0026thinsp;+\u0026thinsp;Aminoglycoside\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCef\u0026thinsp;+\u0026thinsp;Ampicillin\u0026thinsp;+\u0026thinsp;Aminoglycoside\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCef\u0026thinsp;+\u0026thinsp;Glycopeptide\u0026thinsp;+\u0026thinsp;Aminoglycoside\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCef\u0026thinsp;+\u0026thinsp;Glycopeptide\u0026thinsp;+\u0026thinsp;Moxifloxacin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCef\u0026thinsp;+\u0026thinsp;Glycopeptide\u0026thinsp;+\u0026thinsp;metronidazole\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAmpicillin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAmpicillin\u0026thinsp;+\u0026thinsp;Aminoglycoside\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePenicillin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCarbapenem\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e\u003cp\u003eCef\u0026thinsp;=\u0026thinsp;Ceftriaxone or Cefotaxime (3rd -generation cephalosporins)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eAntibiotic susceptibility testing\u003c/h2\u003e\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eAmong the 91 confirmed cases, \u003cem\u003eN. meningitidis\u003c/em\u003e was identified by culture in 37 cases (37/91; 40,6%), whereas the remaining 54 cases (54/91; 59.4%) were confirmed only by PCR performed directly either in the cerebrospinal fluid (CSF) or in blood samples.\u003c/p\u003e\u003cp\u003eAll 37 isolates demonstrated susceptibility to third-generation cephalosporins, specifically cefotaxime and/or ceftriaxone. Penicillin resistance (MIC\u0026thinsp;\u0026gt;\u0026thinsp;0.25 \u0026micro;g/ml) was identified in 15.2% (5/33; 95% CI: 5.1\u0026ndash;31.9%) of the cases.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eDexamethasone treatment\u003c/h3\u003e\n\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eAmong the 91 patients, further subpopulation analysis was carried out in 62 patients who either received (n\u0026thinsp;=\u0026thinsp;31) or did not receive (n\u0026thinsp;=\u0026thinsp;31) dexamethasone (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Twenty-nine patients were excluded from the analysis (6 patients were less than two months old, 16 were diagnosed with septicemia without meningitis symptoms, 4 had incomplete medical records, and 3 patients had no recorded hospital discharge status).\u003c/p\u003e\u003cp\u003eAmong the 31 patients with meningococcal meningitis aged two months and above for whom dexamethasone was administered, the median duration was two days (range: 1\u0026ndash;18 days). All the children except one received dexamethasone for less than four days, as the dexamethasone regimen was initiated alongside the first antibiotic dose, which was discontinued after \u003cem\u003eN. meningitidis\u003c/em\u003e identification. Only one patient with coexistent brain edema received an 18-day course. Septicaemia was less common in the dexamethasone arm (58% vs. 35.5%, p\u0026thinsp;=\u0026thinsp;0.1261); however, this difference was not statistically significant.\u003c/p\u003e\u003cp\u003eFurthermore, hospital length of stay, ICU admission, and sequelae did not significantly differ between patients who received dexamethasone and those who did not.\u003c/p\u003e\u003cp\u003eFurther data analysis on unfavourable outcomes (specifically, neurological sequelae or death) among children receiving dexamethasone revealed that all 4 patients suffered from a single neurological sequela (balance impingement (2 patients) seizures (1 patient)).\u003c/p\u003e\u003cp\u003eAlthough there was no significant difference between the two groups with respect to the occurrence of sequelae or neurological sequelae in particular, multiple neurological sequelae were observed only in the nondexamethasone arm. Specifically, among the 8 patients who did not receive dexamethasone treatment, only 2 patients were found to have a single sequela (seizures (n\u0026thinsp;=\u0026thinsp;1) and speech difficulties (n\u0026thinsp;=\u0026thinsp;1)), while the remaining 3 patients were found to present multiple sequelae (1 patient suffered from five sequelae (cranial nerve pulsy, muscle weakness, balance impairment, mobility problems and seizures), 1 patient suffered four sequelae (paralysis, seizures, visual impairment and hearing loss), and 1 patient suffered 2 sequelae (cranial nerve pulsy, balance impairment)). Notably, no fatal cases were reported in the dexamethasone arm; however, a nonsignificant trend toward fewer composite unfavourable outcomes (sequelae or death) occurred among children receiving dexamethasone (12.9% vs. 29%, p\u0026thinsp;=\u0026thinsp;0.21).\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCharacteristics of 62 patients aged 2 months or older with meningococcal meningitis who either received dexamethasone adjunctive treatment or not.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDexamethasone (n\u0026thinsp;=\u0026thinsp;31)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNo dexamethasone (n\u0026thinsp;=\u0026thinsp;31)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep- value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAge (months) of patients with meningitis\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e36 (8-180)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e36 (3-162)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.0703\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNo. of patients with Concomitant septicemia\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11 (35.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e18 (58%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.1261\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNo. of patients with ICU admission\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e12 (38.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12 (38.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eLength of Hospital stay (median, days)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10 (7\u0026ndash;34)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8 (3-120)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.453\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNo. of patients with sequelae\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (12.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8 (25%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.3354\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNo. of patients with neurological sequelae\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (12.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (16.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eDeath\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (3.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNo. of patients with composite unfavourable outcomes (sequelae or death)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (12.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9 (29%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.21\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003e\u0026yen; Fisher\u0026rsquo;s Exact Test was used for nominal data and Mann‒Whitney U Test for ordinal data\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eThis is the first study that analyses data on therapeutic approaches in relation to outcomes in children with IMD in Greece.\u003c/p\u003e\u003cp\u003eAlthough previous studies reported IMD incidence, serogroup distribution, antibiotic susceptibility, the case fatality ratio [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], and sequelae [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] in Greece, the therapeutic approach was not investigated.\u003c/p\u003e\u003cp\u003eAntibiotic resistance is still a challenge for the treatment of IMD, as it is gradually increasing with respect to first-line antibiotics and can be a potential threat for the control and management of \u003cem\u003eN. meningitidis\u003c/em\u003e in the future. Recently, susceptibility studies on ceftriaxone, one of the 3rd generation cephalosporins currently recommended as the first-choice antibiotic for empirical treatment, have shown that the prevalence of resistance to ceftriaxone and cefotaxime is approximately 2% globally, which is quite low and is mostly related to African countries [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. In the present study, according to the susceptibility testing results, all the isolates were sensitive to 3rd -generation cephalosporins, which are used as empirical first-line treatments in Greece (97.7% of cases), in contrast with emerging resistance reports [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. The use of 3rd \u0026ndash;generation cephalosporins as empirical and targeted therapy adheres to local and international recommendations.\u003c/p\u003e\u003cp\u003eOn the other hand, penicillin is not recommended for empirical use, as evidence suggests an increasing trend in reduced penicillin susceptibility rates since 1985 across several countries, including the UK, Spain, Italy, Greece, Israel, and the USA [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], whereas high resistance rates have recently been reported in Asia (55%) and Africa (38%) [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. In the present study, 15.2% (5/33) of the isolates were resistant to penicillin.\u003c/p\u003e\u003cp\u003eDexamethasone is not currently recommended for the treatment of meningococcal meningitis [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. In the present study, dexamethasone use was not significantly associated with decreased sequelae among meningococcal meningitis survivors. However, this might be due to the small cohort size; both sequelae and composite unfavourable outcomes were more common in the group that did not receive dexamethasone. Although guidelines [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] strongly recommend empirical dexamethasone treatment for all suspected cases of acute bacterial meningitis, it is intended mainly for \u003cem\u003eHaemophilus influenzae\u003c/em\u003e (in infants and children, with the exception of neonates) or \u003cem\u003eStreptococcus pneumoniae\u003c/em\u003e (in adults) to reduce neurological sequelae [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Dexamethasone should be initiated immediately (10\u0026ndash;20 min) before or along with the first antibiotic dose and be administered for four days. The ESCMID guideline committee [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] concluded that dexamethasone should be withdrawn if meningitis is not caused by either \u003cem\u003eHaemophilus influenzae\u003c/em\u003e or \u003cem\u003eStreptococcus pneumoniae\u003c/em\u003e. However, the committee acknowledges that some experts favour continuing dexamethasone treatment regardless of the causative microorganism. In the present study, a trend toward fewer complications and fewer composite unfavourable outcomes (sequelae or death) occurred in dexamethasone-treated meningococcal meningitis patients. No fatal cases were recorded in this specific patient group. The only fatal case was in the nondexamethasone arm, although this arm had more patients (58% vs. 35.5%, p\u0026thinsp;=\u0026thinsp;0.1261) with concomitant septicemia, a known fatality risk factor [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. With respect to complications, there was a trend favouring dexamethasone use, although the study\u0026rsquo;s limited sample size was not able to lead to statistically significant differences. Notably, dexamethasone was discontinued in most cases once \u003cem\u003eN. meningitidis\u003c/em\u003e was identified (median treatment duration: two days) without completing the recommended four-day course. This may also explain why no beneficial effect was observed, despite data suggesting that a two-day regimen might be sufficient [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe main strength of the present study is the nationwide collection of therapeutic data from pediatric patients with IMD in Greece. Limitations of the study include its retrospective nature and the absence of standardized care protocols. Additionally, other therapeutic practices, such as the treatment of acute medical and neurosurgical complications, were not mentioned in the present study because of insufficient data. Furthermore, owing to a lack of electronic medical records, only 56.5% of the pertinent medical records and files were retrieved and included in the analysis. Records that are saved only as paper prints without digital backups can be easily destroyed or even lost, causing valuable data loss [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Nonetheless, the calculated 5.6% fatality rate for the whole 161-patient population is in agreement with the 5.5% fatality rate of the 91 children analysed in the present study, indicating that our sample was likely representative.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003e In the present study, all the isolates demonstrated susceptibility to 3rd -generation cephalosporins, the empirical treatment used in 97.7% of the cases per the guidelines, whereas 15.2% exhibited penicillin resistance. As recent evidence currently suggests low rates of resistance to ceftriaxone and an increasing trend in penicillin resistance rates for \u003cem\u003eN. meningitidis\u003c/em\u003e, there is a critical need for ongoing global surveillance of antibiotic susceptibility patterns to improve the prevention and therapy of IMD. While adjunctive dexamethasone administration in meningococcal meningitis patients did not significantly improve sequelae among survivors, extended prospective studies are warranted to definitively assess the impact of dexamethasone on clinical outcomes and establish optimized treatment protocols.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u003c/strong\u003e Conceptualization, P.P., G.T.; methodology, P.P., M.T., A.M., and G.T.; formal analysis, P.P., and G.T.; statistical analysis, T.S.; investigation, P.P., M.T., A.M., E.M., V.P., A.I., S.K., \u0026Epsilon;.F., and G.T.; resources, G.T.; data curation, M.T., A.M., E.M., V.P., A.I., D.G., D.K., S.K., E.F., S.K., and G.T.; writing\u0026mdash;original draft preparation, P.P., GT. ; writing\u0026mdash;review and editing, M.T., A.M., E.M., V.P., A.I., D.G., D.K., S.K., E.F., T.S. and G.T.; supervision, G.T.; project administration, G.T. All the authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThis research received no external funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement:\u0026nbsp;\u003c/strong\u003eAll data are available within the article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInstitutional Review Board Statement:\u0026nbsp;\u003c/strong\u003eEthical approval for conducting this study was obtained from the corresponding ethical committees of the participating hospitals (approval numbers: 13255 (15/07/2020), 697 (29/12/2020), 29427 (30/12/2021), 26936 (28/09/2023), 221 (22/05/2024), 26164 (10/06/2024), 9156 (28/08/2024), 51294 (08/08/2024), 14(05/11/2024), and 1220 (10/01/2025)).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed Consent Statement:\u0026nbsp;\u003c/strong\u003ePatient consent was waived because of the retrospective, descriptive nature of the study, and the anonymity of patients was retained throughout the study through the use of laboratory coding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number : NA\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest:\u003c/strong\u003e The authors declare that they have no conflicts of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eEuropean Centre for Disease Prevention and Control. Meningococcal disease. Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ecdc.europa.eu/en/meningococcal-disease\u003c/span\u003e\u003cspan address=\"https://www.ecdc.europa.eu/en/meningococcal-disease\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (accessed on 20/03/2025).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWang B, Santoreneos R, Giles L, Afzali HHA, Marshall H. Case fatality rates of invasive meningococcal disease by serogroup and age: A systematic review and meta-analysis. Vaccine. 2019;37:2768\u0026ndash;82.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOlbrich K, M\u0026uuml;ller D, Schumacher S, Beck E, Meszaros K, Koerber F. Systematic Review of Invasive Meningococcal Disease: Sequelae and Quality of Life Impact on Patients and Their Caregivers. Infect Dis Ther. 2018;7:421\u0026ndash;38.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVoss S, Nielsen J, Valentiner-Branth P. Risk of sequelae after invasive meningococcal disease. BMC Infect Dis. 2022;22:148.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePoulikakos P, Kapnisis D, Xirogianni A, Liakou I, Tsolia M, Michos A, Mantadakis E, Papaevangelou V, Iliadis A, Gkentzi D, et al. Invasive Meningococcal Disease in Children: Outcomes and Risk Factors for Sequelae and Fatal Cases in Greece. Microorganisms. 2025;13(4):705.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eShen J, Begum N, Ruiz-Garcia Y, Martinon-Torres F, Bekkat-Berkani R, Meszaros K. Range of invasive meningococcal disease sequelae and health economic application\u0026mdash;a systematic and clinical review. BMC Public Health. 2022;22:1078.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTunkel A, Hartman JB, Kaplan LS, Kaufman AB, Roos LK, Scheld M, Whitley JR. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis. 2004 Nov;1(9):1267\u0026ndash;84.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003evan de Beek D, Brouwer CM, Koedel U, Wall CE. Community-acquired bacterial meningitis. Lancet 2021 Sep 25; 398 (10306):1171\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTian C, Jin S, Zhao Z, Liu X, Cheng H, Wang X, Zhao L. Association of Corticosteroid Treatment With Outcomes in Pediatric Patients With Bacterial Meningitis: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Clin Ther 2022 Feb 13; 44:551\u0026ndash;64.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003evan de Beek D, Brouwer CM, Koedel U, Wall CE. Steroid use in nonpneumococcal and non-Haemophilus bacterial meningitis - Authors' reply Lancet. 2022 Feb 19;399 (10326):718.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNadel S, Ninis N. Invasive Meningococcal Disease in the Vaccine Era. Front Pediatr 2018 Nov 09; 6:321.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003evan de Beek D, Cabellos C, Dzupova O, Esposito S, Klein M, Kloek TA, Leib LS, Mourvillier B, Ostergaard C, Pagliano P, et al. ESCMID Study Group for Infections of the Brain (ESGIB) ESCMID guideline: diagnosis and treatment of acute bacterial meningitis. Clin Microbiol Infect. 2016 May;22(Suppl 3):S37\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eREFERENCE VALUES FOR COMMON LABORATORY TESTS. American College of Clinical Pharmacy. Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.accp.com/docs/sap/Lab_values_Table _PedSAP.pdf\u003c/span\u003e\u003cspan address=\"https://www.accp.com/docs/sap/Lab_values_Table _PedSAP.pdf\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (accessed on 22/03/2025).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLeekha S, Terrell LC, Edson SR et al. General Principles of Antimicrobial Therapy. Mayo Clin Proc. 2011 Feb; 86(2):156\u0026ndash;167.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSvendsen BM, Kofoed RI, Nielsen H, Sch\u0026oslash;nheyder CH, Bodilsen J. Neurological sequelae remain frequent after bacterial meningitis in children. Acta Paediatr. 2020 Feb;109(2):361\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEucast NS, I and, Definitions R. May Available online: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.eucast.org/newsiandr\u003c/span\u003e\u003cspan address=\"https://www.eucast.org/newsiandr\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (accessed on 12 2025).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFlountzi A, Georgakopoulou T, Balasegaram S, Kesanopoulos K, Xirogianni A, Papandreou A, Tzanakaki G. Members of the Hellenic network for Invasive meningococcal disease. Epidemiology of invasive meningococcal disease in Greece, 2006\u0026ndash;2016. Eur J Clin Microbiol Infect Dis. 2019 Dec;38(12):2197\u0026ndash;203.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSpiliopoulou I, Xirogianni A, Simantirakis S, Tzanakaki G. Meningococcal Antibiotic Resistance: Molecular Characterization of Isolates from Patients with Invasive Meningococcal Disease (IMD) in Greece. Antibiotics. 2023;12:1136.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDeghmane A, Hong E, Taha MK. Emergence of meningococci with reduced susceptibility to third-generation cephalosporins. J Antimicrob Chemother. 2017 Jan;72(1):95\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRostamian M, Chegene Lorestani R, Jafari S, Mansouri R, Rezaeian S, Ghadiri K, Akya A. A systematic review and meta-analysis on the antibiotic resistance of \u003cem\u003eNeisseria meningitidis\u003c/em\u003e in the last 20 years in the world. Indian J Med Microbiol. 2022;40(3):323\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRodriguez E, Tzeng LY, Berry I, Howie R, McNamara L, Stephens SD. Progression of antibiotic resistance in \u003cem\u003eNeisseria meningitidis\u003c/em\u003e. Clin Microbiol Rev 2025 Mar 13; 38(1):e0021524.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGorla MC, de Paiva MV, Salgueiro VC, Lemos AP, Brand\u0026atilde;o AP, V\u0026aacute;zquez JA, Brandileone MC. Antimicrobial susceptibility of \u003cem\u003eNeisseria meningitidis\u003c/em\u003e strains isolated from meningitis cases in Brazil from 2006 to 2008. Enferm Infecc Microbiol Clin. 2011;29(2):85\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBrouwer M, McIntyre P, Prasad K et al. Corticosteroids for acute bacterial meningitis. Cochrane Database Syst Rev. 2015 Sep 12; 2015(9):CD004405.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOlivares R, Bouyer J, Hubert B. Risk factors for death in meningococcal disease Pathol Biol (Paris). 1993 Feb; 41(2):164\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSyrogiannopoulos GA, Lourida AN, Theodoridou MC, Pappas IG, Babilis GC, Economidis JJ, Zoumboulakis DJ, Beratis NG, Matsaniotis NS. Dexamethasone therapy for bacterial meningitis in children: 2- versus 4-day regimen. J Infect Dis. 1994 Apr;169(4):853\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDerecho KC, Cafino R, Aquino-Cafino SL, Isla A, Esencia JA, Lactuan NJ, Maranda JAG, Velasco LCP. Technology adoption of electronic medical records in developing economies: A systematic review on physicians' perspective. Digit Health. 2024;10:20552076231224605.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Invasive meningococcal disease, Antibiotic treatment, Dexamethasone","lastPublishedDoi":"10.21203/rs.3.rs-7714619/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7714619/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eInvasive meningococcal disease (IMD) is an acute, severe infection that continues to pose a significant public health challenge worldwide because of its potential for mortality and long-term sequelae.\u003c/p\u003e\u003ch2\u003eObjectives\u003c/h2\u003e\u003cp\u003eThis study aimed to assess therapeutic approaches focused on the use of first-line antibiotics as well as practices for dexamethasone treatment in patients with meningococcal meningitis in Greece.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eA retrospective analysis was conducted on pediatric patients aged up to 16 years identified through laboratory records from the Hellenic National Meningitis Reference Laboratory (HNML) between 2010 and 2020. The data collected included age, treatment regimens, antibiotic susceptibility, and clinical outcomes.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eA total of 161 patients admitted to 9 hospitals across Greece were identified. The medical records of 91 (56.5%) patients were retrieved. The median age was 36 months. All the meningococcal isolates were susceptible to third-generation cephalosporins (ceftriaxone, cefotaxime), which are empirical treatments for 97.7% of the cases, whereas penicillin resistance was recorded in 15.2% of the isolates. The case fatality rate was 5.5% (5 cases). The administration of dexamethasone to 31 patients (34%) with meningococcal meningitis was associated with a nonsignificant reduction in adverse outcomes (12.9% vs. 29%). One fatal case occurred in the nondexamethasone group.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eThird-generation cephalosporins are confirmed as effective empirical treatments for IMD in Greece. Owing to the small size of our cohort, the use of adjunctive dexamethasone was not significantly associated with improved outcomes in this cohort.\u003c/p\u003e","manuscriptTitle":"Therapeutic Approaches in Children with Invasive Meningococcal Disease (IMD) in Greece.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-01 06:51:13","doi":"10.21203/rs.3.rs-7714619/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"295212818054921626316288862309998269262","date":"2025-12-04T12:19:51+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-11-27T14:26:29+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-09-29T09:07:46+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-27T13:41:47+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-27T13:41:47+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pediatrics","date":"2025-09-25T15:29:18+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f2edbaf1-7dfe-44e5-9db2-42243301da34","owner":[],"postedDate":"December 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-12-01T06:51:13+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-01 06:51:13","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7714619","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7714619","identity":"rs-7714619","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}