Partial Oral Antibiotic Treatment for Bacterial Brain Abscess

Official title

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

Overview

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

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.

Interventions

• Drug Early transition to oral antibiotics
  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
• Drug Standard treatment of intravenous antibiotics
  Patients will continue standard intravenous antibiotic therapy for brain abscess (e.g. 3rd generation cephalosporin + metronidazole) according to international guidelines and pathogen susceptibility patterns.

Primary outcome measures

• Treatment failure [Time frame: Six months after randomisation]

Secondary outcome measures (12)

• Treatment failure [Time frame: At last day of antibiotic treatment for brain abscess, and 3- and 12-months after randomisation]
• Unfavourable outcome [Time frame: At last day of antibiotic treatment for brain abscess, and 3-, 6-, and 12-months after randomisation]
• All-cause mortality [Time frame: At last day of antibiotic treatment for brain abscess, and 3-, 6-, and 12-months after randomisation]
• Unplanned neurosurgery [Time frame: At 6 months since randomisation]
• IVROBA [Time frame: At 6 months since randomisation]
• Relapse [Time frame: At 6 months since randomisation]
• Recurrence [Time frame: At 6 months since randomisation]
• Unfavourable outcome - sliding dichotomy [Time frame: At last day of antibiotic treatment for brain abscess, and 3-, 6-, and 12-months after randomisation]
• Central line associated complications [Time frame: 6 months since randomisation]
• Clostridial diarrhea [Time frame: From randomisation up until last day antibiotic treatment for brain abscess]
• Duration of admission [Time frame: From randomisation until hospital discharge to home or rehabilitation unit or death, whichever comes first, assessed up to 6 months]
• Duration of treatment [Time frame: From randomisation until last day of antibiotic treatment for brain abscess up to 6 months since randomisation]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

Denmark · 4 centers

• Aalborg University Hospital — Aalborg
• Aarhus University Hospital — Aarhus
• Rigshospitalet — Copenhagen
• Odense University Hospital — Odense

Publications

• Bodilsen J, Brouwer MC, van de Beek D, Tattevin P, Tong S, Naucler P, Nielsen H. Partial oral antibiotic treatment for bacterial brain abscess: an open-label randomized non-inferiority trial (ORAL). Trials. 2021 Nov 12;22(1):796. doi: 10.1186/s13063-021-05783-8. PMID 34772441

Identifiers

NCT: NCT04140903 · 1

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗