Partial Oral Antibiotic Treatment for Bacterial Brain Abscess

Study Overview
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Brief Summary
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The investigators aim to determine if oral antibiotics are clinically acceptable as treatment of brain abscess. Following 2 weeks of standard intravenous antibiotic therapy, half of patients will continue with this treatment for another 4 weeks or longer while the other half will be assigned to oral antibiotics for the remaining duration of treatment.

Detailed Description
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Treatment of brain abscess remains a considerable challenge due to the precarious location of the infection and the impenetrability of the blood-brain-barrier for most drugs. Thus, cure usually requires a combination of neurosurgical evacuation of abscess material and 6-8 weeks of high-dose intravenous (IV) antibiotic therapy to ensure eradication of bacteria within the abscess cavity. Disadvantages include risks of nosocomial infections and line-associated complications (e.g. bleeding, venous thrombosis, or need for replacement due to malfunction) in addition to the considerable costs of such long-term admission. However, improved insights into the pharmacokinetic properties and favourable bioavailability of some oral antibiotics may allow such treatment at an early stage. To date, there are no randomised controlled trials to guide treatment of bacterial brain abscess. The investigators wish to determine whether a treatment strategy of transition to oral antibiotics after two weeks of treatment is non-inferior to continued IV antibiotics in clinically stable brain abscess patients assessed by the proportion with a favourable outcome at six months since randomisation.

Official Title
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Partial Oral Antibiotic Treatment for Bacterial Brain Abscess: An Open-label Randomised Non-inferiority Trial

Conditions
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Brain Abscess, Cerebral Abscess

Intervention / Treatment
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* Drug: Early transition to oral antibiotics
* Drug: Standard treatment of intravenous antibiotics


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A clinical presentation (e.g. headache, neurological deficit or fever) and cranial imaging (CT or MRI) consistent with brain abscess AND The physician responsible for the patient decides to treat the patient for bacterial brain abscess AND Ability to take and absorb oral medications (including by nasogastric tube) AND To have received relevant antibiotic therapy for bacterial brain abscess for 14 consecutive days before randomisation AND Expected to be treated with antibiotic therapy for at least another 14 days after time of randomisation AND No progression in symptom intensity or occurrence of new-onset neurological symptoms (excluding seizures) within five days before time of randomisation. Exclusion Criteria (patients fulfilling either criteria): Expected substantially reduced compliance with treatment (e.g. IV drug abuse) Pregnancy (proven by positive urine or plasma human chorionic gonadotropin test in fertile women <50 years of age) Concomitant (empirical) brain abscess treatment for tuberculosis, nocardiosis, Pseudomonas spp., fungi, toxoplasmosis or other CNS parasites Device related brain abscesses (e.g. deep brain stimulators, ventriculo-peritoneal shunts) Severe immuno-compromise defined as ongoing need for biological- or chemotherapy, prednisolone >20 mg/day for 14 days or longer, uncontrolled HIV/AIDS, haematological malignancies, and organ transplant recipients Concomitant or unrelated infections necessitating IV antibiotics beyond seven days of duration after time of randomisation Previous enrolment into this trial

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Investigator-initiated, international, multi-centre, randomised, parallel groups, non-inferiority trial
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oral antibiotics<br>Patients will be randomised to oral antibiotics after two weeks of appropriate antibiotic therapy for bacterial brain abscess since definitive aspiration/excision of brain abscess or, in case of no planned diagnostic neurosurgical procedure, since initiation of guideline recommended antibiotics for bacterial brain abscess | Drug: Early transition to oral antibiotics<br>* Patients will be treated with an oral antibiotic regimen (e.g. amoxicillin + metronidazole) based upon pharmacokinetic and pharmacodynamic properties of the drugs, pathogen susceptibility, and any existing drug allergies or interactions<br>|
| Active Comparator: Standard treatment<br>Patients will be randomised to continuation of standard intravenous antibiotics after two weeks of appropriate antibiotic therapy for bacterial brain abscess since definitive aspiration/excision of brain abscess or, in case of no planned diagnostic neurosurgical procedure, since initiation of guideline recommended antibiotics for bacterial brain abscess | Drug: Standard treatment of intravenous antibiotics<br>* Patients will continue standard intravenous antibiotic therapy for brain abscess (e.g. 3rd generation cephalosporin + metronidazole) according to international guidelines and pathogen susceptibility patterns.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment failure | A composite of number of participants with all-cause mortality, risk of intraventricular rupture of brain abscess (IVROBA), unplanned neurosurgery, relapse, or recurrence | Six months after randomisation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment failure | A composite of number of participants with all-cause mortality, risk of intraventricular rupture of brain abscess (IVROBA), unplanned neurosurgery, relapse, or recurrence | At last day of antibiotic treatment for brain abscess, and 3- and 12-months after randomisation | 
| Unfavourable outcome | Number of participants with Extended Glasgow Outcome Scale score <7, overall and stratified by study centre, oral cavity bacteria (yes/no) and largest brain abscess diameter (+/- 3 cm) | At last day of antibiotic treatment for brain abscess, and 3-, 6-, and 12-months after randomisation | 
| All-cause mortality | Number of participants with fatal outcome, overall and stratified by study centre, oral cavity bacteria (yes/no) and largest brain abscess diameter (+/- 3 cm) | At last day of antibiotic treatment for brain abscess, and 3-, 6-, and 12-months after randomisation | 
| Unplanned neurosurgery | Number of participants with unplanned (re-)aspiration or excision, overall and stratified by study centre, oral cavity bacteria (yes/no) and largest brain abscess diameter (+/- 3 cm) | At 6 months since randomisation | 
| IVROBA | Number of participants with intraventricular rupture of brain abscess, overall and stratified by study centre, oral cavity bacteria (yes/no) and largest brain abscess diameter (+/- 3 cm) | At 6 months since randomisation | 
| Relapse | Number of participants with increase in brain abscess volume by 20% since randomisation, clinical deterioration attributable to brain abscess or lack of cure of at least 4 weeks or longer of assigned study treatment, overall and stratified by study centre, oral cavity bacteria (yes/no) and largest brain abscess diameter (+/- 3 cm) | At 6 months since randomisation | 
| Recurrence | New brain abscess formation after end of treatment, overall and stratified by study centre, oral cavity bacteria (yes/no) and largest brain abscess diameter (+/- 3 cm) | At 6 months since randomisation | 
| Unfavourable outcome - sliding dichotomy | Sliding dichotomy of extended Glasgow Outcome Scale scores according to Charlson comorbidity index score (range: 0=no comorbidity and more likely to have a favourable outcome to 40=high degree of comorbidity with a poor prognosis of a favourable outcome) at time of randomisation (0 vs. 1-2 vs. >2). | At last day of antibiotic treatment for brain abscess, and 3-, 6-, and 12-months after randomisation | 
| Central line associated complications | Number of participants with bleeding, infection, venous thrombosis or need for replacement of central line due to mechanical malfunction | 6 months since randomisation | 
| Clostridial diarrhea | Number of participants who develop Clostridioides difficile associated gastro-enteritis during antibiotic treatment for brain abscess | From randomisation up until last day antibiotic treatment for brain abscess | 
| Duration of admission | Days spent as admitted patient in hospital up to 6 months since randomisation (does not include outpatient hospital care) | From randomisation until hospital discharge to home or rehabilitation unit or death, whichever comes first, assessed up to 6 months | 
| Duration of treatment | Number of days treated with antibiotics for brain abscess up to 6 months since randomisation | From randomisation until last day of antibiotic treatment for brain abscess up to 6 months since randomisation | 
| Adherence to treatment | Adherence to allocated treatment. For oral treatment this will be measured using Morisky 8-item Medication Adherence scale scores (range 0=high adherence to 8=low adherence) up to 6 months since randomisation | From randomisation until last day of antibiotic treatment for brain abscess, assessed up to 6 months since randomisation | 
| Oedema on cranial imaging | Number of participants with residual perilesional oedema on cranial imaging up to 3 months since randomisation | 3 months since randomisation | 
| SAE | Number of participants with severe adverse events | From randomisation until last day of antibiotic treatment for brain abscess | 
| SF36 | Short Form 36 is a 36 item survey of patient-reported health-related quality of life (range 0=maximum disability to 100=no disability) | At time of randomisation, last day of antibiotic treatment for brain abscess, and 3-, 6-, and 12-months since randomisation | 
| EQ-5D-5L | EuroqQol - 5 dimensions - 5 level scores are derived from a standardized instrument for measuring generic health status including mobility, self-care, usual acitivities, pain/discomfort, and anxiety/depression (range 5=good health status to 25=poor health status) | At time of randomisation, last day of antibiotic treatment for brain abscess, and 3-, 6-, and 12-months since randomisation | 
| EQ-VAS | EuroqQol Visual Analogue Scale (range 0=poor health status to 100=excellent health status) | At time of randomisation, last day of antibiotic treatment for brain abscess, and 3-, 6-, and 12-months since randomisation | 
| Cognitive impairment | Montreal Cognitive Assessment (MoCA) scores (range 0=poor cognitive performance to 30=normal cognitive performance) | At time of randomisation, last day of antibiotic treatment for brain abscess, and 3-, 6-, and 12-months since randomisation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Oral antibiotics