RESUMEN
Namibia is among 30 countries with a high burden of tuberculosis (TB), with an estimated incidence of 460 per 100,000 population and around 800 new multidrug-resistant (MDR) TB cases per year. Still, data on the transmission and evolution of drug-resistant Mycobacterium tuberculosis complex (Mtbc) strains are not available. Whole-genome sequencing data of 136 rifampicin-resistant (RIFr) Mtbc strains obtained from 2016 to 2018 were used for phylogenetic classification, resistance prediction, and cluster analysis and linked with phenotypic drug susceptibility testing (pDST) data. Roughly 50% of the strains investigated were resistant to all first-line drugs. Furthermore, 13% of the MDR Mtbc strains were already pre-extensively drug resistant (pre-XDR). The cluster rates were high, at 74.6% among MDR and 85% among pre-XDR strains. A significant proportion of strains had borderline resistance-conferring mutations, e.g., inhA promoter mutations or rpoB L430P. Accordingly, 25% of the RIFr strains tested susceptible by pDST. Finally, we determined a potentially new bedaquiline resistance mutation (Rv0678 D88G) occurring in two independent clusters. High rates of resistance to first-line drugs in line with emerging pre-XDR and likely bedaquiline resistance linked with the ongoing recent transmission of MDR Mtbc clones underline the urgent need for the implementation of interventions that allow rapid diagnostics to break MDR TB transmission chains in the country. A borderline RIFr mutation in the dominant outbreak strain causing discrepancies between phenotypic and genotypic resistance testing results may require breakpoint adjustments but also may allow individualized regimens with high-dose treatment. IMPORTANCE The transmission of drug-resistant tuberculosis (TB) is a major problem for global TB control. Using genome sequencing, we showed that 13% of the multidrug-resistant (MDR) M. tuberculosis complex strains from Namibia are already pre-extensively drug resistant (pre-XDR), which is substantial in an African setting. Our data also indicate that the ongoing transmission of MDR and pre-XDR strains contributes significantly to the problem. In contrast to other settings with higher rates of drug resistance, we found a high proportion of strains having so-called borderline low-level resistance mutations, e.g., inhA promoter mutations or rpoB L430P. This led to the misclassification of 25% of the rifampicin-resistant strains as susceptible by phenotypic drug susceptibility testing. This observation potentially allows individualized regimens with high-dose treatment as a potential option for patients with few treatment options. We also found a potentially new bedaquiline resistance mutation in rv0678.
Asunto(s)
Mycobacterium tuberculosis , Tuberculosis Resistente a Múltiples Medicamentos , Humanos , Antituberculosos/farmacología , Antituberculosos/uso terapéutico , Pruebas de Sensibilidad Microbiana , Rifampin/uso terapéutico , Filogenia , Namibia/epidemiología , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Mutación , Farmacorresistencia Bacteriana Múltiple/genéticaRESUMEN
SETTING: Namibia ranks among the 30 high TB burden countries worldwide. Here, we report results of the second nationwide anti-TB drug resistance survey.OBJECTIVE: To assess the prevalence and trends of multidrug-resistant TB (MDR-TB) in Namibia.METHODS: From 2014 to 2015, patients with presumptive TB in all regions of Namibia had sputum subjected to mycobacterial culture and phenotypic drug susceptibility testing (DST) for rifampicin, isoniazid, ethambutol and streptomycin if positive on smear microscopy and/or Xpert MTB/RIF.RESULTS: Of the 4124 eligible for culture, 3279 (79.5%) had Mycobacterium tuberculosis isolated. 3126 (95%) had a first-line DST completed (2392 new patients, 699 previously treated patients, 35 with unknown treatment history). MDR-TB was detected in 4.5% (95%CI 3.7-5.4) of new patients, and 7.9% (95%CI 6.0-10.1) of individuals treated previously. MDR-TB was significantly associated with previous treatment (OR 1.8, 95%CI 1.3-2.5) but not with HIV infection, sex, age or other demographic factors. Prior treatment failure demonstrated the strongest association with MDR-TB (OR 17.6, 95%CI 5.3-58.7).CONCLUSION: The prevalence of MDR-TB among new TB patients in Namibia is high and, compared with the first drug resistance survey, has decreased significantly among those treated previously. Namibia should implement routine screening of drug resistance among all TB patients.
Asunto(s)
Antibióticos Antituberculosos/uso terapéutico , Tuberculosis Resistente a Múltiples Medicamentos/epidemiología , Tuberculosis Pulmonar/epidemiología , Adolescente , Adulto , Anciano , Antibióticos Antituberculosos/farmacología , Niño , Preescolar , Comorbilidad , Femenino , Infecciones por VIH , Humanos , Lactante , Recién Nacido , Masculino , Tamizaje Masivo , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/aislamiento & purificación , Namibia/epidemiología , Prevalencia , Encuestas y Cuestionarios , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/microbiología , Tuberculosis Resistente a Múltiples Medicamentos/prevención & control , Tuberculosis Pulmonar/tratamiento farmacológico , Tuberculosis Pulmonar/microbiología , Tuberculosis Pulmonar/prevención & control , Adulto JovenRESUMEN
Asunto(s)
Antituberculosos/administración & dosificación , Servicios de Salud Comunitaria/métodos , Terapia por Observación Directa/métodos , Tuberculosis/tratamiento farmacológico , Humanos , Namibia , Resultado del TratamientoRESUMEN
SETTING: To compare renal insufficiency among multidrug-resistant tuberculosis (MDR-TB) patients treated with kanamycin (KM) based regimens and those treated concomitantly with tenofovir disoproxil fumarate (TDF) or other antiretroviral therapy (ART) regimens in Namibia. DESIGN: Retrospective review of the treatment records and laboratory tests of patients initiated on MDR-TB treatment (January-December 2014). The glomerular filtration rates (eGFR) estimated pre- and post-treatment were compared using the analysis of variance test. Renal insufficiency was defined as an eGFR of <60 ml/min/1.73 m2. Use of KM or TDF and association with renal insufficiency was assessed using Kaplan-Meier plots and Cox proportional hazards analysis. RESULTS: The baseline mean eGFR for the three groups was similar (P = 0.24): 139.3 ± 25.6 ml/min for the KM group (n = 68), 131.1 ± 25.7 ml/min for the KM+TDF group (n = 44) and 134.2±34.4 ml/min for the KM+Other group (n = 23). After 8 months, the values had declined significantly to respectively 104.8 ± 37.5 ml/min (P < 0.001), 101.5 ± 38.3 ml/min (P < 0.001) and 111.5 ± 41.7 ml/min (P = 0.01). Co-treatment with KM+ART was associated with an increased risk of renal insufficiency (hazard ratio [HR] 1.8, 95%CI 0.7-4.1, P = 0.20 for KM+TDF, and HR 3.5, 95%CI 1.4-8.2, P = 0.005 for KM+Other ART). CONCLUSION: Renal function declined at a similar rate in MDR-TB patients treated with KM-based regimens compared with patients treated concomitantly with TDF-based or other ART. The risk of renal insufficiency was greater for patients on ART.