Rifampicin-susceptible Tuberculosis Research Articles

Surveillance of fluoroquinolones resistance in rifampicin-susceptible tuberculosis in eastern China with whole-genome sequencing-based approach.

Leveraging well-established DNA-level drug resistance mechanisms, whole-genome sequencing (WGS) has emerged as a valuable methodology for predicting drug resistance. As the most effective second-line anti-tuberculosis (anti-TB) drugs, fluoroquinoloness (FQs) are generally used to treat multidrug-resistant tuberculosis (MDR-TB, defined as being resistant to resistant to rifampicin and isoniazid) or rifampicin-resistant tuberculosis (RR-TB). However, FQs are also commonly used in the management of other bacterial infections. There are few published data on the rates of FQs resistance among rifampicin-susceptible TB. The prevalence of FQs resistance among TB patients who are rifampicin-susceptible has not been studied in Zhejiang Province, China. The goal of this study was to provide a baseline characterization of the prevalence of FQs resistance, particularly among rifampicin-susceptible TB in Zhejiang Province, China. Based on WGS, we have investigated the prevalence of FQs resistance among rifampicin-susceptible TB in Zhejiang Province. All pulmonary TB patients with positive cultures who were identified in Zhejiang area during TB drug resistance surveillance from 2018 to 2019 have enrolled in this population-based retrospective study. The rate of FQs resistance was 4.6% (32/698) among TB, 4.0% (27/676) among rifampicin-susceptible TB, and 22.7% (5/22) among RR-TB. According to WGS, strains that differ within 12 single-nucleotide polymorphisms (SNPs) were considered to be transmission of FQ-resistant strains. Specifically, 3.7% (1/27) of FQs resistance was caused by the transmission of FQs-resistant strains among the rifampicin-susceptible TB and 40.7% (11/27) of FQs resistance was identified as hetero-resistance. The prevalence of FQs resistance among TB patients who were rifampicin-susceptible was severe in Zhejiang. The emergence of FQs resistance in TB isolates that are rifampicin-susceptible was mainly caused by the selection of drug-resistant strains. In order to prevent the emergence of FQs resistance, the WGS-based surveillance system for TB should be urgently established, and clinical awareness of the responsible use of FQs for respiratory infections should be enhanced.

Risk factors of adult isoniazid-resistant and rifampicin-susceptible tuberculosis in Nanjing, 2019–2021

IntroductionThis study aimed to analyze the risk factors associated with isoniazid-resistant and rifampicin-susceptible tuberculosis (Hr-TB) in adults.MethodThe clinical data of 1,844 adult inpatients diagnosed with culture-positive pulmonary tuberculosis (PTB) in Nanjing Second Hospital from January 2019 and December 2021 were collected. All culture positive strain from the patient specimens underwent drug susceptibility testing (DST). Among them, 166 patients with Hr-TB were categorized as the Hr-TB group, while the remaining 1,678 patients were classified as having drug-susceptible tuberculosis (DS-TB). Hierarchical logistic regression was employed for multivariate analysis to identify variables associated with Hr-TB. Results: Multivariate logistic regression analysis revealed that individuals with diabetes mellitus (DM) (OR 1.472, 95% CI 1.037–2.088, p = 0.030) and a history of previous tuberculosis treatment (OR 2.913, 95% CI 1.971–4.306, p = 0.000) were at higher risk of developing adult Hr-TB, with this risk being more pronounced in male patients. Within the cohort, 1,640 patients were newly treated, and among them, DM (OR 1.662, 95% CI 1.123–2.461, p = 0.011) was identified as risk factors for Hr-TB. Conclusions: Diabetes mellitus is a risk factor for Hr-TB in adults, and the contribution of diabetes as a risk factor was more pronounced in the newly treatment or male subgroup. And previous TB treatment history is also a risk factor for Hr-TB in adults.

Rapid decrease in IL-1Ra and IP-10 plasma levels following tuberculosis treatment initiation

ObjectivesMonitoring tools that could provide quick predictions of tuberculosis (TB) treatment outcomes are urgently needed. Here, we assessed whether the evolution of selected biomarkers of innate immunity may help monitoring TB treatment response within 2 weeks of treatment initiation. MethodsANRS12394-LILAC-TB was a proof-of-concept prospective study: adults with a rifampicin-susceptible TB who are HIV-negative and HIV-infected documented by a positive Xpert MTB/RIF test were enrolled in Cambodia and Côte d'Ivoire. Plasma concentrations of interleukin-1 receptor antagonist (IL-1Ra), interferon-γ–induced protein-10 and clusters of differentiation (CD) (scavenging CD163) were measured by commercial enzyme-linked immunosorbent assay kits. A Wilcoxon test for paired data was used for longitudinal comparisons. ResultsA total of 55 patients were enrolled (women: 31%, median age: 37 years; median CD4 count in the 10 of 13 participants with HIV: 53 cells/mm3). Overall, 83% were considered in TB treatment success. Compared with baseline, the IL-1Ra plasma levels significantly decreased as soon as week (W) 1, independent of HIV status (−71% in HIV-positive vs −33% in HIV-negative; P <0.001). The IP-10 plasma levels significantly decreased at W1 and W2 compared with baseline (P <0.0001); however, that decrease was less marked in participants with HIV. ConclusionsOur findings suggest that measuring IL-1Ra plasma levels with a standard enzyme-linked immunosorbent assay technique at baseline and then 1 week after TB treatment onset could help clinicians to quickly assess TB treatment response.

Incidence, Outcomes, and Risk Factors for Isoniazid-Resistant Tuberculosis from 2012 to 2022 in Eastern China.

Isoniazid-resistant, rifampicin-susceptible tuberculosis (Hr-TB) is the most frequent drug-resistant tuberculosis (DR-TB) in the world, and unfavorable outcomes of Hr-TB are more common compared to drug-susceptible TB. Considering there is no optimal regimen accepted worldwide, we undertook a retrospective cohort study in eastern China to estimate incidence trends and risk factors associated with unfavorable outcomes of Hr-TB. Between January 2012 and December 2022, all Hr-TB patients' information was extracted from the Tuberculosis Information Management System (TIMS), which is a national electronic information platform, to record TB patients' clinical information in this study. The incidence of Hr-TB was determined by the mid-year population according to census data published by the government. We categorized treatment regimens depending on fluoroquinolone (FQ) use, and potential risk factors were analyzed using multivariable logistic regression. A total of 3116 Hr-TB patients fulfilled the inclusion criteria and were enrolled in this study. The average annual rate of Hr-TB in the 11 years under investigation was 0.34 per 100,000 and increased to 0.53 per 100,000 until 2019. In total, six different treatment regimens were utilized in the study sites, and less than 1% of regimens adopted FQ. There was no difference in the unfavorable outcomes between the FQ-included and FQ-excluded groups (p = 0.22). The average treatment duration was 7.06 months, and the longest treatment was 26 months. Approximately 20% (637/3116) of Hr-TB patients had unfavorable outcomes, and 60.13% (383/637) of them proceeded to multidrug-resistant tuberculosis (MDR-TB). Treatment duration and a positive smear at the end of the 5th month were significantly associated with unfavorable outcomes (p < 0.001). The unfavorable treatment outcomes of Hr-TB are still high in eastern China, and the efficacy of FQ-containing regimens needs to be validated for Hr-TB treatment.

Multidrug-resistant tuberculosis.

Tuberculosis (TB) remains the foremost cause of death by an infectious disease globally. Multidrug-resistant or rifampicin-resistant TB (MDR/RR-TB; resistance to rifampicin and isoniazid, or rifampicin alone) is a burgeoning public health challenge in several parts of the world, and especially Eastern Europe, Russia, Asia and sub-Saharan Africa. Pre-extensively drug-resistant TB (pre-XDR-TB) refers to MDR/RR-TB that is also resistant to a fluoroquinolone, and extensively drug-resistant TB (XDR-TB) isolates are additionally resistant to other key drugs such as bedaquiline and/or linezolid. Collectively, these subgroups are referred to as drug-resistant TB (DR-TB). All forms of DR-TB can be as transmissible as rifampicin-susceptible TB; however, it is more difficult to diagnose, is associated with higher mortality and morbidity, and higher rates of post-TB lung damage. The various forms of DR-TB often consume >50% of national TB budgets despite comprising <5-10% of the total TB case-load. The past decade has seen a dramatic change in the DR-TB treatment landscape with the introduction of new diagnostics and therapeutic agents. However, there is limited guidance on understanding and managing various aspects of this complex entity, including the pathogenesis, transmission, diagnosis, management and prevention of MDR-TB and XDR-TB, especially at the primary care physician level.

Spatial pattern of isoniazid-resistant tuberculosis and its associated factors among a population with migrants in China: a retrospective population-based study.

Isoniazid-resistant, rifampicin-susceptible tuberculosis (Hr-TB) globally exhibits a high prevalence and serves as a potential precursor to multidrug-resistant tuberculosis (MDR-TB). Recognizing the spatial distribution of Hr-TB and identifying associated factors can provide strategic entry points for interventions aimed at early detection of Hr-TB and prevention of its progression to MDR-TB. This study aims to analyze spatial patterns and identify socioeconomic, demographic, and healthcare factors associated with Hr-TB in Shanghai at the county level. We conducted a retrospective study utilizing data from TB patients with available Drug Susceptible Test (DST) results in Shanghai from 2010 to 2016. Spatial autocorrelation was explored using Global Moran's I and Getis-Ord statistics. A Bayesian hierarchical model with spatial effects was developed using the INLA package in R software to identify potential factors associated with Hr-TB at the county level. A total of 8,865 TB patients with DST were included in this analysis. Among 758 Hr-TB patients, 622 (82.06%) were new cases without any previous treatment history. The drug-resistant rate of Hr-TB among new TB cases in Shanghai stood at 7.20% (622/8014), while for previously treated cases, the rate was 15.98% (136/851). Hotspot areas of Hr-TB were predominantly situated in southwestern Shanghai. Factors positively associated with Hr-TB included the percentage of older adult individuals (RR = 3.93, 95% Crl:1.93-8.03), the percentage of internal migrants (RR = 1.35, 95% Crl:1.15-1.35), and the number of healthcare institutions per 100 population (RR = 1.17, 95% Crl:1.02-1.34). We observed a spatial heterogeneity of Hr-TB in Shanghai, with hotspots in the Songjiang and Minhang districts. Based on the results of the models, the internal migrant population and older adult individuals in Shanghai may be contributing factors to the emergence of areas with high Hr-TB notification rates. Given these insights, we advocate for targeted interventions, especially in identified high-risk hotspots and high-risk areas.

Identifying adolescents at risk for suboptimal adherence to tuberculosis treatment: A prospective cohort study.

Adolescents account for an estimated 800,000 incident tuberculosis (TB) cases annually and are at risk for suboptimal adherence to TB treatment. Most studies of adolescent TB treatment adherence have used surveillance data with limited psychosocial information. This prospective cohort study aimed to identify risk factors for suboptimal adherence to rifampicin-susceptible TB treatment among adolescents (10-19 years old) in Lima, Peru. We collected psychosocial data using self-administered surveys and clinical data via medical record abstraction. Applying k-means cluster analysis, we grouped participants by psychosocial characteristics hypothesized to impact adherence. Then, we conducted mixed effects regression to compare suboptimal adherence-defined as <90% (missing >10% of doses)-between clusters. Treatment setting (facility vs. home) and drug formulation (single drug vs. fixed dose combination) were interaction terms. Of 249 participants, 90 (36.1%) were female. Median age was 17 (IQR: 15, 16.6) years. We identified three clusters-A, B, and C-of participants based on psychosocial characteristics. Cluster C had the lowest support from caregivers, other family members, and friends; had the weakest motivation to complete TB treatment; were least likely to live with their mothers; and had experienced the most childhood adversity. Among the 118 (47.4%) participants who received facility-based treatment with single drug formulations, adherence did not differ between Clusters A and B, but Cluster C had six-fold odds of suboptimal adherence compared to Cluster A. In Clusters B and C, adherence worsened over time, but only in Cluster C did mean adherence fall below 90% within six months. Our findings have implications for the care of adolescents with TB. When caring for adolescents with low social support and other risk factors, clinicians should take extra measures to reinforce adherence, such as identifying a community health worker or peer to provide treatment support. Implementing newly recommended shorter regimens also may facilitate adherence.

A first-in-class leucyl-tRNA synthetase inhibitor, ganfeborole, for rifampicin-susceptible tuberculosis: a phase 2a open-label, randomized trial

New tuberculosis treatments are needed to address drug resistance, lengthy treatment duration and adverse reactions of available agents. GSK3036656 (ganfeborole) is a first-in-class benzoxaborole inhibiting the Mycobacterium tuberculosis leucyl-tRNA synthetase. Here, in this phase 2a, single-center, open-label, randomized trial, we assessed early bactericidal activity (primary objective) and safety and pharmacokinetics (secondary objectives) of ganfeborole in participants with untreated, rifampicin-susceptible pulmonary tuberculosis. Overall, 75 males were treated with ganfeborole (1/5/15/30 mg) or standard of care (Rifafour e-275 or generic alternative) once daily for 14 days. We observed numerical reductions in daily sputum-derived colony-forming units from baseline in participants receiving 5, 15 and 30 mg once daily but not those receiving 1 mg ganfeborole. Adverse event rates were comparable across groups; all events were grade 1 or 2. In a participant subset, post hoc exploratory computational analysis of 18F-fluorodeoxyglucose positron emission tomography/computed tomography findings showed measurable treatment responses across several lesion types in those receiving ganfeborole 30 mg at day 14. Analysis of whole-blood transcriptional treatment response to ganfeborole 30 mg at day 14 revealed a strong association with neutrophil-dominated transcriptional modules. The demonstrated bactericidal activity and acceptable safety profile suggest that ganfeborole is a potential candidate for combination treatment of pulmonary tuberculosis.ClinicalTrials.gov identifier: NCT03557281.

Global burden of disease due to rifampicin-resistant tuberculosis: a mathematical modeling analysis

In 2020, almost half a million individuals developed rifampicin-resistant tuberculosis (RR-TB). We estimated the global burden of RR-TB over the lifetime of affected individuals. We synthesized data on incidence, case detection, and treatment outcomes in 192 countries (99.99% of global tuberculosis). Using a mathematical model, we projected disability-adjusted life years (DALYs) over the lifetime for individuals developing tuberculosis in 2020 stratified by country, age, sex, HIV, and rifampicin resistance. Here we show that incident RR-TB in 2020 was responsible for an estimated 6.9 (95% uncertainty interval: 5.5, 8.5) million DALYs, 44% (31, 54) of which accrued among TB survivors. We estimated an average of 17 (14, 21) DALYs per person developing RR-TB, 34% (12, 56) greater than for rifampicin-susceptible tuberculosis. RR-TB burden per 100,000 was highest in former Soviet Union countries and southern African countries. While RR-TB causes substantial short-term morbidity and mortality, nearly half of the overall disease burden of RR-TB accrues among tuberculosis survivors. The substantial long-term health impacts among those surviving RR-TB disease suggest the need for improved post-treatment care and further justify increased health expenditures to prevent RR-TB transmission.

Rosuvastatin adjunctive therapy for rifampicin-susceptible pulmonary tuberculosis: a phase 2b, randomised, open-label, multicentre trial

Shorter treatments are needed for drug-susceptible tuberculosis. Adjunctive statins increase bactericidal activity in preclinical tuberculosis models. We investigated the safety and efficacy of adjunctive rosuvastatin in people with tuberculosis. We tested the hypothesis that adjunctive rosuvastatin accelerates sputum culture conversion within the first 8 weeks of treatment of rifampicin-susceptible tuberculosis. This phase 2b, randomised, open-label, multicentre trial conducted in five hospitals or clinics in three countries with high tuberculosis burden (ie, the Philippines, Viet Nam, and Uganda) enrolled adult participants aged 18-75 years with sputum smear or Xpert MTB/RIF positive, rifampicin-susceptible tuberculosis who had received less than 7 days of previous tuberculosis treatment. Participants were randomly assigned via a web-based system to receive either 10 mg rosuvastatin once per day for 8 weeks plus standard tuberculosis therapy (rifampicin, isoniazid, pyrazinamide, and ethambutol; rosuvastatin group) or standard tuberculosis therapy alone (control group). Randomisation was stratified by trial site, history of diabetes, and HIV co-infection. Laboratory staff and central investigators involved in data cleaning and analysis were masked to treatment allocation, but study participants and site investigators were not. Both groups continued standard treatment to week 24. Sputum samples were collected once per week for the first 8 weeks after randomisation, and then at weeks 10, 12, and 24. The primary efficacy outcome was time to culture conversion (TTCC; days) in liquid culture by week 8, assessed in randomised participants who had microbiological confirmation of tuberculosis, took at least one dose of rosuvastatin, and who did not show resistance to rifampicin (modified intention-to-treat population), for which groups were compared with the Cox proportional hazards model. The main safety outcome was grade 3-5 adverse events by week 24, assessed in the intention-to-treat population, for which groups were compared with Fisher's exact test. All participants completed 24 weeks of follow-up. This trial is registered with ClinicalTrials.gov (NCT04504851). Between Sept 2, 2020, and Jan 14, 2021, 174 participants were screened and 137 were randomly assigned to the rosuvastatin group (70 participants) or control group (67 participants). In the modified intention-to-treat population of 135 participants, 102 (76%) were men and 33 (24%) were women. Median TTCC in liquid media was 42 days (95% CI 35-49) in the rosuvastatin group (68 participants) and 42 days (36-53) in the control group (67 participants; hazard ratio 1·30 [0·88-1·91], p=0·19). Grade 3-5 adverse events occurred in six (9%) of 70 in the rosuvastatin group (none were considered related to rosuvastatin) and four (6%) of 67 in the control group (p=0·75). There were no serious adverse events that were considered to be related to rosuvastatin. Adjunctive rosuvastatin at 10 mg once per day was safe but did not produce substantive benefits on culture conversion in the overall study population. Future trials could explore the safety and efficacy of higher doses of adjunctive rosuvastatin. National Medical Research Council, Singapore.

Rifampicin resistance and mortality in patients hospitalised with HIV-associated tuberculosis.

BackgroundPatients with HIV and drug-resistant tuberculosis (TB) are at high risk of death.ObjectivesWe investigated the association between rifampicin-resistant TB (RR-TB) and mortality in a cohort of patients who were admitted to hospital at the time of TB diagnosis.MethodAdults hospitalised at Khayelitsha Hospital and diagnosed with HIV-associated TB during admission, were enrolled between 2013 and 2016. Clinical, biochemical and microbiological data were prospectively collected and participants were followed up for 12 weeks.ResultsParticipants with microbiologically confirmed TB (n = 482) were enrolled a median of two days (interquartile range [IQR]: 1–3 days) following admission. Fifty-three participants (11.0%) had RR-TB. Participants with rifampicin-susceptible TB (RS-TB) received appropriate treatment a median of one day (IQR: 1–2 days) following enrolment compared to three days (IQR: 1–9 days) in participants with RR-TB. Eight participants with RS-TB (1.9%) and six participants with RR-TB (11.3%) died prior to the initiation of appropriate treatment. Mortality at 12 weeks was 87/429 (20.3%) in the RS-TB group and 21/53 (39.6%) in the RR-TB group. RR-TB was a significant predictor of 12-week mortality (hazard ratio: 1.88; 95% confidence interval: 1.07–3.29; P = 0.03).ConclusionMortality at 12 weeks in participants with RR-TB was high compared to participants with RS-TB. Delays in the initiation of appropriate treatment and poorer regimen efficacy are proposed as contributors to higher mortality in hospitalised patients with HIV and RR-TB.

Whole-genome sequencing for surveillance of fluoroquinolone resistance in rifampicin-susceptible tuberculosis in a rural district of Shanghai: A 10-year retrospective study.

BackgroundFluoroquinolones (FQs) are the most important second-line anti-tuberculosis (anti-TB) drugs, primarily used for the treatment of multidrug- or rifampicin-resistant TB (MDR/RR-TB). However, FQs are also commonly used to treat other bacterial infections. There are few published data on the rates of FQ resistance among rifampicin-susceptible TB.MethodsWe used whole-genome sequencing (WGS) to determine the prevalence of FQ resistance among rifampicin-susceptible TB in a rural district of Shanghai. This was a population-based retrospective study of all culture-positive pulmonary TB patients diagnosed in the Chongming district of Shanghai, China during 2009–2018.ResultsThe rate of FQ resistance was 8.4% (29/345) among TB, 6.2% (20/324) among rifampicin-susceptible TB, and 42.9% (9/21) among MDR/RR-TB. Transmission of FQ-resistant strains was defined as strains differing within 12 single-nucleotide polymorphisms (SNPs) based on WGS. Among the rifampicin-susceptible TB, 20% (4/20) of FQ resistance was caused by the transmission of FQ-resistant strains and 45% (9/20) of FQ resistance was identified as hetero-resistance.ConclusionsThe prevalence of FQ resistance in rifampicin-susceptible TB was higher than expected in Shanghai. Both the transmission and the selection of drug-resistant strains drive the emergence of FQ resistance in rifampicin-susceptible TB isolates. Therefore, the WGS-based surveillance system for TB should be urgently established and the clinical awareness of the rational use of FQs for respiratory infections should be enhanced to prevent the premature occurrence of FQ resistance.

Clinical Relevance of Rifampicin-Moxifloxacin Interaction in Isoniazid-Resistant/Intolerant Tuberculosis Patients.

Moxifloxacin is an attractive drug for the treatment of isoniazid-resistant rifampicin-susceptible tuberculosis (TB) or drug-susceptible TB complicated by isoniazid intolerance. However, co-administration with rifampicin decreases moxifloxacin exposure. It remains unclear whether this drug-drug interaction has clinical implications. This retrospective study in a Dutch TB center investigated how rifampicin affected moxifloxacin exposure in patients with isoniazid-resistant or -intolerant TB. Moxifloxacin exposures were measured between 2015 and 2020 in 31 patients with isoniazid-resistant or -intolerant TB receiving rifampicin, and 20 TB patients receiving moxifloxacin without rifampicin. Moxifloxacin exposure, i.e., area under the concentration-time curve (AUC0-24h), and attainment of AUC0-24h/MIC > 100 were investigated for 400 mg moxifloxacin and 600 mg rifampicin, and increased doses of moxifloxacin (600 mg) or rifampicin (900 mg). Moxifloxacin AUC0-24h and peak concentration with a 400 mg dose were decreased when rifampicin was co-administered compared to moxifloxacin alone (ratio of geometric means 0.61 (90% CI (0.53, 0.70) and 0.81 (90% CI (0.70, 0.94), respectively). Among patients receiving rifampicin, 65% attained an AUC0-24h/MIC > 100 for moxifloxacin compared to 78% of patients receiving moxifloxacin alone; this difference was not significant. Seven out of eight patients receiving an increased dose of 600 mg moxifloxacin reached the target AUC0-24h/MIC > 100. This study showed a clinically significant 39% decrease in moxifloxacin exposure when rifampicin was co-administered. Moxifloxacin dose adjustment may compensate for this drug-drug interaction. Further exploring the impact of higher doses of these drugs in patients with isoniazid resistance or intolerance is paramount.

An All-Oral 6-Month Regimen for Multi-Drug Resistant/Rifampicin-Resistant Tuberculosis: A Multi-Centre, Phase 3, Open Label, Randomised Controlled Trial (NeXT Study)

Background: Improving treatment outcomes, reducing drug toxicity, eliminating the need for injectable agents, and shortening the treatment duration to 6-months (the same as rifampicin-susceptible tuberculosis) remains an aspirational goal for the treatment of multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB). Methods: We conducted a multicentre randomised controlled trial in adults with MDR/RR-TB (i.e. without resistance to fluoroquinolones or aminoglycosides). Participants were randomly assigned (1:1 ratio) to a 6-month all-oral regimen that included levofloxacin, bedaquiline and linezolid, or the standard-of-care ≥ 9-month WHO-approved injectable-based regimen. The primary endpoint was a favourable WHO-defined treatment outcome 24 months after treatment initiation. Findings: 93 of 111 participants randomised were included in the modified intention-to-treat analysis; 51 (55%) were HIV co-infected (median CD4 count 158 cells/ml). Participants in the intervention arm were 2·2 times more likely to experience a favourable 24-month outcome ( 95% CI) than participants in the standard-of-care arm [RR 2·2 (1·2–4·1); p=0·006]. They were also less likely, over a 24-month period, to experience an unfavourable outcome event than participants in the standard-of-care arm [HR 0·4, (0·2–0·6), p<0·001]. Toxicity-related drug substitution occurred more frequently in the standard-of-care arm [(65·9% (29/44) versus 36·7% (18/49), p= 0·001)]; 79.3% (23/29) due to kanamycin (mainly hearing loss; replaced by bedaquiline) in the standard-of-care arm, and 83·3% (15/18) due to linezolid (mainly anaemia) in the interventional arm. Time to culture conversion was significantly better in the interventional arm [HR 2·6 (1·4–4·9); p= 0·003] after censoring those with bedaquiline replacement in the standard-of-care arm. Interpretation: An all-oral 6-month levofloxacin, bedaquiline and linezolid-containing MDR/RR-TB regimen was associated with significantly improved 24-month treatment outcomes compared with traditional injectable-containing regimens. However, drug toxicity occurred frequently in both arms. These findings inform strategies to develop future regimens for MDR/RR-TB. Trial Registration: The trial was registered on clinicaltrials.gov (NCT02454205). Funding: South African MRC, Pfizer, and the European and Developing Country Clinical Trial Partnership (EDCTP) Declaration of Interest: None to declare. Ethical Approval: An institutional review board or ethics committee at each participating trial site reviewed and approved the protocol and informed consent documents.

Disseminated extrapulmonary MDRTB in a patient with systemic lupus erythematosus initially masquerading as drug-susceptible tuberculosis

Background: Patients with systemic lupus erythematosus (SLE) are at increased risk for opportunistic infections due to impaired cellular immunity inherent to the disease and the immunosuppressive effects of drugs used to treat it. Tuberculosis (TB) is endemic in the Philippines, and multidrug-resistant tuberculosis (MDRTB) is on the rise. SLE patients have a seven-fold higher prevalence of tuberculosis and more commonly develop extrapulmonary tuberculosis (EPTB) more than the general population. Case description: We report a 29-year-old female diagnosed with SLE for seven years who was maintained on daily doses of prednisone 10 mg and hydroxychloroquine 200 mg. With a chronic non-healing ulcer on the right ankle, she had headache, fever, vomiting and photophobia for three weeks. While admitted, she had decreased sensorium and meningeal irritation. Cerebrospinal fluid studies showed lymphocytosis, hypoglycorrhachia, elevated protein level, and positive rifampicin-susceptible TB on Xpert. Patient was started on first-line TB regimen with no improvement of symptoms. Stool was also positive for acid fast bacilli (AFB). Repeat ankle wound aspirate continued to be AFB-positive and culture grew MDRTB. Switching to an MDR anti-TB regimen resulted in marked clinical improvement and recovery. Discussion: Diagnosis and management of TB in SLE is perplexing due to similarities in clinical presentations. This is accounted for by molecular mimicry evidenced by antigen resemblance between mycobacterial cell wall glycolipids and DNA. Moreover, management of MDRTB in SLE is more challenging due to drug toxicities and interactions, and lack of literature. The development of disseminated EPTB MDRTB in our patient may be from the interplay of tuberculosis endemicity, the lupus autoimmunity, and the consequence of immunosuppressive treatment. Fortunately, the TB culture from the repeat debridement of her chronic foot ulcer grew a more clinically-compatible MDRTB, leading to the initiation of a more appropriate treatment regimen. Although this case has a grave prognosis, the patient recovered. Conclusion: To our knowledge, this is the first report of disseminated EPTB (meningitis, musculoskeletal and gastrointestinal) MDRTB in SLE. It is also notable because it demonstrates that MDRTB may appear “drug-susceptible” on TB culture, but should be strongly suspected if AFB smears do not clear, necessitating a repeat TB culture.

Comparison of first-line tuberculosis treatment outcomes between previously treated and new patients: a retrospective study in Machakos subcounty, Kenya.

BackgroundSince 2016, patients with rifampicin-susceptible tuberculosis (TB) have been treated with the 6-month first-line regimen, regardless of treatment history. We assessed treatment outcomes of previously treated and new patients in Machakos subcounty, Kenya.MethodsWe performed a retrospective cohort study in patients started on first-line treatment between 2016 and 2017. Firth's logistic regression was used to estimate the effect of previous treatment on having a programmatic adverse outcome (either lost to follow-up, death, failure) and treatment failure vs treatment success (either cure or completion).ResultsOf 1024 new and 79 previously treated patients, 88.1% and 74.7% were treated successfully, 6.5% and 7.6% died, 4.2% and 10.1% were lost to follow-up and 1.2% and 7.6% had treatment failure, respectively. Previous treatment predicted having a programmatic adverse outcome (adjusted odds ratio [aOR] 2.4 [95% confidence interval {CI} 1.4 to 4.2]) and treatment failure (aOR 7.3 [95% CI 2.6 to 20.4]) but not mortality. Similar correlations were found in 334 new and previously treated patients with confirmed baseline rifampicin susceptibility.ConclusionPreviously treated patients were more at risk of experiencing a poor treatment outcome, mainly lost to follow-up and treatment failure. Adherence support may reduce lost to follow-up. Rifampicin drug susceptibility testing coverage should increase. More robust retreatment regimens may reduce treatment failure.

A retrospective cohort study of isoniazid-resistant tuberculosis treatment outcomes and isoniazid resistance-associated mutations in eastern China from 2013 to 2018

ObjectivesThe current situation of isoniazid-resistant, rifampicin-susceptible tuberculosis (Hr-TB) and associated genetic factors is not clear in China. MethodsA retrospective cohort study was conducted from 2013 to 2018 in Jiangsu Province, China. Phenotypic Hr-TB were identified by drug susceptibility testing on Lowenstein–Jensen medium and using a Mycobacterium Growth Indicator Tube 960 (MGIT 960) system, and mutations in the katG 315 codon and inhA promoter nucleotides –8, –15 and –16 were determined by GenoType MTBDRplus and sequencing. All of the Hr-TB patients enrolled were followed up until June 2019. ResultsA total of 1416 smear-positive sputum samples were collected, of which 57 were excluded due to the presence of nontuberculous mycobacteria. Finally, 63/1359 (4.6%) were determined as Hr-TB. After follow-up, 11 Hr-TB patients (17.5%) showed an unfavourable outcome, of whom 5 (7.9%) relapsed, 4 (6.3%) had treatment failure and 2 (3.2%) died. A total of 52 isolates (82.5%) were detected with either katG 315 or inhA promoter nucleotide –8, –15 or –16 mutations, whereas no canonical mutations were found in 8 isolates (12.7%); 3 isolates failed in mutation detection. TB history was found to be associated with unfavourable outcomes for Hr-TB (odds ratio = 6.13, 95% confidence interval 1.05–35.82; P = 0.04). However, mutations in katG 315 and the inhA promoter region were not found to be associated with Hr-TB unfavourable outcomes (P = 0.15). ConclusionUnfavourable outcomes for Hr-TB are serious in eastern China, especially for previously treated patients. Meanwhile, current genetic determination of Hr-TB is inadequate.

Prevalence and genetic profiles of isoniazid resistance in tuberculosis patients: A multicountry analysis of cross-sectional data.

BackgroundThe surveillance of drug resistance among tuberculosis (TB) patients is central to combatting the global TB epidemic and preventing the spread of antimicrobial resistance. Isoniazid and rifampicin are two of the most powerful first-line anti-TB medicines, and resistance to either of them increases the risk of treatment failure, relapse, or acquisition of resistance to other drugs. The global prevalence of rifampicin resistance is well documented, occurring in 3.4% (95% CI 2.5%–4.4%) of new TB patients and 18% (95% CI 7.6%–31%) of previously treated TB patients in 2018, whereas the prevalence of isoniazid resistance at global and regional levels is less understood. In 2018, the World Health Organization (WHO) recommended a modified 6-month treatment regimen for people with isoniazid-resistant, rifampicin-susceptible TB (Hr-TB), which includes rifampicin, pyrazinamide, ethambutol, and levofloxacin. We estimated the global prevalence of Hr-TB among TB patients and investigated associated phenotypic and genotypic drug resistance patterns.Methods and findingsAggregated drug resistance data reported to WHO from either routine continuous surveillance or nationally representative periodic surveys of TB patients for the period 2003–2017 were reviewed. Isoniazid data were available from 156 countries or territories for 211,753 patients. Among these, the global prevalence of Hr-TB was 7.4% (95% CI 6.5%–8.4%) among new TB patients and 11.4% (95% CI 9.4%–13.4%) among previously treated TB patients. Additional data on pyrazinamide and levofloxacin resistance were available from 6 countries (Azerbaijan, Bangladesh, Belarus, Pakistan, the Philippines, and South Africa). There were no cases of resistance to both pyrazinamide and levofloxacin among Hr-TB patients, except for the Philippines (1.8%, 95% CI 0.2–6.4) and Belarus (5.3%, 95% CI 0.1–26.0). Sequencing data for all genomic regions involved in isoniazid resistance were available for 4,563 patients. Among the 1,174 isolates that were resistant by either phenotypic testing or sequencing, 78.6% (95% CI 76.1%–80.9%) had resistance-conferring mutations in the katG gene and 14.6% (95% CI 12.7%–16.8%) in both katG and the inhA promoter region. For 6.8% (95% CI 5.4%–8.4%) of patients, mutations occurred in the inhA promoter alone, for whom an increased dose of isoniazid may be considered. The main limitations of this study are that most analyses were performed at the national rather than individual patient level and that the quality of laboratory testing may vary between countries.ConclusionsIn this study, the prevalence of Hr-TB among TB patients was higher than the prevalence of rifampicin resistance globally. Many patients with Hr-TB would be missed by current diagnostic algorithms driven by rifampicin testing, highlighting the need for new rapid molecular technologies to ensure access to appropriate treatment and care. The low prevalence of resistance to pyrazinamide and fluoroquinolones among patients with Hr-TB provides further justification for the recommended modified treatment regimen.

Isoniazid-resistant Mycobacterium tuberculosis: prevalence, resistance spectrum and genetic determinants of resistance

The lack of simple, rapid diagnostic tests for isoniazid-resistant rifampicin-susceptible tuberculosis infection (Hr-TB) can result in low treatment efficacy and further amplification of drug resistance. Based on the clinical data, this study sought to estimate the prevalence of Hr-TB in the general population and characterize the phenotypic susceptibility and genetic determinants of isoniazid resistance in M. tuberculosis strains. Molecular-genetic and culture-based drug susceptibility tests were performed on M. tuberculosis isolates and M. tuberculosis DNA obtained from the patients with pulmonary TB undergoing treatment at the Central Tuberculosis Research Institute between 2011 and 2018. The tests revealed that Hr-TB accounted for 12% of all TB cases in the studied sample. Hr-TB strains were either resistant to isoniazid only (45%) or had multiple resistance to 2–6 anti-TB agents. Resistance to isoniazid was caused by mutations in the katG gene. Based on the literature analysis and our own observations, we emphasize the importance of developing simple molecular drug susceptibility tests capable of detecting simultaneous resistance to rifampicin and isoniazid and the necessity of their translation into clinical practice.

Variation in pre-therapy levels of selected Mycobacterium tuberculosis transcripts in sputum and their relationship with 2-month culture conversion

Background:The abundance of transcripts arising fromMycobacterium tuberculosis(MTB) in sputum pre-chemotherapy may enhance our understanding of factors influencing treatment response. We hypothesized that differences in the prevalence of pre-existing slowly metabolizing MTB in sputum may be partially responsible for differences in the rate of sputum clearance during treatment.Methods:Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to characterize a selected limited transcription profile of MTB in sputum pre-chemotherapy and assess inter-individual variation. The difference in cycle threshold (Ct) per gene, normalized to 16S, between exponential/stationary phase culture and sputum was calculated and stratified by 2-month culture converter status.Results:HIV-1 uninfected patients with rifampicin-susceptible tuberculosis provided sputum pre-chemotherapy; 11 patients were negative for MTB culture after two months of therapy and 8 remained culture-positive.Increasedicl1andprpDandrpsN2:rpsN1in sputum relative to culture suggested cholesterol utilization and a low-zinc environment respectively. IncreasedhspXand decreasedatpAandnuoGrelative to exponential culture suggested a slowly metabolizing subpopulation of MTB. While the thehspXhiatpAlonuoGlosignal varied, we did not observe statistically significant enrichment of this phenotype in the non-converter population nor an association with MTB-lineage.Conclusion:Differential abundance of selected informative transcripts suggested a metabolically less-active subpopulation with a prevalence that varied between individual untreated patients.