Intracalvariosseous Plus Intravenous Antibiotics for Moderate-to-Severe Bacterial Meningitis (FLAME)

Efficacy and Safety of Intracalvariosseous Combined With Intravenous Injection of Antibiotics in Moderate-to-Severe Bacterial Meningitis

Multiple preclinical and clinical studies, including the investigators' published work and the ongoing SOLUTION series, have consistently demonstrated that intracalvariosseous (ICO) injection can markedly increase drug exposure within the central nervous system with acceptable safety. This trial is designed to further evaluate the efficacy and safety of antibiotic delivery via the ICO route in the treatment of bacterial meningitis, particularly in patients with moderate-to-severe disease who have shown an inadequate response to standard therapy.

Study Overview

• Status: Not yet recruiting
• Conditions: Bacterial Meningitis; Blood-Brain Barrier
• Intervention / Treatment: Procedure: Intracalvariosseous injection vancomycin/tigecycline/polymyxin B; Drug: Intravenous injection vancomycin/tigecycline/polymyxin B; Other: Conventional treatment

Detailed Description

Bacterial meningitis remains a major cause of death and neurological disability despite advances in antimicrobial therapy, vaccination, and critical care. Moderate-to-severe disease, particularly healthcare-associated infection and cases caused by multidrug-resistant pathogens, continues to pose substantial therapeutic challenges because intravenous antibiotic therapy alone may not achieve sufficiently rapid or sustained drug exposure in cerebrospinal fluid and at the meningeal surface. Although intrathecal and intraventricular administration can increase local drug concentrations, these approaches are invasive and have limited diffusion.

Anatomical and physiological studies have demonstrated communication among calvarial bone marrow, dura, cerebrospinal fluid spaces, and glymphatic pathways, supporting the rationale for intracalvariosseous (ICO) injection as a regional route for drug delivery to the central nervous system. Preclinical and clinical studies, including the investigators' published work and the ongoing SOLUTION series, suggest that ICO injection can enhance local central nervous system drug exposure with an acceptable safety profile. In addition, an exploratory study conducted by the investigators, using vancomycin administered via ICO injection in an experimental animal model of bacterial meningitis, further supported the potential of this route to improve anti-infective efficacy.

This trial is a multicenter, prospective, randomized, open-label, blinded-endpoint study comparing ICO injection plus intravenous antibiotic therapy with intravenous antibiotic therapy alone.

The study aims to evaluate differences in efficacy and safety between combined treatment with ICO injection and intravenous antibiotics versus intravenous antibiotics alone in participants with moderate-to-severe bacterial meningitis who have shown a suboptimal response to treatment.

Participants with moderate-to-severe bacterial meningitis and inadequate improvement after 48-72 hours of initial intravenous treatment will be randomized in a 1:1 ratio.

In the intervention group, bilateral parietal ICO access devices will be placed, and the selected antibiotic will be continuously administered through the calvarial bone marrow route for 7 days while the same antibiotic is also given intravenously.

In the control group, treatment will consist of intravenous antibiotic therapy alone.

Guideline-based supportive care, including intracranial pressure management, seizure control, organ support, and other standard measures, will be provided in both groups.

Face-to-face visits will be conducted at randomization (baseline), 48-72 hours, Day 5, Day 8, Day 10, Day 14, Day 30 (±3 days), or on the day of discharge. A telephone follow-up visit will be conducted at Month 3 (±7 days).

A Data and Safety Monitoring Board (DSMB) will regularly monitor safety throughout the study. The trial has been approved by the Institutional Review Board (IRB) and Ethics Committee (EC) of Beijing Tiantan Hospital, Capital Medical University.

• Study Type: Interventional
• Enrollment (Estimated): 86
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Yilong Wang, PhD+MD; Phone Number: 13569869755; Email: yilong528@aliyun.com

Study Locations

• China
  • Beijing Municipality
    • Beijing, Beijing Municipality, China, 100071
      • Beijing Tiantan Hospital
      • Contact: Yilong Wang, MD+PhD; Phone Number: 13569869755; Email: yilong528@aliyun.com
  • Henan
    • Kaifeng, Henan, China
      • Kaifeng Central Hospital
    • Xinxiang, Henan, China
      • The First Affiliated Hospital of Xinxiang Medical University
    • Zhengzhou, Henan, China, 450000
      • Henan Provincial People's Hospital
      • Contact: Guang Feng
  • Shandong
    • Linyi, Shandong, China
      • Linyi City People Hospital
  • Tianjin Municipality
    • Tianjin, Tianjin Municipality, China, 300000
      • Tianjin Huanhu Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 1. Age 18-75 years, gender not limited;

• 2. Meeting the diagnostic criteria for moderate to severe bacterial meningitis:

  1. Meeting the diagnostic criteria for bacterial meningitis, i.e., meeting at least item i:

     i. Abnormal body temperature (>38℃ or <36℃), turbid or purulent Cerebrospinal fluid (CSF) , CSF leukocytosis (>500×10⁶/L), CSF glucose/serum glucose concentration <0.4, CSF protein concentration >50mg/dL, meeting the clinical diagnosis; ii. In addition to item i, positive microbial tests or cultures of specimen smears, drainage tube heads, implants, and CSF (excluding contamination and colonization), meeting the etiological diagnosis;

  2. GCS score ≤12 points or a decrease of 2 points from the previous score;
  3. At least one of the following conditions is present: altered consciousness, seizures, brain parenchymal involvement, severe manifestations such as mechanical ventilation or circulatory support.

• 3. After 48-72 hours of antibiotic treatment, if the investigator determines that the patient's condition shows no significant improvement or continues to worsen, or if at least one of the following conditions is present:

  1. Symptoms and signs related to intracranial infection show no trend of relief or worsen;
  2. CSF white blood cell count shows no trend of decrease, or increases after decreasing;
  3. CSF protein concentration shows no trend of decrease, or increases after decreasing;
  4. CSF/serum glucose concentration shows no trend of increase, or decreases after increasing;
  5. CSF bacterial culture remains positive or becomes positive again after initially being negative.
• 4. Based on the patient's condition, treatment with polymyxin B, tigecycline, or vancomycin may be necessary.
• 5. Obtain informed consent.

Exclusion Criteria:

• 1. History of allergy to polymyxin B, tigecycline, or vancomycin;
• 2. Received intrathecal or intraventricular antibiotic treatment before randomization;
• 3. Patients with severe pulmonary infection/acute respiratory distress syndrome (PaO₂/FiO₂ < 150 mmHg, FiO₂ ≥ 0.6, PEEP ≥ 5 cmH₂O) or whose primary cause of mechanical ventilation is not determined to be intracranial infection;
• 4. Patients with a primary extracranial infection focus (e.g., lungs, abdomen, urinary tract, etc.) who, after adequate fluid resuscitation, require vasoactive drugs to maintain MAP ≥ 65 mmHg (e.g., norepinephrine ≥ 0.25 μg/kg/min) and lactate > 2 mmol/L, or whose primary cause of critical illness is not determined to be intracranial infection;
• 5. Patients with contraindications to transcranial administration, such as severe skull fracture, poor visualization of the skull diploic, or planned decompressive craniectomy, which may affect transcranial administration.
• 6. Clinical signs of brain herniation, such as unilateral or bilateral pupillary dilation and fixation; or loss of other brainstem reflexes determined by the investigator to be caused by meningitis or brain herniation; or other uncontrollable signs of unstable vital signs;
• 7. Bleeding tendency deemed unfavorable for the procedure by the investigator: abnormal coagulation function (e.g., platelet count <50×10⁹/L; prothrombin time [PT]>3s), patients with a previous diagnosis of hemophilia or other coagulation disorders;
• 8. Patients with severe hepatic or renal insufficiency (where severe hepatic insufficiency is defined as alanine aminotransferase (ALT) value ≥3 times the upper limit of normal (ULN) or aspartate aminotransferase (AST) value ≥3 times the ULN; severe renal insufficiency is defined as serum creatinine (CRE) ≥1.5 times the ULN or glomerular filtration rate (eGFR) <40 mL/min/1.73m²;
• 9. Within the past 3 months, the patient has experienced an acute ST-segment elevation myocardial infarction and/or decompensated heart failure (meeting New York Heart Association [NYHA] functional class III or IV).
• 10. Patients with severe or extremely severe anemia (hemoglobin < 60 g/L) at the time of randomization;
• 11. Patients with active hepatitis B infection (positive hepatitis B surface antigen and/or positive serum HBV DNA or serum HBV DNA > 2 × 10⁸ IU/ml);
• 12. Patients with positive hepatitis C virus antibody or a history of positive testing;
• 13. Patients with positive HIV test or a history of positive testing;
• 14. Pregnant, lactating, or potentially pregnant patients, or patients planning to become pregnant;
• 15. Patients currently participating in other interventional trials or who have used other investigational drugs within one month or five drug half-lives;
• 16. Patients deemed unsuitable for participation in this study by the investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intracalvariosseous injection + Intravenous injection; 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 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. If a change in antibiotic selection is required during the period of combined treatment, the antibiotic administered via the intracalvariosseous route must remain consistent with that administered intravenously.	Procedure: Intracalvariosseous injection vancomycin/tigecycline/polymyxin B; Continuous intracalvariosseous infusion of polymyxin B (12.5 mg/day), tigecycline (12.5 mg/day), and vancomycin (125 mg/day).; Drug: Intravenous injection vancomycin/tigecycline/polymyxin B; Intravenous infusion of polymyxin B (100 mg/day), tigecycline (100 mg/day), and vancomycin (2000 mg/day).; Other: Conventional treatment; Standard treatment and management according to related guidelines during the entire treatment period
Active Comparator: Intravenous injection; 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). The duration of intravenous therapy will be adjusted according to treatment response, including clinical symptoms, signs, and laboratory findings.	Drug: Intravenous injection vancomycin/tigecycline/polymyxin B; Intravenous infusion of polymyxin B (100 mg/day), tigecycline (100 mg/day), and vancomycin (2000 mg/day).; Other: Conventional treatment; Standard treatment and management according to related guidelines during the entire treatment period

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall effective rate after 7 days of randomization	Overall effective rate = [(Cure + Improvement) / Total Number of Case] * 100% Cure: Cerebrospinal fluid (CSF) white blood cell count, CSF protein concentration, CSF/serum glucose ratio, and CSF bacterial culture are all normal in three consecutive tests. Improvement: At least one of the following three CSF white blood cell counts, CSF protein concentration, CSF/serum glucose ratio, and CSF bacterial culture is normal. Ineffective: All three of the following CSF white blood cell counts, CSF protein concentration, CSF/serum glucose ratio, and CSF bacterial culture are abnormal. Normal Reference Values for CSF Indicators: white blood cell count < 100 × 10⁶/L, protein concentration < 50 mg/dL, CSF/serum glucose ratio > 0.5.	8,10 and 14 days after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cure rate after 7 days of randomization	Cure: Cerebrospinal fluid (CSF) white blood cell count, CSF protein concentration, CSF/serum glucose ratio, and CSF bacterial culture are all normal in three consecutive tests. Reference Values for CSF Indicators: white blood cell count < 100 × 10⁶/L, protein concentration < 50 mg/dL, CSF/serum glucose ratio > 0.5.	8,10 and 14 days after randomization
Improvement rate after 7 days of randomization	Improvement: At least one of the following three CSF white blood cell counts, CSF protein concentration, CSF/serum glucose ratio, and CSF bacterial culture is normal. Reference Values for CSF Indicators: white blood cell count < 100 × 10⁶/L, protein concentration < 50 mg/dL, CSF/serum glucose ratio > 0.5.	8,10 and 14 days after randomization
Cerebrospinal fluid white blood cell count at 48-72 hours and Days 5, 8, 10, and 14 after randomization	Cerebrospinal fluid white blood cell count	48-72 hours after randomization, Days 5, 8, 10, and 14 after randomization
Cerebrospinal fluid protein concentration at 48-72 hours and Days 5, 8, 10, and 14 after randomization	Cerebrospinal fluid protein concentration	48-72 hours after randomization, Days 5, 8, 10, and 14 after randomization
Cerebrospinal fluid-to-serum glucose concentration ratio at 48-72 hours and Days 5, 8, 10, and 14 after randomization	Cerebrospinal fluid-to-serum glucose concentration ratio	48-72 hours after randomization, Days 5, 8, 10, and 14 after randomization
Cerebrospinal fluid bacteriological culture results at 48-72 hours and Days 5, 8, 10, and 14 after randomization	Cerebrospinal fluid bacteriological culture results	48-72 hours after randomization, Days 5, 8, 10, and 14 after randomization
Glasgow Coma Scale (GCS) scores at 48-72 hours and Days 5, 8, 10, and 14 after randomization	Glasgow Coma Scale (GCS) is a neurological scale that assesses level of consciousness using 3 components: eye opening, verbal response, and motor response. The total score ranges from 3 to 15, with higher scores indicating a better neurological outcome / level of consciousness and lower scores indicating a worse outcome / deeper impairment of consciousness.	48-72 hours after randomization, Days 5, 8, 10, and 14 after randomization
Proportion of participants who require conversion to intrathecal or intraventricular antibiotic therapy during the 48-72 hour period after randomization	This proportion is defined as the number of participants who are evaluated during the 48-72-hour period after randomization and are judged to have an unsatisfactory treatment response requiring conversion to intrathecal or intraventricular antibiotic therapy, divided by the total number of participants in the corresponding treatment group. An unsatisfactory treatment response is defined as the absence of an improving trend, compared with baseline, in cerebrospinal fluid white blood cell count, protein concentration, and cerebrospinal fluid-to-serum glucose concentration ratio.	During the 48-72 hour period after randomization
All-cause mortality from baseline to 14-day	All-cause mortality	Baseline to Day 14
Mortality due to meningitis from baseline to 14-day	Mortality due to meningitis. The diagnostic criteria are the absence of a downward trend in the cerebrospinal fluid leukocyte count, protein concentration, and the ratio of cerebrospinal fluid glucose concentration to serum glucose concentration prior to death.	Baseline to Day 14

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
The ratio of the concentrations of the antibiotics used after randomization in cerebrospinal fluid and plasma	The ratio of cerebrospinal fluid drug concentration to plasma drug concentration	0.25, 0.5, 1, 2, 4, 8, 12, 24 hours after randomization
Glasgow Outcome Scale (GOS) scores at 1 month ± 3 days (or on the day of discharge) and at 3 months ± 7 days after randomization	Glasgow Outcome Scale (GOS) is a 5-point functional outcome scale used to assess recovery after brain injury or severe neurological disease. The total score ranges from 1 to 5, where 1 = death, 2 = vegetative state, 3 = severe disability, 4 = moderate disability, and 5 = good recovery; therefore, higher scores indicate a better outcome and lower scores indicate a worse outcome.	1 month ± 3 days (or on the day of discharge) and at 3 months ± 7 days after randomization
Cure rate without neurological sequelae at 1 month ± 3 days (or on the day of discharge) and at 3 months ± 7 days after randomization	Cure rate without neurological sequelae：Cerebrospinal fluid (CSF) white blood cell count, CSF protein concentration, CSF/serum glucose ratio, and CSF bacterial culture are all normal in three consecutive tests, and were not accompanied by neurological symptoms attributable to meningitis at baseline. Normal Reference Values for CSF Indicators: white blood cell count < 100 × 10⁶/L, protein concentration < 50 mg/dL, CSF/serum glucose ratio > 0.5.	1 month ± 3 days (or on the day of discharge) and at 3 months ± 7 days after randomization
All-cause mortality rate at 1 month ± 3 days (or on the day of discharge) and at 3 months ± 7 days after randomization	All-cause mortality is equal to the ratio of the number of all-cause deaths to the total number of cases within the same treatment group.	1 month ± 3 days (or on the day of discharge) and at 3 months ± 7 days after randomization
Meningitis-related mortality rate at 1 month ± 3 days (or on the day of discharge) and at 3 months ± 7 days after randomization	Meningitis-related mortality is equal to the ratio of the number of deaths due to meningitis to the total number of cases within the same treatment group. Meningitis-related mortality. The diagnostic criteria are the absence of a downward trend in the cerebrospinal fluid leukocyte count, protein concentration, and the ratio of cerebrospinal fluid glucose concentration to serum glucose concentration prior to death.	1 month ± 3 days (or on the day of discharge) and at 3 months ± 7 days after randomization
Reinfection with the same microorganism occurred at 1 month ± 3 days (or on the day of discharge) and at 3 months ± 7 days after randomization	Reinfection with the same microorganism	1 month ± 3 days (or on the day of discharge) and at 3 months ± 7 days after randomization
Breach of the inner table of the skull during calvarial drilling	Breach of the inner table of the skull	Baseline
Dislodgement, leakage, or occlusion of the intracalvariosseous injection device	Dislodgement, leakage, or occlusion of the intracalvariosseous injection device	Baseline to Day 8
Infection events related to intracalvariosseous injection, such as skin infection or calvarial bone marrow osteomyelitis	For example, skin infection or calvarial bone marrow osteomyelitis	Baseline to Day 8
First occurrence of seizures after randomization, including seizures considered to be associated with antibiotic use	Seizures considered to be associated with antibiotic use	Baseline to Day 8
Nucleated cell count in calvarial bone marrow fluid before and after intracalvariosseous injection	Nucleated cell count in calvarial bone marrow fluid	Baseline and Day 8
Hepatic or renal dysfunction/failure after randomization	Definition: Hepatic dysfunction/failure is defined as alanine aminotransferase or aspartate aminotransferase levels greater than 3 times the upper limit of normal. Renal dysfunction/failure is defined as serum creatinine greater than 1.5 times the upper limit of normal or an estimated glomerular filtration rate of <40 mL/min/1.73 m²	Baseline to Day 8
Incidence of sensorineural hearing loss after randomization	Based on distortion-product otoacoustic emission + multiple auditory steady-state evoked responses / auditory brainstem response. Definition: Compared with baseline, hearing loss is defined as an increase of ≥20 dB at any single frequency, an increase of ≥10 dB at two adjacent frequencies, or an increase of ≥10 dB in the average threshold across three frequencies.	Baseline to Day 8
Incidence of red man syndrome after randomization	Red man syndrome is defined as an infusion-related reaction occurring during or shortly after vancomycin administration, characterized by flushing/erythema and pruritus predominantly involving the face, neck, upper trunk, or upper extremities, with or without rash, and possibly accompanied by chest or back pain and/or hypotension, in the absence of features suggesting IgE-mediated anaphylaxis	Baseline to Day 8
Incidence of skin hypersensitivity reactions after randomization	For example, rash and urticaria	Baseline to Day 8
Incidence of gastrointestinal adverse reactions after randomization	For example, nausea and vomiting	Baseline to Day 8
Length of stay in the intensive care unit (ICU) after randomization	Calculate the number of days of ICU stay	From date of randomization until first ICU discharge or death, whichever comes first, assessed up to 3 months ± 7 days
Total length of hospital stay after randomization	Calculate the number of days from baseline to discharge	From date of randomization until hospital discharge or death, whichever comes first, assessed up to 3 months ± 7 days
Duration of antibiotic use after randomization	Calculate the number of days from baseline to the discontinuation of antibiotics	From date of randomization until discontinuation of systemic antibiotic therapy or death, whichever comes first, assessed up to 3 months ± 7 days
ICU costs after randomization	Costs from baseline to ICU discharge	From date of randomization until first ICU discharge or death, whichever comes first, assessed up to 3 months ± 7 days
Total hospitalization costs after randomization	Total cost from baseline to discharge	From date of randomization until hospital discharge or death, whichever comes first, assessed up to 3 months ± 7 days

Collaborators and Investigators

• Sponsor: yilong Wang
• Investigators: Principal Investigator: Yilong Wang, PhD+MD, Beijing Tiantan Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2026
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): July 1, 2027

Study Registration Dates

• First Submitted: March 9, 2026
• First Submitted That Met QC Criteria: March 21, 2026
• First Posted (Actual): March 27, 2026

Study Record Updates

• Last Update Posted (Actual): March 27, 2026
• Last Update Submitted That Met QC Criteria: March 21, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Prognosis; Antibiotic; Blood-Brain Barrier; Bacterial meningitis; Intracalvariosseous
• Additional Relevant MeSH Terms: Neuroinflammatory Diseases; Central Nervous System Diseases; Nervous System Diseases; Infections; Bacterial Infections; Bacterial Infections and Mycoses; Central Nervous System Infections; Meningitis; Central Nervous System Bacterial Infections; Meningitis, Bacterial
• Other Study ID Numbers: CX25YZ07

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No