Multidrug-resistant tuberculosis treatment failure detection depends on monitoring interval and microbiological method.

Debate persists about monitoring method (culture or smear) and interval (monthly or less frequently) during treatment for multidrug-resistant tuberculosis (MDR-TB). We analysed existing data and estimated the effect of monitoring strategies on timing of failure detection.We identified studies reporting microbiological response to MDR-TB treatment and solicited individual patient data from authors. Frailty survival models were used to estimate pooled relative risk of failure detection in the last 12 months of treatment; hazard of failure using monthly culture was the reference.Data were obtained for 5410 patients across 12 observational studies. During the last 12 months of treatment, failure detection occurred in a median of 3 months by monthly culture; failure detection was delayed by 2, 7, and 9 months relying on bimonthly culture, monthly smear and bimonthly smear, respectively. Risk (95% CI) of failure detection delay resulting from monthly smear relative to culture is 0.38 (0.34-0.42) for all patients and 0.33 (0.25-0.42) for HIV-co-infected patients.Failure detection is delayed by reducing the sensitivity and frequency of the monitoring method. Monthly monitoring of sputum cultures from patients receiving MDR-TB treatment is recommended. Expanded laboratory capacity is needed for high-quality culture, and for smear microscopy and rapid molecular tests.

Aggressive Regimens Reduce Risk of Recurrence After Successful Treatment of MDR-TB.

BACKGROUND: We sought to determine whether treatment with a "long aggressive regimen" was associated with lower rates of relapse among patients successfully treated for pulmonary multidrug-resistant tuberculosis (MDR-TB) in Tomsk, Russia. METHODS: We conducted a retrospective cohort study of adult patients that initiated MDR-TB treatment with individualized regimens between September 2000 and November 2004, and were successfully treated. Patients were classified as having received "aggressive regimens" if their intensive phase consisted of at least 5 likely effective drugs (including a second-line injectable and a fluoroquinolone) used for at least 6 months post culture conversion, and their continuation phase included at least 4 likely effective drugs. Patients that were treated with aggressive regimens for a minimum duration of 18 months post culture conversion were classified as having received "long aggressive regimens." We used recurrence as a proxy for relapse because genotyping was not performed. After treatment, patients were classified as having disease recurrence if cultures grew MDR-TB or they re-initiated MDR-TB therapy. Data were analyzed using Cox proportional hazard regression. RESULTS: Of 408 successfully treated patients, 399 (97.5%) with at least 1 follow-up visit were included. Median duration of follow-up was 42.4 months (interquartile range: 20.5-59.5), and there were 27 recurrence episodes. In a multivariable complete case analysis (n = 371 [92.9%]) adjusting for potential confounders, long aggressive regimens were associated with a lower rate of recurrence (adjusted hazard ratio: 0.22, 95% confidence interval, .05-.92). CONCLUSIONS: Long aggressive regimens for MDR-TB treatment are associated with lower risk of disease recurrence.

Improving outcomes for multidrug-resistant tuberculosis: aggressive regimens prevent treatment failure and death.

BACKGROUND: Evidence is sparse regarding the optimal construction of regimens to treat multidrug-resistant (MDR) tuberculosis disease due to strains of Mycobacterium tuberculosis resistant to at least both isoniazid and rifampin. Given the low potency of many second-line antituberculous drugs, we hypothesized that an aggressive regimen of at least 5 likely effective drugs during the intensive phase, including a fluoroquinolone and a parenteral agent, would be associated with a reduced risk of death or treatment failure. METHODS: We conducted a retrospective cohort study of patients initiating MDR tuberculosis treatment between 2000 and 2004 in Tomsk, Russian Federation. We used a multivariate Cox proportional hazards model to assess whether monthly exposure to an aggressive regimen was associated with the risk of death or treatment failure. RESULTS: Six hundred fourteen individuals with confirmed MDR tuberculosis were eligible for analysis. On multivariable analysis that adjusted for extensively drug-resistant (XDR) tuberculosis-MDR tuberculosis isolates resistant to fluoroquinolones and parenteral agents-we found that monthly exposure to an aggressive regimen was significantly associated with a lower risk of death or treatment failure (hazard ratio, 0.52 [95% confidence interval, .29-.94]; P = .030). CONCLUSIONS: Receipt of an aggressive treatment regimen was a robust predictor of decreased risk of death or failure during MDR tuberculosis treatment. These findings further support the use of this regimen definition as the benchmark for the standard of care of MDR tuberculosis patients and should be used as the basis for evaluating novel therapies.

Development of extensively drug-resistant tuberculosis during multidrug-resistant tuberculosis treatment.

RATIONALE: Extensively drug-resistant (XDR) tuberculosis (TB) may arise in individuals on treatment for multidrug-resistant (MDR) TB. Preventing this amplification of resistance will likely improve clinical outcomes and delay the secondary spread of XDR-TB. OBJECTIVES: To measure the proportion of individuals that develops XDR-TB during the course of MDR-TB treatment, and to identify those factors associated with the development of XDR. METHODS: We performed a retrospective analysis of 608 consecutive patients with documented MDR-TB who were started on MDR-TB treatment between September 10, 2000 and November 1, 2004 in the Tomsk Oblast TB Treatment Services in Western Siberia, Russian Federation. MEASUREMENTS AND MAIN RESULTS: A total of 6% of patients were observed to develop XDR-TB while on MDR-TB treatment. These patients were significantly less likely to be cured or to complete treatment. Using Cox proportional hazard models, we found that the presence of bilateral and cavitary lesions was associated with a greater than threefold increase in hazard (adjusted hazard ratio [HR], 3.47; 95% confidence interval [CI], 1.32-9.14). Prior exposure to a second-line injectable antibiotic was associated with a greater than threefold increase in hazard (adjusted HR, 3.65; 95% CI, 1.81-7.37), and each additional month in which a patient failed to take at least 80% of their prescribed drugs was associated with nearly an additional 20% hazard of developing XDR-TB (adjusted HR, 1.17; 95% CI, 1.01-1.35). CONCLUSIONS: Early and rapid diagnosis, timely initiation of appropriate therapy, and programmatic efforts to optimize treatment adherence during MDR-TB therapy are crucial to avoiding the generation of excess XDR-TB in MDR-TB treatment programs.

Treatment of extensively drug-resistant tuberculosis in Tomsk, Russia: a retrospective cohort study.

BACKGROUND: Mycobacterium tuberculosis strains that cause untreatable drug-resistant disease are a threat worldwide. We describe the treatment, management, and outcomes of patients with extensively drug-resistant tuberculosis in Tomsk, Russia. METHODS: We undertook a retrospective cohort study of 608 patients with multidrug resistant tuberculosis who had treatment in civilian or prison services, between Sept 10, 2000, and Nov 1, 2004, according to the treatment strategy recommended by WHO. Clinical characteristics, management practices, and treatment outcomes of patients with extensively drug-resistant (XDR) tuberculosis and non-extensively drug-resistant (non-XDR) tuberculosis are described. The main outcome was the frequency of poor and favourable outcomes at the end of treatment. FINDINGS: Of 608 patients with multidrug resistant tuberculosis, 29 (4.8%) patients had baseline XDR tuberculosis. Treatment failure was more common in patients with XDR tuberculosis than in those with non-XDR tuberculosis (31%vs 8.5%, p=0.0008). 48.3% of patients with XDR tuberculosis and 66.7% of patients with non-XDR tuberculosis had treatment cure or completion (p=0.04). The frequency and management of adverse events did not differ between patients with XDR and non-XDR tuberculosis. INTERPRETATION: The chronic features of tuberculosis in these patients suggest that extensively drug-resistant tuberculosis may be acquired through previous treatments that include second-line drugs. Aggressive management of this infectious disease is feasible and can prevent high mortality rates and further transmission of drug-resistant strains of Mycobacterium tuberculosis.