Feasibility, Safety, and Preliminary Efficacy of Combined Intracalvariosseous and Intravenous Antibiotic Infusion for Moderate to Severe Bacterial Meningitis
试验速览
- 阶段
- 不适用
- 状态
- 尚未招募
- 发起方
- 入组人数
- 9
- 试验地点
- 1
- 主要终点
- Feasibility and safety of cranial burr hole procedure and 7-day continuous intracalvariosseous antibiotic infusion
研究概览
简要总结
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.
详细描述
Bacterial meningitis remains a major cause of death and long-term neurological disability despite advances in antimicrobial therapy, vaccination and critical care. Moderate-to-severe disease, particularly healthcare-associated ventriculitis/meningitis and infections caused by multidrug-resistant (MDR) pathogens, continues to pose substantial therapeutic challenges. Intravenous antibiotic therapy alone often fails to achieve sufficiently rapid and sustained therapeutic drug concentrations in cerebrospinal fluid (CSF) and at the meningeal surface due to the blood-brain barrier. Although intrathecal and intraventricular administration can increase local drug concentrations, these approaches carry high complication risks and have limited diffusion in the subarachnoid space.
Anatomical and physiological studies have demonstrated direct communication pathways between calvarial bone marrow, dura mater, CSF spaces and the glymphatic system, providing a biological rationale for intracalvariosseous (ICO) injection as a regional drug delivery route to the central nervous system. Preclinical and clinical evidence, including the investigators' published work and the ongoing SOLUTION series clinical trials, confirms that ICO delivery can enhance local CNS drug exposure without disrupting the blood-brain barrier, with a manageable safety profile. In addition, the investigators' exploratory animal study of vancomycin delivered via ICO in a bacterial meningitis model further demonstrated improved anti-infective efficacy at reduced systemic doses.
This trial is a multicenter, prospective, single-arm, open-label, exploratory clinical study. A total of 9 eligible patients will be enrolled across 3+ medical centers led by Beijing Tiantan Hospital, Capital Medical University.
Eligible participants are adults aged 18-75 years with moderate-to-severe bacterial meningitis who show no improvement or clinical deterioration after a course of empiric or targeted intravenous antibiotic therapy, and for whom treatment with polymyxin B, tigecycline or vancomycin is clinically indicated.
All enrolled participants will receive guideline-concordant standard supportive care (including intracranial pressure management, seizure control, organ support and symptomatic treatment) plus optimized intravenous antibiotic therapy. In addition, all participants will undergo bilateral parietal burr hole placement of cranial bolt delivery devices, followed by continuous infusion of the selected antibiotic via the calvarial bone marrow route for 7 consecutive days (7×24 hours). The ICO delivery device will be removed after the 7-day infusion course, and the duration of subsequent intravenous antibiotic therapy will be adjusted according to clinical and laboratory response. Rescue intrathecal or intraventricular antibiotic therapy will be initiated if predefined criteria of no improvement are met within the first 3 days of combined treatment.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •1. Age 18-75 years, gender not limited;
- •2. 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.
- •3. 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.
- •4. Treatment with polymyxin B, tigecycline or vancomycin is clinically indicated for intracranial anti infective therapy, as judged by the investigator.
- •5. Written informed consent obtained.
排除标准
- •1. History of allergy to polymyxin B, tigecycline or vancomycin;
- •2. Unilateral skull craniotomy edge within 30 mm of the parietal eminence, as confirmed by cranial imaging or physical measurement;
- •3. 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;
- •4. 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;
- •5. 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;
- •6. 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;
- •7. 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;
- •8. 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;
- •9. 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;
- •10. Active hepatitis B infection (positive hepatitis B surface antigen and/or serum HBV DNA positive, or serum HBV DNA > 2 × 10⁸ IU/mL);
- •11. Positive hepatitis C virus antibody or history of positive testing;
- •12. Positive HIV test or history of positive testing;
- •13. Pregnant, lactating, or potentially pregnant patients, or patients planning pregnancy;
- •14. Currently participating in other interventional trials, or having received other investigational drugs within 1 month or 5 drug half lives;
- •15. Patients deemed unsuitable for the study by the investigator.
研究组 & 干预措施
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 (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.
干预措施: Intracalvariosseous injection vancomycin/tigecycline/polymyxin B (Procedure)
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 (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.
干预措施: Intravenous injection vancomycin/tigecycline/polymyxin B (Drug)
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 (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.
干预措施: Conventional treatment (Other)
结局指标
主要结局
Feasibility and safety of cranial burr hole procedure and 7-day continuous intracalvariosseous antibiotic infusion
时间窗: From Day 1 (device placement) to Day 8 (device removal)
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.
Proportion of participants requiring rescue intrathecal/intraventricular antibiotic therapy within 3 days after intervention initiation
时间窗: Within 3 days after initiation of intracalvariosseous treatment, such as Day 2, 3, 4.
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
Overall clinical response rate at Day 8 and Day 15
时间窗: Day 8, Day 15 after intervention initiation
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
次要结局
- 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)
- 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)
- CSF bacterial culture results and pathogen clearance status(Days 2-4 and Day 8, Day 15 after intervention initiation)
- Glasgow Coma Scale (GCS) score and its change from baseline(Days 2-4 and Day 8, Day 15 after intervention initiation)
- All-cause mortality within 14 days of intervention initiation(Within 14 days of the start of the intervention)
- Mortality due to meningitis within 14 days of intervention initiation(Within 14 days of the start of the intervention)
- Antibiotic concentrations in CSF and plasma, and CSF/plasma concentration ratio(0.25, 0.5, 1, 2, 4, 8, 12, 24 hours and Days 2-4, Day 8 after intervention initiation.)
- Bacterial culture results of calvarial bone marrow fluid before and after intracalvariosseous treatment(Day 1 (device placement) and Day 8 (device removal))
- Glasgow Outcome Scale (GOS) score at 1 month (±3 days), 3 months (±7 days) after intervention initiation(1 month (±3 days), 3 months (±7 days) after intervention initiation)
- Cure rate without neurological sequelae at 1 month (±3 days), 3 months (±7 days) after intervention initiation(1 month (±3 days), 3 months (±7 days) after intervention initiation)
- All-cause mortality at 1 month (±3 days), 3 months (±7 days) after intervention initiation(1 month (±3 days), 3 months (±7 days) after intervention initiation)
- Meningitis-related mortality at 1 month (±3 days), 3 months (±7 days) after intervention initiation(1 month (±3 days), 3 months (±7 days) after intervention initiation)
- Reinfection with the same microorganism occurred at 1 month (±3 days), 3 months (±7 days) after intervention initiation(1 month (±3 days), 3 months (±7 days) after intervention initiation)
- Breach of the inner table of the skull during calvarial drilling(Day 1 (device placement))
- Infection events related to intracalvariosseous injection, such as skin infection or calvarial bone marrow osteomyelitis(From Day 1 (device placement) to Day 8 (device removal))
- First occurrence of seizures after intervention initiation, including seizures considered to be associated with antibiotic use(From Day 1 (device placement) to Day 8 (device removal))
- Nucleated cell count in calvarial bone marrow fluid before and after intracalvariosseous injection(Day 1 (device placement) and Day 8 (device removal))
- Hepatic or renal dysfunction/failure after intervention initiation(From Day 1 (device placement) to Day 8 (device removal))
- Incidence of sensorineural hearing loss after intervention initiation(From Day 1 (device placement) to Day 8 (device removal))
- Incidence of red man syndrome after intervention initiation(From Day 1 (device placement) to Day 8 (device removal))
- Incidence of skin hypersensitivity reactions after intervention initiation(From Day 1 (device placement) to Day 8 (device removal))
- Incidence of gastrointestinal adverse reactions after intervention initiation(From Day 1 (device placement) to Day 8 (device removal))
- Length of stay in the intensive care unit (ICU) after intervention initiation(From date of intervention initiation until first ICU discharge or death, whichever comes first, assessed up to 3 months ± 7 days)
- Total length of hospital stay after intervention initiation(From date of intervention initiation until hospital discharge or death, whichever comes first, assessed up to 3 months ± 7 days)
- Duration of antibiotic use after intervention initiation(From date of intervention initiation until discontinuation of systemic antibiotic therapy or death, whichever comes first, assessed up to 3 months ± 7 days)
- ICU costs after intervention initiation(From date of intervention initiation until first ICU discharge or death, whichever comes first, assessed up to 3 months ± 7 days)
- Total hospitalization costs after intervention initiation(From date of intervention initiation until hospital discharge or death, whichever comes first, assessed up to 3 months ± 7 days)
研究者
yilong Wang
Vice President of Beijing Tiantan Hospital
Beijing Tiantan Hospital