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BACKGROUND:
Antibiotic tolerant bacterial persistence prevents treatment shortening in drug susceptible tuberculosis (TB) and accumulation of intracellular lipid bodies has been proposed to identify a persister phenotype of Mycobacterium tuberculosis cells. In Malawi, we modelled Bacillary Elimination Rates (BERs) from sputum cultures and calculated the percentage of lipid body positive acid fast bacilli (%LB+AFB) on sputum smears. We assessed whether these putative measurements of persistence predict unfavourable outcomes (treatment failure/relapse).
METHODS:
Adults with pulmonary TB received standard 6 month therapy. Sputum samples were collected during the first 8 weeks for Serial Sputum Colony Counting (SSCC) on agar and Time to Positivity (TTP) measurement in BACTEC MGIT broth. BERs were extracted from non-linear and linear mixed effects models fitted respectively to these datasets. %LB+AFB counts were assessed by fluorescence microscopy. Patients were followed until one year post-treatment. Individual BERs and %LB+AFB counts were related to final outcomes.
RESULTS:
133 patients (56% HIV co-infected) participated and 15 unfavourable outcomes were reported. These were inversely associated with faster sterilisation phase bacillary elimination from the SSCC model (Odds Ratio [OR]: 0.39, 95% Confidence interval [CI]: 0.22-0.70) and a faster BER from the TTP model (OR: 0.71, 95% CI: 0.55-0.94). Higher %LB+AFB counts on day 21-28 were recorded in patients who suffered unfavourable final outcomes compared to those who achieved stable cure (p=0.008).
CONCLUSIONS:
Modelling BERs predicts final outcome and high %LB+AFB counts 3-4 weeks into therapy may identify a persister bacterial phenotype. These methods deserve further evaluation as surrogate endpoints for clinical trials.
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