Risk Factors for Adverse Events in Household Contacts Prescribed Preventive Treatment for Drug-resistant Tuberculosis Exposure.

BACKGROUND: Completion of tuberculosis (TB) preventive treatment is important to optimize efficacy; treatment-related adverse events (AEs) sometimes result in discontinuation. This study describes the occurrence of AEs and their risk factors during a 6-month, 2-drug, fluoroquinolone-based preventive treatment for household contacts of patients with drug-resistant TB in Karachi, Pakistan. METHODS: The primary outcome was development of any clinical AE during preventive treatment. Adverse events were categorized using the AE grading tables of the National Institutes of Health. Time-to-event analysis with Kaplan-Meier curves and Cox proportional hazards models accounting for recurrence were used to analyze associated risk factors. RESULTS: Of the 172 household contacts on preventive treatment, 36 (21%) developed 64 AEs during 813 months of treatment. The incidence of AEs over 6 months of treatment was 7.9 per 100 person-months; 16 per 100 person-months with a fluoroquinolone and ethionamide, and 4.4 per 100 person-months with a fluoroquinolone and ethambutol. There were 53 (83%) grade 1 and 11 grade 2 AEs, with no grade 3 or 4 AEs. In multivariable analysis, the risk of AEs was higher in contacts prescribed ethionamide as compared to ethambutol adjusting for age, sex, and body mass index (adjusted hazard ratio, 2.1 [95% confidence interval {CI}, 1.2-3.6]). Overall, there was no notable difference in treatment completion among the contacts who experienced an AE and those who did not (crude odds ratio, 1.1 [95% CI, .52-2.5]). CONCLUSIONS: A fluoroquinolone-based preventive treatment regimen for drug-resistant TB exposure is well tolerated. Regimens with ethionamide are more likely to result in AEs.

Tuberculosis Preventive Therapy for Individuals Exposed to Drug-resistant Tuberculosis: Feasibility and Safety of a Community-based Delivery of Fluoroquinolone-containing Preventive Regimen.

BACKGROUND: Observational studies have demonstrated the effectiveness of a fluoroquinolone-based regimen to treat individuals presumed to be infected with drug-resistant tuberculosis (DR-TB). We sought to assess the feasibility of this approach in an urban setting in South Asia. METHODS: From February 2016 until March 2017, all household contacts of DR-TB patients enrolled at the Indus Hospital were screened for TB symptoms at home. Children aged 0-17 years, symptomatic adults, and those with an immunocompromising condition (human immunodeficiency virus, diabetes, or malnutrition) were evaluated for TB disease. Contacts diagnosed with TB disease were started on treatment. Contacts without TB disease aged <5 years, contacts aged between 5 and 17 years with either a positive tuberculin skin test or an immunocompromising condition, or contacts aged ≥18 years with an immunocompromising condition were offered 6 months of treatment with a fluoroquinolone. RESULTS: One hundred households with 800 contacts were enrolled: 353 (44.1%) individuals aged ≤17 years with a median age of 19 years (interquartile range, 10-32); 423 (52.9%) were males. In total, 737 (92.1%) individuals were screened, of which 8 were already on treatment for TB (1.1%); another 3 (0.4%) contacts were diagnosed with TB disease and started on treatment. Of 215 eligible for infection treatment, 172 (80.0%) contacts initiated and 121 (70.3%) completed treatment. No TB disease or significant adverse events were observed during 12 months of follow-up. CONCLUSIONS: Fluoroquinolone-based treatment for contacts with presumed DR-TB infection is feasible and well tolerated in a high TB burden setting.

Pharmacokinetics of Levofloxacin in Children Treated for Exposure to Drug-Resistant Tuberculosis.

Levofloxacin is used to treat and prevent drug-resistant tuberculosis in children. We assessed levofloxacin serum drug concentrations in 24 children aged 2 to 10 years who received levofloxacin-based tuberculosis preventive therapy in Karachi, Pakistan. Only 9 children (37.5%) achieved adequate drug exposure. Target serum drug concentration was met in 4 (26.7%) of 15 children dosed consistently with World Health Organization recommendations and 4 (80.0%) of 5 who received higher-than-recommended doses. Levofloxacin dosing recommendations may require reevaluation.

Evaluation of GenoType MTBDRplus for the detection of drug-resistant Mycobacterium tuberculosis on isolates from Karachi, Pakistan.

OBJECTIVE: To compare the diagnostic performance of the GenoType MRBDRplus assay with the gold standard phenotypic drug susceptibility testing in the detection of drug resistance among culture isolates obtained from patients in Karachi, Pakistan. DESIGN: Mycobacterium tuberculosis isolates were obtained from 96 consecutive tuberculosis patients found to have resistance to isoniazid from two health centers in Karachi (January-November 2017). Isolates were tested for drug resistance against rifampin and isoniazid using the MTBDRplus assay. Results were compared with conventional drug-susceptibility testing and the frequency of specific mutations were reported. RESULTS: The MTBDRplus assay had a sensitivity for rifampin resistance of 98.8% (95% CI: 93.4-100) and for isoniazid resistance of 90.6% (95% CI: 83.0-95.6). The MTBDRplus assay showed mutations in rpoB in 81 of the 96 (84.4%) isolates. Of the 87 isolates showing resistance to isoniazid via the MTBDRplus assay, 71 (74.0%) isolates had mutations in the katG gene only, 15 (15.6%) isolates had mutations in the inhA promoter region, and 1 (1.0%) showed mutations in both genes. CONCLUSION: The GenoType MTBDRplus assay in Pakistan can identify subgroups at high-risk of having isolates with mutations in the katG and/or inhA genes. Understanding the local burden of these mutations have implications for local diagnostic and treatment guidelines.