Time to Culture Conversion and Regimen Composition in Multidrug-Resistant Tuberculosis Treatment

Sputum cultures are an important tool in monitoring the response to tuberculosis treatment, especially in multidrug-resistant tuberculosis. There has, however, been little study of the effect of treatment regimen composition on culture conversion. Well-designed clinical trials of new anti-tuberculosis drugs require this information to establish optimized background regimens for comparison. We conducted a retrospective cohort study to assess whether the use of an aggressive multidrug-resistant tuberculosis regimen was associated with more rapid sputum culture conversion. We conducted Cox proportional-hazards analyses to examine the relationship between receipt of an aggressive regimen for the 14 prior consecutive days and sputum culture conversion. Sputum culture conversion was achieved in 519 (87.7%) of the 592 patients studied. Among patients who had sputum culture conversion, the median time to conversion was 59 days (IQR: 31–92). In 480 patients (92.5% of those with conversion), conversion occurred within the first six months of treatment. Exposure to an aggressive regimen was independently associated with sputum culture conversion during the first six months of treatment (HR: 1.36; 95% CI: 1.10, 1.69). Infection with human immunodeficiency virus (HR 3.36; 95% CI: 1.47, 7.72) and receiving less exposure to tuberculosis treatment prior to the individualized multidrug-resistant tuberculosis regimen (HR: 1.58; 95% CI: 1.28, 1.95) were also independently positively associated with conversion. Tachycardia (HR: 0.77; 95% CI: 0.61, 0.98) and respiratory difficulty (HR: 0.78; 95% CI: 0.62, 0.97) were independently associated with a lower rate of conversion. This study is the first demonstrating that the composition of the multidrug-resistant tuberculosis treatment regimen influences the time to culture conversion. These results support the use of an aggressive regimen as the optimized background regimen in trials of new anti-TB drugs

Rates of sputum culture conversion in patients receiving individualized MDR-TB regimens, by treatment semester.

<p>Rates of sputum culture conversion in patients receiving individualized MDR-TB regimens, by treatment semester.</p

Aggressive regimens are associated with unadjusted rates of culture conversion in the first six months of treatment.

<p>Aggressive regimens are associated with unadjusted rates of culture conversion in the first six months of treatment.</p

Illustration of daily exposure status defined by receipt of an aggressive regimen in the 14 days prior (example of three patients assessed at day 44 of treatment).

<p>Illustration of daily exposure status defined by receipt of an aggressive regimen in the 14 days prior (example of three patients assessed at day 44 of treatment).</p

Multivariable proportional-hazards analysis of aggressive regimen and sputum culture conversion.

<p>Multivariable proportional-hazards analysis of aggressive regimen and sputum culture conversion.</p

Distribution of covariates at initiation of the individualized MDR-TB regimen.

<p>*Patients enrolled prior to March 1, 2001 were more likely to have received the standard Category II retreatment regimen after failure of Category I than patients enrolled after this date, when national policy changed.</p>‡<p><18.5 in women, <20 in men; or malnutrition established clinically.</p>€<p>≤30% in women, ≤36% in men; when missing, also used hemoglobin ≤10 in women and ≤12 in men.</p>¥<p>Dyspnea; resting heart rate >26/minute.</p>£<p>Isolate resistant to at least isoniazid, rifampin, fluoroquinolone, and injectable (kanamycin, capreomycin or amikacin).</p>§<p>This includes the following comorbidities: cardiovascular disease (12), diabetes (15), hepatitis or cirrhosis (7), epilepsy/seizures (10), renal insufficiency (6), psychiatric disorder (101), ever smoked (59), ever used/abused alcohol or other substance (49).</p><p>Distribution of covariates at initiation of the individualized MDR-TB regimen.</p