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

Aggressive Regimens for Multidrug-Resistant Tuberculosis Decrease All-Cause Mortality

Rationale: A better understanding of the composition of optimal treatment regimens for multidrug-resistant tuberculosis (MDR-TB) is essential for expanding universal access to effective treatment and for developing new therapies for MDR-TB. Analysis of observational data may inform the definition of an optimized regimen. Objectives: This study assessed the impact of an aggressive regimen–one containing at least five likely effective drugs, including a fluoroquinolone and injectable–on treatment outcomes in a large MDR-TB patient cohort. Methods: This was a retrospective cohort study of patients treated in a national outpatient program in Peru between 1999 and 2002. We examined the association between receiving an aggressive regimen and the rate of death. Measurements and Main Results: In total, 669 patients were treated with individualized regimens for laboratory-confirmed MDR-TB. Isolates were resistant to a mean of 5.4 (SD 1.7) drugs. Cure or completion was achieved in 66.1% (442) of patients; death occurred in 20.8% (139). Patients who received an aggressive regimen were less likely to die (crude hazard ratio [HR]: 0.62; 95% CI: 0.44,0.89), compared to those who did not receive such a regimen. This association held in analyses adjusted for comorbidities and indicators of severity (adjusted HR: 0.63; 95% CI: 0.43,0.93). Conclusions: The aggressive regimen is a robust predictor of MDR-TB treatment outcome. TB policy makers and program directors should consider this standard as they design and implement regimens for patients with drug-resistant disease. Furthermore, the aggressive regimen should be considered the standard background regimen when designing randomized trials of treatment for drug-resistant TB

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

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

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

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

Comprehensive treatment of extensively drug-resistant tuberculosis

BACKGROUND: Extensively drug-resistant tuberculosis has been reported in 45 countries, including countries with limited resources and a high burden of tuberculosis. We describe the management of extensively drug-resistant tuberculosis and treatment outcomes among patients who were referred for individualized outpatient therapy in Peru. METHODS: A total of 810 patients were referred for free individualized therapy, including drug treatment, resective surgery, adverse-event management, and nutritional and psychosocial support. We tested isolates from 651 patients for extensively drug-resistant tuberculosis and developed regimens that included five or more drugs to which the infecting isolate was not resistant. RESULTS: Of the 651 patients tested, 48 (7.4%) had extensively drug-resistant tuberculosis; the remaining 603 patients had multidrug-resistant tuberculosis. The patients with extensively drug-resistant tuberculosis had undergone more treatment than the other patients (mean [+/-SD] number of regimens, 4.2+/-1.9 vs. 3.2+/-1.6; P\u3c0.001) and had isolates that were resistant to more drugs (number of drugs, 8.4+/-1.1 vs. 5.3+/-1.5; P\u3c0.001). None of the patients with extensively drug-resistant tuberculosis were coinfected with the human immunodeficiency virus (HIV). Patients with extensively drug-resistant tuberculosis received daily, supervised therapy with an average of 5.3+/-1.3 drugs, including cycloserine, an injectable drug, and a fluoroquinolone. Twenty-nine of these patients (60.4%) completed treatment or were cured, as compared with 400 patients (66.3%) with multidrug-resistant tuberculosis (P=0.36). CONCLUSIONS: Extensively drug-resistant tuberculosis can be cured in HIV-negative patients through outpatient treatment, even in those who have received multiple prior courses of therapy for tuberculosis