The BLAST- 1 Trial - Cephalexin+Amoxicillin-clavulanate for Tuberculosis

The goal of this randomized controlled trial is to study the early bactericidal activity in adult patients with smear-positive pulmonary tuberculosis.

The main question it aims to answer are if cephalexin, in combination with amoxicillin-clavulanate, is effective in the treatment of tuberculosis.

Participants with smear-positive tuberculosis will be randomized to either of two groups:

Intervention group: cephalexin and amoxicillin-clavulanate. Control group: Standard of care TB treatment. The study period is 2 weeks and participants will be asked to submit multiple sputum samples to measure the bacterial sputum load. They will also submit saliva samples for estimation of drug concentrations in the body.

Researchers will compare the intervention group with the control group to see if the trial drugs result in a reduced bacterial sputum load

Overall aim: To study the early bactericidal activity of cephalexin, in combination with amoxicillin-clavulanate, in comparison to standard treatment in patients with active pulmonary tuberculosis during the first 2 weeks of treatment.

Primary aim:

1. To evaluate the early bactericidal activity (measured as 'time to culture positivity') of cephalexin-clavulanate in comparison, to standard TB treatment (rifampicin, isoniazid, pyrazinamide, and ethambutol).

   Secondary aim:
2. To asses safety and tolerability of cephalexin together with amoxicillin-clavulanate.
3. To determine key pharmacokinetic (PK) parameters of cephalexin, especially half-life and drug exposure (maximal concentration; Cmax and area under the concentration versus time curve, AUC).

Given the need for alternative and well-tolerated tuberculosis (TB) treatment options, there is scope to re-assess the potential value of already approved drugs that are known to be safe, cheap and widely available. Cephalexin, in combination with amoxicillin-clavulanate, have shown high in vitro efficacy against the TB bacteria. Both cephalexin and amoxicillin-clavulanate are Therapeutic Goods Administration (TGA) approved and are widely used in Australia for common infections.

In order to compare the bacterial killing effect of cephalexin, in combination with amoxicillin-clavulanate, with current standard of care TB treatment, we will perform an open-label randomized controlled trial.

Eligible and consenting study participants with bacteriologically confirmed sputum-smear positive pulmonary TB will be randomised to an intervention or control arm in a 1:1 ratio (15 patients in each arm) for the two weeks duration of the trial.

* Intervention arm: cephalexin 1g thrice daily + amoxicillin-clavulanate 500/125 mg thrice daily.
* Control arm: standard of care treatment for TB (rifampicin, isoniazid, ethambutol and pyrazinamide) The primary outcome is the fall in bacterial load measured by 'time to positive culture' using the BACTEC MGIT system with automated detection. Multiple sputum samples (10 in total) will be collected during the first 2 weeks of TB treatment. Six saliva samples will be collected after 4 days of treatment, in order to estimate the drug concentrations of cephalexin in the body (intervention arm only).

For a small subset of patients receiving cephalexin (n=5), a more intensive simultaneous blood and saliva sampling will be done in order to calculate the saliva:plasma ratio, in order to facilitate the estimation of plasma drug concentrations from saliva samples.

Eligibility Criteria:
Inclusion Criteria:

* Consenting adults (≥18 years)
* ≥40 kg
* Smear-positive patients with active tuberculosis, confirmed by sputum smear, TB PCR and/or GeneXpert.

Exclusion Criteria:

* On TB treatment for \>1 day
* Condition affecting ability of an informed consent (i.e. dementia, delirium etc).
* Pregnancy or breast-feeding
* HIV
* Known allergy or sensitivity to any of the study drugs
* Drug-resistant TB (resistance to rifampicin and/or isoniazid)
* Poor general condition or severe infection such that, in the opinion of the investigator at screening, any delay in initiation of definitive TB treatment cannot be tolerated
* TB with concomitant central nervous system and/or cardiac involvement.
* Any condition as determined by physical examination, medical history, laboratory data, or chest x-ray which, in the opinion of the investigator, would interfere with safety or endpoint assessments in the study.
* Use of metformin, probenecid or allopurinol
* Known previous Clostridium difficile infection due to the risk of colitis. (In case no medical records are available, it should be suspected in elderly patients reporting severe gastrointestinal infections in relation to courses of antibiotics)