Sputum Pharmacokinetics of TB Drugs and Bacterial Drug Resistance

This study will support two avenues of research, pharmacokinetics (PK) of drugs used to treat
tuberculosis and resistance to those drugs that has been developed by the pathogen. Given the
high inter-individual variability in TB drug exposure, therapeutic drug monitoring would be
of value to adjust the drug dose in TB patients in order to improve clinical outcome and
minimize toxicity. It is not practiced in most settings for reasons associated with costs but
also because blood collection is an invasive procedure. Sputum on the other hand is often
produced spontaneously and discarded as waste. Drug levels can be measured in sputum just as
in plasma. Here we will test the hypothesis that sputum drug levels are predictive of drug
concentrations in plasma and/or in specific lesion compartments such as the caseum of open
cavities. We will also characterize the exposure of standard 1st and 2nd line TB drugs at one
of the sites of infection, since sputum is in direct contact with cavity caseum. The subjects
will contribute three or more sputum samples spontaneously produced over at least two days
and four blood samples following drug administration on two different days (8 blood samples
total). The data will be analyzed using population PK modeling approaches to generate
concentration-time profiles and 24-hour area under the curve (AUC) of each study drug in
sputum. Correlations between these values, plasma and lesion AUCs will be examined. We will
draw from a recently completed TB lesion pharmacokinetic study (www.ClinicalTrials.gov
#NCT00816426) to seek correlations between drug exposure in sputum and in pulmonary lesions.
In addition to drug concentrations, sputum will be cultured by standard methods to isolate
Mycobacterium tuberculosis (Mtb), determine the drug resistance profile, and be saved for
testing a second generation of the Xpert TB XDR assay.

- INCLUSION CRITERIA:

1. At least 18 years of age

2. Diagnosis of TB (and/or NTM for NIH clinical center subjects)

3. Ongoing signs and/or symptoms of pulmonary TB (and/or NTM at the NIH CC)

4. Suspected drug resistance (drug susceptible allowed at the NIH CC)

5. Available to provide at least 3 sputa over 2 or more days

6. Taking anti-tuberculosis medicines (or NTM meds at NIH CC) during the time sputa
are provided

7. Thought likely to be Mycobacterium culture positive (including NTM infected for
the NIH CC) by enrolling physician

8. GeneXpert MTB/RIF sputum TBpositive (China subjects only)

9. Likely able to produce sputum samples while on study

10. Willing to provide blood samples

11. Willing to have samples stored

EXCLUSION CRITERIA:

1. Acute liver or kidney disease

2. Conditions which compromise the subject s ability to take or absorb oral drugs