Exploring the Combination of Intracalvariosseous and Intravenous Antibiotics for Moderate to Severe Bacterial Meningitis

NCT07826351 | Not Yet Recruiting DMC

• 1 other identifier: Pre-CX25YZ07
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 1

Brief Summary

Multiple preclinical and clinical studies, including the investigators' published work and the ongoing SOLUTION series trials, have consistently demonstrated that intracalvariosseous (ICO) injection can markedly increase drug exposure in the central nervous system with an acceptable safety profile. This is a multicenter, prospective, single-arm, open-label, exploratory clinical study designed to evaluate the feasibility, safety and preliminary efficacy of antibiotic delivery via the ICO route combined with standard intravenous therapy in patients with moderate-to-severe bacterial meningitis who have shown an inadequate response to standard antibiotic treatment.

Conditions

Blood-Brain Barrier; Bacterial Meningitis

Keywords

Blood-Brain Barrier; Bacterial meningitis; Prognosis; Intracalvariosseous; Antibiotic

Outcome Measures

Primary Outcomes (3)

• Feasibility and safety of cranial burr hole procedure and 7-day continuous intracalvariosseous antibiotic infusion

  Success rate of parietal burr hole placement; proportion of participants who complete 7×24-hour continuous antibiotic infusion via the intracalvariosseous route; incidence of device dislodgement, leakage, occlusion and unplanned infusion interruption.

  From Day 1 (device placement) to Day 8 (device removal)

• Proportion of participants requiring rescue intrathecal/intraventricular antibiotic therapy within 3 days after intervention initiation

  The proportion of participants who meet predefined inadequate response criteria within the first 3 days (such as Day 2, 3, 4) of combined therapy and thus receive rescue intrathecal (IT) or intraventricular (IVT) antibiotics. Inadequate response is defined as ≥2 of the following 4 items showing no improving trend or deterioration compared with baseline in at least 2 consecutive clinical evaluations: Intracranial infection-related clinical signs and symptoms Cerebrospinal fluid (CSF) white blood cell count CSF protein concentration CSF/serum glucose concentration ratio

  Within 3 days after initiation of intracalvariosseous treatment, such as Day 2, 3, 4.

• Overall clinical response rate at Day 8 and Day 15

  Overall response rate = \[(Cure + Improvement) / Total number of evaluable participants\] × 100% Cure: CSF white blood cell count, CSF protein concentration, CSF/serum glucose ratio, and CSF bacterial culture are all normal in 2 consecutive tests. Improvement: All 4 above CSF indicators are normal in at least 1 test. Ineffective: All 4 above CSF indicators remain abnormal in 2 consecutive tests. Normal reference values for CSF indicators: White blood cell count: \< 100 × 10⁶/L Protein concentration: \< 50 mg/dL CSF/serum glucose ratio: \> 0.5

  Day 8, Day 15 after intervention initiation

Secondary Outcomes (30)

• Cure rate at Day 8 and Day 15

  Day 8, Day 15 after intervention initiation

• Improvement rate at Day 8 and Day 15

  Day 8, Day 15 after intervention initiation

• Cerebrospinal fluid white blood cell count at Days 2-4 and Day 8, Day 15 after intervention initiation

  Days 2-4 and Day 8, Day 15 after intervention initiation

• Cerebrospinal fluid protein concentration at Days 2-4 and Day 8, Day 15 after intervention initiation

  Days 2-4 and Day 8, Day 15 after intervention initiation

• Cerebrospinal fluid-to-serum glucose concentration ratio at Days 2-4 and Day 8, Day 15 after intervention initiation

  Days 2-4 and Day 8, Day 15 after intervention initiation

Study Arms (1)

Intracalvariosseous injection + Intravenous injection

EXPERIMENTAL

In patients who fail to respond to the initial intravenous antibiotic regimen, intravenous treatment will be switched to the indicated antibiotic (polymyxin B, tigecycline, or vancomycin). At the same time, bilateral parietal outer-table drill holes will be created, delivery devices will be secured, and the corresponding antibiotic (polymyxin B, tigecycline, or vancomycin) will be continuously infused via the intracalvariosseous route. The combined ICO and intravenous treatment will be administered concurrently for 7 × 24 hours, after which the ICO devices will be removed. The duration of intravenous therapy will then be adjusted according to treatment response, including clinical symptoms, signs, and laboratory findings.

Procedure: Intracalvariosseous injection vancomycin/tigecycline/polymyxin B; Drug: Intravenous injection vancomycin/tigecycline/polymyxin B; Other: Conventional treatment

Interventions

Intracalvariosseous injection vancomycin/tigecycline/polymyxin B PROCEDURE

Continuous intracalvariosseous infusion of polymyxin B (12.5 mg/day), tigecycline (12.5 mg/day), and vancomycin (125 mg/day).

Intracalvariosseous injection + Intravenous injection

Intravenous injection vancomycin/tigecycline/polymyxin B DRUG

Intravenous infusion of polymyxin B (100 mg/day), tigecycline (100 mg/day), and vancomycin (2000 mg/day).

Intracalvariosseous injection + Intravenous injection

Conventional treatment OTHER

Standard treatment and management according to related guidelines during the entire treatment period

Intracalvariosseous injection + Intravenous injection

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \. Age 18-75 years, gender not limited;
• \. Meeting the diagnostic criteria for moderate-to-severe bacterial meningitis:
• Meeting the diagnostic criteria for bacterial meningitis (at least item i must be satisfied):
• i. Clinical diagnosis: abnormal body temperature (\>38 ℃ or \<36 ℃), turbid or purulent cerebrospinal fluid (CSF), CSF leukocytosis (\>500 × 10⁶/L), CSF glucose/serum glucose ratio \< 0.4, CSF protein concentration \> 50 mg/dL; ii. Etiological diagnosis: on the basis of item i, positive microbial detection or culture from specimen smears, drainage catheter tips, implants or CSF (excluding contamination and colonization).
• Glasgow Coma Scale (GCS) score ≤ 12, or a decrease of ≥ 2 points from the previous assessment; At least one of the following: altered consciousness, seizures, brain parenchymal involvement, mechanical ventilation, or circulatory support.
• \. No significant improvement or progressive worsening of the condition after empirical or targeted antibiotic therapy, as confirmed by at least 2 consecutive treatment evaluations, with at least one of the following: No relief or worsening of intracranial infection-related signs and symptoms; No decreasing trend in CSF white blood cell count, or re elevation after an initial decrease; No decreasing trend in CSF protein concentration, or re elevation after an initial decrease; No increasing trend in CSF/serum glucose concentration ratio, or re decrease after an initial increase; Persistently positive CSF bacterial culture, or re positivity after initial negative conversion.
• \. Treatment with polymyxin B, tigecycline or vancomycin is clinically indicated for intracranial anti infective therapy, as judged by the investigator.
• \. Written informed consent obtained.

You may not qualify if:

• \. History of allergy to polymyxin B, tigecycline or vancomycin;
• \. Unilateral skull craniotomy edge within 30 mm of the parietal eminence, as confirmed by cranial imaging or physical measurement;
• \. Severe pulmonary infection / acute respiratory distress syndrome (PaO₂/FiO₂ \< 150 mmHg, FiO₂ ≥ 0.6, PEEP ≥ 5 cmH₂O), or mechanical ventilation whose primary cause is not intracranial infection;
• \. Primary extracranial focus of infection (e.g., lung, abdomen, urinary tract) requiring vasoactive agents to maintain MAP ≥ 65 mmHg (e.g., norepinephrine ≥ 0.25 μg/kg/min) and lactate \> 2 mmol/L after adequate fluid resuscitation, or critical illness whose primary cause is not intracranial infection;
• \. Contraindications to intracalvariosseous (ICO) administration: severe skull fracture, poor visualization of the calvarial diploic space, planned decompressive craniectomy, or other conditions that may interfere with ICO drug delivery;
• \. Clinical signs of brain herniation: unilateral or bilateral pupillary dilation and fixation; loss of other brainstem reflexes judged by the investigator to be caused by meningitis or brain herniation; or other uncontrollable signs of vital sign instability;
• \. Bleeding tendency considered unfavorable for the procedure by the investigator: coagulopathy (e.g., platelet count \< 50 × 10⁹/L; prothrombin time \[PT\] prolongation \> 3 seconds), or previously diagnosed hemophilia or other coagulation disorders;
• \. Severe hepatic or renal insufficiency: Severe hepatic insufficiency: alanine aminotransferase (ALT) ≥ 3 × upper limit of normal (ULN) or aspartate aminotransferase (AST) ≥ 3 × ULN; Severe renal insufficiency: serum creatinine (CRE) ≥ 1.5 × ULN or estimated glomerular filtration rate (eGFR) \< 40 mL/min/1.73 m²;
• \. Acute ST segment elevation myocardial infarction and/or decompensated heart failure (New York Heart Association \[NYHA\] class III or IV) within the past 3 months;
• \. Active hepatitis B infection (positive hepatitis B surface antigen and/or serum HBV DNA positive, or serum HBV DNA \> 2 × 10⁸ IU/mL);
• \. Positive hepatitis C virus antibody or history of positive testing;
• \. Positive HIV test or history of positive testing;
• \. Pregnant, lactating, or potentially pregnant patients, or patients planning pregnancy;
• \. Currently participating in other interventional trials, or having received other investigational drugs within 1 month or 5 drug half lives;
• \. Patients deemed unsuitable for the study by the investigator.

Sponsors & Collaborators

• yilong Wang: lead

Study Sites (1)

Beijing Tiantan Hospital, Beijing

Beijing, Beijing Municipality, 100071, China

Location

MeSH Terms

Conditions

Meningitis, Bacterial

Condition Hierarchy (Ancestors)

Central Nervous System Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Central Nervous System Infections; Central Nervous System Diseases; Nervous System Diseases; Meningitis; Neuroinflammatory Diseases

Study Officials

• Yilong Wang, PhD, MD

  Beijing Tiantan Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Yilong Wang, PhD, MD

CONTACT

13569869755; yilong528@aliyun.com

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Vice President of Beijing Tiantan Hospital

Study Record Dates

• First Submitted: September 13, 2026
• First Posted: September 17, 2026
• Study Start: September 21, 2026
• Primary Completion (Estimated): January 31, 2027
• Study Completion (Estimated): March 31, 2027
• Last Updated: September 17, 2026

Record last verified: 2026-09

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)