ORCID Profile
0000-0002-6538-7192
Current Organisations
Médecins Sans Frontières
,
University of Cape Town
,
Burnet Institute
,
Baker IDI Heart and Diabetes Institute
,
University of Melbourne
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Publisher: Cold Spring Harbor Laboratory
Date: 21-06-2021
DOI: 10.1101/2021.06.14.21258812
Abstract: Rif icin mono-resistant TB (RMR-TB) constitutes 38% of all rif icin-resistant TB (RR-TB) in South Africa and is increasing. We aimed to compare RMR-TB with multidrug-resistant TB (MDR-TB) within a high TB, RR-TB and HIV burden setting. Patient-level clinical data and stored RR-TB isolates from 2008-2017 with available whole genome sequencing (WGS) data were used to describe risk factors associated with RMR-TB and to compare rif icin-resistance (RR) conferring mutations between RMR-TB and MDR-TB. A subset of isolates with particular RR-conferring mutations were subjected to semi-quantitative rif icin phenotypic drug susceptibility testing. Among 2,041 routinely diagnosed RR-TB patients, 463 (22.7%) had RMR-TB. HIV-positive in iduals (adjusted Odds Ratio 1.4, 95% CI 1.1-1.9) and diagnosis between 2013-2017 versus 2008-2012 (aOR 1.3, 1.1-1.7) were associated with RMR-TB. Among 1,119 (54.8%) patients with available WGS data showing RR-TB, significant differences in the distribution of rpoB RR-conferring mutations between RMR-TB and MDR-TB isolates were observed. Mutations associated with high-level RR were more commonly found among MDR-TB isolates (811/889, 90.2% versus 162/230, 70.4% among RMR-TB, p .01). In particular, the rpoB L430P mutation, conferring low-level RR, was identified in 32/230 (13.9%) RMR-TB versus 10/889 (1.1%) in MDR-TB (p .01). Among 10 isolates with an rpoB L430P mutation, 7 were phenotypically susceptible using the critical concentration of 0.5 µg/ml (range 0.125-1 µg/ml). The majority (215/230, 93.5%) of RMR-TB isolates showed susceptibility to all other TB drugs, highlighting the potential benefits of WGS for simplified treatment. These data suggest that the evolution of RMR-TB differs from MDR-TB with a potential contribution from HIV infection.
Publisher: Public Library of Science (PLoS)
Date: 26-05-0011
Publisher: Elsevier BV
Date: 11-2021
Publisher: Public Library of Science (PLoS)
Date: 30-07-2013
Publisher: International Union Against Tuberculosis and Lung Disease
Date: 04-2014
Abstract: Khayelitsha, South Africa, a peri-urban township with high burdens of tuberculosis (TB), drug-resistant tuberculosis (DR-TB), and human immunodeficiency virus (HIV) infection. To describe case detection and patient outcomes in a community-based DR-TB programme. DR-TB management was integrated into primary health care in Khayelitsha from 2007 onwards. Implementation was incremental, and included training and clinician support, counselling and home visits, tuberculous infection control, a local in-patient service, and routine monitoring. Patients received treatment rapidly through their local clinic, and were only hospitalised if clinically unwell. DR-TB case notification (any rif icin resistance) increased from 28 per 100 000 population per year (2005-2007) to 55/100 000/year in 2009-2011 (72% HIV-infected). From 2008 to 2011, 754 patients received treatment (86% of those diagnosed). The median time between diagnostic sputum and treatment decreased over the years of implementation to 27 days in 2011 (P < 0.001). Treatment success was 52% in 2010, with 31% default, 13% death and 4% treatment failure. Two-year survival was 65%, with poorer survival in those with HIV (HR 2.0, 95%CI 1.4-2.8), second-line drug resistance (HR 3.3, 95%CI 2.2-4.8), and diagnosis in earlier programme years (HR 1.4, 95%CI 1.1-2.0). Community-based DR-TB management is feasible, and contributes to improved case detection, reduced treatment delay and improved survival. Treatment outcomes remain poor, highlighting the poor efficacy, tolerability and lengthy duration of current treatment.
Publisher: Springer International Publishing
Date: 2020
DOI: 10.1007/978-3-030-27874-8_10
Abstract: The lack of access to effective diagnosis and treatment for drug-resistant tuberculosis (DR-TB) remains a persistent ethical, human rights and public health challenge globally. In addressing this challenge, arguments based on a Human Rights-Based Approach (HRBA) to health have most often been focused on the Right to Health. However, a key challenge in multidrug-resistant (MDR-) and extensively drug-resistant (XDR-) TB is the glaring absence of scientific research ranging from basic science and drug discovery through to implementation science once new tools have been developed. Although the Right to Enjoy the Benefits of Scientific Progress and its Applications (REBSP) is a little theorised human right, it has the potential to enrich our understanding and use of the Rights-Based Approach to health. In this chapter, we argue that States’ duties to respect, protect and fulfil the REBSP within and outside their borders is an important vehicle that can be drawn on to redress the lack of research into new drug development and appropriate use of existing drugs for DR-TB in high burden settings. We call for urgent attention to minimum core obligations for the REBSP and the need for a General Comment by a UN human rights monitoring body to provide for its interpretation. We also note that conceptualization of the REBSP has the potential to complement Right to Health claims intended to enhance access to treatment for DR-TB on a global scale.
Publisher: BMJ
Date: 04-02-2008
Publisher: Elsevier BV
Date: 04-2011
Publisher: Springer Science and Business Media LLC
Date: 08-11-2005
Abstract: After the collapse of the Soviet Union, dramatically increasing rates of tuberculosis and multidrug-resistant tuberculosis (MDR-TB) have been reported from several countries. This development has been mainly attributed to the widespread breakdown of TB control systems and declining socio-economic status. However, recent studies have raised concern that the Beijing genotype of Mycobacterium tuberculosis might be contributing to the epidemic through its widespread presence and potentially enhanced ability to acquire resistance. A total of 397 M. tuberculosis strains from a cross sectional survey performed in the Aral Sea region in Uzbekistan and Turkmenistan have been analysed by drug susceptibility testing, IS 6110 fingerprinting, and spoligotyping. Fifteen isolates showed mixed banding patterns indicating simultaneous infection with 2 strains. Among the remaining 382 strains, 152 (40%) were grouped in 42 clusters with identical fingerprint and spoligotype patterns. Overall, 50% of all isolates were Beijing genotype, with 55% of these strains appearing in clusters compared to 25% of non-Beijing strains. The percentage of Beijing strains increased with increasing drug resistance among both new and previously treated patients 38% of fully-susceptible isolates were Beijing genotype, while 75% of MDR-TB strains were of the Beijing type. The Beijing genotype is a major cause of tuberculosis in this region, it is strongly associated with drug resistance, independent of previous tuberculosis treatment and may be strongly contributing to the transmission of MDR-TB. Further investigation around the consequences of Beijing genotype infection for both tuberculosis transmission and outcomes of standard short course chemotherapy are urgently needed.
Publisher: BMJ
Date: 07-09-2015
DOI: 10.1136/THORAXJNL-2015-207245
Abstract: Ototoxicity is a severe side effect of aminoglycoside antibiotics. Aminoglycosides are recommended for the treatment of multidrug-resistant TB (MDR-TB). N-Acetylcysteine (NAC) appears to protect against drug- and noise-induced hearing loss. This review aimed to determine if coadministering NAC with aminoglycoside affected ototoxicity development, and to assess the safety and tolerability of prolonged NAC administration. Eligible studies reported on the efficacy of concomitant NAC and aminoglycoside administration for ototoxicity prevention or long-term (≥ 6 weeks) administration of NAC regardless of indication. Pooled estimates were calculated using a fixed-effects model. Heterogeneity was assessed using the I(2) statistic. Three studies reported that NAC reduced ototoxicity in 146 patients with end-stage renal failure receiving aminoglycosides. Pooled relative risk for otoprotection at 4-6 weeks was 0.14 (95% CI 0.05 to 0.45), and the risk difference was -33.3% (95% CI 45.5% to 21.2%). Eighty-three studies (N=9988) described the administration of NAC for >6 weeks. Abdominal pain, nausea and vomiting, diarrhoea and arthralgia were increased 1.4-2.2 times. This review provides evidence for the safety and otoprotective effect of NAC when coadministered with aminoglycoside. It represents a strong justification for a clinical trial to investigate the effect of concomitant NAC treatment in patients receiving aminoglycosides as part of MDR-TB treatment.
Publisher: Elsevier BV
Date: 02-2023
Publisher: Elsevier BV
Date: 07-2006
DOI: 10.1016/J.PUHE.2006.01.013
Abstract: In many parts of the world where unsafe injection practices in health settings are common, the prevalence of blood-borne viruses (BBVs) is high amongst injecting drug users (IDUs). If IDUs in these settings are receiving injections for health-related reasons, the possibility of lification of BBV transmission via medical injections exists. The aim of this study is to describe the nature and extent of injections received for health-related reasons amongst IDUs in two Indian cities, New Delhi and Imphal. A cross-sectional survey of 200 IDUs was conducted in late 2004. Trained peer outreach workers asked participants about health problems experienced, consultations with healthcare providers and health-related injections received in the preceding 4 weeks. Most participants (99.5%) were male, the average age was 29 years, and the average time since first injection of illicit drugs was 6 years. A total of 133 injections were received for health-related reasons during the preceding 4 weeks by 15% of the participants. The average number of injections was 8.6 articipant/year. Injections for health-related reasons were commonplace amongst these IDUs. Therefore, lification of BBV transmission within communities due to unsafe injections is possible and warrants further investigation.
Publisher: Elsevier BV
Date: 06-2013
Publisher: International Union Against Tuberculosis and Lung Disease
Date: 02-2022
Abstract: BACKGROUND: Data suggest that treatment with newer TB drugs (linezolid [LZD], bedaquiline [BDQ] and delamanid [DLM]), used in Khayelitsha, South Africa, since 2012, reduces mortality due to rif icin-resistant TB (RR-TB). METHODS: This was a retrospective cohort study to assess 6-month mortality among RR-TB patients diagnosed between 2008 and 2019. RESULTS: By 6 months, 236/2,008 (12%) patients died 12% (78/651) among those diagnosed in 2008–2011, and respectively 8% (49/619) and 15% (109/738) with and without LZD/BDQ/DLM in 2012–2019. Multivariable analysis showed a small, non-significant mortality reduction with LZD/BDQ/DLM use compared to the 2008–2011 period (aOR 0.79, 95% CI 0.5–1.2). Inpatient treatment initiation (aOR 3.2, 95% CI 2.4–4.4), fluoroquinolone (FQ) resistance (aOR 2.7, 95% CI 1.8–4.2) and female sex (aOR 1.5, 95% CI 1.1–2.0) were also associated with mortality. When restricted to 2012–2019, use of LZD/BDQ/DLM was associated with lower mortality (aOR 0.58, 95% CI 0.39–0.87). CONCLUSIONS: While LZD/BDQ/DLM reduced 6-month mortality between 2012 and 2019, there was no significant effect overall. These findings may be due to initially restricted LZD/BDQ/DLM use for those with high-level resistance or treatment failure. Additional contributors include increased treatment initiation among in iduals who would have otherwise died before treatment due to universal drug susceptibility testing from 2012, an effect that also likely contributed to higher mortality among females (survival through to care-seeking).
Publisher: Elsevier BV
Date: 08-2015
Publisher: BMJ
Date: 12-2022
DOI: 10.1136/BMJGH-2022-008907
Abstract: Ch ions are recognised as important to driving organisational change in healthcare quality improvement initiatives in high-income settings. In low-income and middle-income countries with a high disease burden and constrained human resources, their role is highly relevant yet understudied. Within a broader study on policy implementation for decentralised drug-resistant tuberculosis care in South Africa, we characterised the role, strategies and organisational context of emergent policy ch ions. Interviews with 34 healthcare workers in three South African provinces identified the presence of in iduals who had a strong influence on driving policy implementation forward. Additional interviews were conducted with 13 participants who were either identified as ch ions in phase II or were healthcare workers in facilities in which the ch ions operated. Thematic analyses using a socio-ecological framework further explored their strategies and the factors enabling or obstructing their agency. All ch ions occupied senior managerial posts and were accorded legitimacy and authority by their communities. ‘Disease-centred’ ch ions had a high level of clinical expertise and placed emphasis on clinical governance and clinical outcomes, while ‘patient-centred’ ch ions promoted pathways of care that would optimise patients’ recovery while minimising disruption in other spheres of their lives. Both types of ch ions displayed high levels of resourcefulness and flexibility to adapt strategies to the resource-constrained organisational context. Policymakers can learn from ch ions’ experiences regarding barriers and enablers to implementation to adapt policy. Research is needed to understand what factors can promote the sustainability of ch ion-led policy implementation, and to explore best management practices to support their initiatives.
Publisher: Elsevier BV
Date: 03-2009
Publisher: International Union Against Tuberculosis and Lung Disease
Date: 05-2014
Publisher: Elsevier BV
Date: 05-2016
Publisher: Public Library of Science (PLoS)
Date: 12-2011
Publisher: Elsevier BV
Date: 06-2012
Publisher: European Respiratory Society (ERS)
Date: 30-11-2015
Publisher: Elsevier BV
Date: 08-2013
Publisher: Public Library of Science (PLoS)
Date: 04-04-2023
DOI: 10.1371/JOURNAL.PPAT.1010893
Abstract: In settings with high tuberculosis (TB) endemicity, distinct genotypes of the Mycobacterium tuberculosis complex (MTBC) often differ in prevalence. However, the factors leading to these differences remain poorly understood. Here we studied the MTBC population in Dar es Salaam, Tanzania over a six-year period, using 1,082 unique patient-derived MTBC whole-genome sequences (WGS) and associated clinical data. We show that the TB epidemic in Dar es Salaam is dominated by multiple MTBC genotypes introduced to Tanzania from different parts of the world during the last 300 years. The most common MTBC genotypes deriving from these introductions exhibited differences in transmission rates and in the duration of the infectious period, but little differences in overall fitness, as measured by the effective reproductive number. Moreover, measures of disease severity and bacterial load indicated no differences in virulence between these genotypes during active TB. Instead, the combination of an early introduction and a high transmission rate accounted for the high prevalence of L3.1.1, the most dominant MTBC genotype in this setting. Yet, a longer co-existence with the host population did not always result in a higher transmission rate, suggesting that distinct life-history traits have evolved in the different MTBC genotypes. Taken together, our results point to bacterial factors as important determinants of the TB epidemic in Dar es Salaam.
Publisher: International Union Against Tuberculosis and Lung Disease
Date: 10-2015
Publisher: Public Library of Science (PLoS)
Date: 09-01-2012
Publisher: Elsevier BV
Date: 11-2003
Publisher: American Society for Microbiology
Date: 08-2009
DOI: 10.1128/AAC.00050-09
Abstract: The rapid detection of Mycobacterium tuberculosis isolates resistant to second-line drugs is crucial for the institution of appropriate treatment regimens as early as possible. Although molecular methods have successfully been used for the rapid detection of resistance to first-line drugs, there are limited data on mutations that confer resistance to second-line drugs. To address this question, we analyzed Mycobacterium tuberculosis strains resistant to ofloxacin ( n = 26) and to capreomycin and/or amikacin ( n = 48) from Uzbekistan for variations in target genes ( gyrA , gyrB , rrs , and tlyA ). Strains susceptible to ofloxacin ( n = 49) and capreomycin and/or amikacin ( n = 39) were included as controls. Mutations in gyrA or gyrB were found in 96% (25/26 strains) of the ofloxacin-resistant strains, while none of the susceptible strains displayed mutations in those two genes. The most common mutation occurred in gyrA at codon 94 (17/26 strains [65.4%]), followed by mutations at codons 90 and 91. Two strains showed a mutation in gyrB , at codons 485 and 543, respectively both mutations have not been reported previously. The most frequent mutation in strains resistant to both amikacin and capreomycin was A1401G in rrs (34/40 strains [85.0%]). Three strains had mutations in tlyA , of which two (at codons 18 and 118) were associated with resistance to capreomycin alone. Overall, none of the 10 resistant strains (5 amikacin-resistant and capreomycin-susceptible strains) and none of the 39 susceptible control strains had mutations in the genes investigated. Our results clearly demonstrate the potential of sequence analyses of short regions of relatively few target genes for the rapid detection of resistance to second-line drugs among strains isolated from patients undergoing treatment for multidrug-resistant tuberculosis. The mechanisms that confer amikacin resistance in this setting remain unclear.
Publisher: American Society for Microbiology
Date: 16-03-2022
DOI: 10.1128/JCM.02362-21
Abstract: Treatment of multidrug-resistant or rif icin-resistant tuberculosis (MDR/RR-TB), although improved in recent years with shorter, more tolerable regimens, remains largely standardized and based on limited drug susceptibility testing (DST). More in idualized treatment with expanded DST access is likely to improve patient outcomes.
Publisher: Briefland
Date: 06-03-2014
Publisher: Informa UK Limited
Date: 1994
DOI: 10.3109/08037059409101522
Abstract: In this study we aimed to elucidate the role of central noradrenergic, dopaminergic, adrenergic and serotonergic neuronal systems in the development of essential hypertension. Fifteen untreated essential hypertensive subjects (aged 44 +/- 3 years) and 32 healthy volunteers (aged 38 +/- 3 years) participated in this study. By combining direct blood s ling techniques with cerebral blood flow scans we were able to differentiate between cortical and subcortical venous drainage of the brain. Veno-arterial MHPG, HVA and 5-HIAA plasma concentration gradients combined with internal jugular vein plasma flows were used, according to the Fick Principle, to derive metabolite spillovers which in turn were used as indicators of central noradrenergic, dopaminergic and serotonergic neuronal activity, respectively. These amine systems, in both the brainstem and forebrain, have been implicated in the regulation of sympathetic outflow and blood pressure. Total body noradrenaline spillover to plasma was concurrently measured to assess the relationship between central monoamine turnover and sympathetic activity. Compared to their healthy counterparts the hypertensive subjects had an elevated release of MHPG from subcortical brain regions (1.4 +/- 0.3 v 0.5 +/- 0.2 nmol/min, p < 0.05). An inverse relationship between blood pressure and subcortical HVA overflow existed, with the HVA overflow being significantly lower in the hypertensives (0.5 +/- 0.2 v 2.1 +/- 0.5 nmol/min, p < 0.05). Subcortical 5-HUAA overflow did not differ between the two groups, and adrenaline spillover from the brain was not detected in either group. Subcortical MHPG overflow was significantly correlated with total body NA spillover to plasma (p < 0.05). These results indicate that reciprocal aberrations in subcortical noradrenaline and dopamine turnover exist in essential hypertension. Although the physiological significance of this remains to be unequivocally elucidated we postulate that elevated subcortical noradrenergic activity, presumably in the forebrain where noradrenergic neurons are pressor, may cause sympathoexcitation and play a role in the development of essential hypertension.
Publisher: International Union Against Tuberculosis and Lung Disease
Date: 21-09-2021
DOI: 10.5588/PHA.20.0083
Abstract: OBJECTIVE: To describe the medical, socio-economic and geographical profiles of patients with rif icin-resistant TB (RR-TB) and the implications for the provision of patient-centred care. SETTING: Thirteen districts across three South African provinces. DESIGN: This descriptive study examined laboratory and healthcare facility records of 194 patients diagnosed with RR-TB in the third quarter of 2016. RESULTS: The median age was 35 years 120/194 (62%) of patients were male. Previous TB treatment was documented in 122/194 (63%) patients and 56/194 (29%) had a record of fluoroquinolone and/or second-line injectable resistance. Of 134 (69%) HIV-positive patients, viral loads were available for 68/134 (51%) (36/68 [53%] had viral loads of copies/ml) and CD4 counts were available for 92/134 (69%) (20/92 [22%] had CD4 cells/mm 3 ). Patients presented with varying other comorbidities, including hypertension (13/194, 7%) and mental health conditions (11/194, 6%). Of 194 patients, 44 (23%) were reported to be employed. Other socio-economic challenges included substance abuse (17/194, 9%) and ill family members (17/194, 9%). Respectively 13% and 42% of patients were estimated to travel more than 20 km to reach their diagnosing and treatment-initiating healthcare facility. CONCLUSIONS: RR-TB patients had erse medical and social challenges highlighting the need for integrated, differentiated and patient-centred healthcare to better address specific needs and underlying vulnerabilities of in idual patients.
Publisher: Informa UK Limited
Date: 1994
DOI: 10.3109/10641969409067946
Abstract: This study examined haemodynamics and noradrenaline spillover in five normal men before and on day 7 of oral fludrocortisone treatment, 0.3 mg/day. Resting systolic (105 to 115 mm Hg, standard error of the difference +/- 2.0, p < 0.01) and diastolic (65 to 73 mm Hg, +/- 3.0, p < 0.05) blood pressure increased, as did cardiac output, from 5.0 to 5.7 L/min (+/- 0.1, p < 0.01). Calculated total peripheral resistance fell from 21.2 to 20.0 mm Hg/L/min (+/- 0.4, p < 0.05). Fludrocortisone produced a fall in plasma potassium, renin and aldosterone concentrations and haematocrit and a rise in body weight. Cold pressor responses were increased by fludrocortisone, from 7.5 to 20 mm Hg (+/- 3.0, p < 0.01), and forearm vascular resistance rose 12 arbitrary resistance units (R) before and 36 R units after treatment (+/- 5.0, p < 0.01). Total body spillover of noradrenaline was decreased from 9.48 to 7.36 ng/kg/min (+/- 0.86, p < 0.05). There were no changes in forearm noradrenaline spillover at rest or during cold pressor stimulation. It appears unlikely that the sympathetic nervous system plays a major role in the pathogenesis of mineralocorticoid hypertension in man.
Publisher: Elsevier BV
Date: 2011
Publisher: Oxford University Press (OUP)
Date: 13-02-2021
Abstract: In 2011, the South African National TB Programme launched a policy of decentralized management of drug-resistant tuberculosis (DR-TB) in order to expand the capacity of facilities to treat patients with DR-TB, minimize delays to access care and improve patient outcomes. This policy directive was implemented to varying degrees within a rapidly evolving diagnostic and treatment landscape for DR-TB, placing new demands on already-stressed health systems. The variable readiness of district-level systems to implement the policy prompted questions not only about differences in health systems resources but also front-line actors’ capacity to implement change in resource-constrained facilities. Using a grounded theory approach, we analysed data from in-depth interviews and small group discussions conducted between 2016 and 2018 with managers (n = 9), co-ordinators (n = 15), doctors (n = 7) and nurses (n = 18) providing DR-TB care. Data were collected over two phases in district-level decentralized sites of three South African provinces. While health systems readiness assessments conventionally map the availability of ‘hardware’, i.e. resources and skills to deliver an intervention, a notable absence of systems ‘hardware’ meant that systems ‘software’, i.e. health care workers (HCWs) agency, behaviours and interactions provided the basis of locally relevant strategies for decentralized DR-TB care. ‘Software readiness’ was manifest in four areas of DR-TB care: re-organization of service delivery, redressal of resource shortages, creation of treatment adherence support systems and extension of care parameters for vulnerable patients. These strategies demonstrate adaptive capacity and everyday resilience among HCW to withstand the demands of policy change and innovation in stressed systems. Our work suggests that a useful extension of health systems ‘readiness’ assessments would include definition and evaluation of HCW ‘software’ and adaptive capacities in the face of systems hardware gaps.
Publisher: Elsevier
Date: 1997
Publisher: American Society for Microbiology
Date: 21-09-2020
DOI: 10.1128/AAC.00782-20
Abstract: We analyzed 312 drug-resistant genomes of Mycobacterium tuberculosis isolates collected from HIV-coinfected and HIV-negative TB patients from nine countries with a high tuberculosis burden. We found that rif icin-resistant M. tuberculosis strains isolated from HIV-coinfected patients carried disproportionally more resistance-conferring mutations in rpoB that are associated with a low fitness in the absence of the drug, suggesting these low-fitness rpoB variants can thrive in the context of reduced host immunity.
Publisher: Elsevier
Date: 1997
Publisher: Oxford University Press (OUP)
Date: 26-04-2016
DOI: 10.1093/CID/CIW012
Publisher: Cold Spring Harbor Laboratory
Date: 31-03-2021
DOI: 10.1101/2021.03.29.21254563
Abstract: Assessment of the unknown performance of saliva for the detection of the novel SARS-CoV-2 variant of concern (VOC) B.1.351 (501Y.V2) lineage is essential as saliva has been shown to be an equivalent, less invasive and a less costly alternative to nasopharyngeal swabs for the molecular detection of SARS-CoV-2 infection in pre-variant studies. Between 1st August 2020 and 16th January 2021, we enrolled 410 eligible ambulatory participants who presented to Groote Schuur Hospital (GSH) in Cape Town, South Africa for SARS-CoV-2 testing. Of these, 300 were enrolled prior to, and 110 after, the initial detection and replacement of wild-type by the B.1.351 variant. All participants provided a supervised self-collected mid-turbinate (MT) and saliva (SA) swab, in addition to the standard HCW collected NP swab which were all tested by RT-PCR in an accredited diagnostic laboratory. Positive percent agreement to NP swab for SA swabs pre- and post-variant were 51.5% and 72.5% respectively while these values for MT swabs were 75.8% and 77.5%. The negative percent agreement for all swab types during all periods was %. The basis for this marked improvement of SA swabs as a diagnostic s le for B.1.351 virus is still being investigated.
Publisher: WHO Press
Date: 15-05-2015
Publisher: Oxford University Press (OUP)
Date: 24-09-2013
DOI: 10.1093/CID/CIT655
Abstract: Evidence is limited to guide the management of children exposed to multidrug-resistant (MDR) tuberculosis. We aimed to study the tolerability and toxicity of a standard preventive therapy regimen given to children exposed to infectious MDR tuberculosis, and explore risk factors for poor outcome. In this prospective cohort study in the Western Cape, South Africa, children <5 years of age, or human immunodeficiency virus (HIV)-positive children aged <15 years, were recruited from May 2010 through April 2011 if exposed to an ofloxacin-susceptible, MDR tuberculosis source case. Children were started on preventive therapy as per local guidance: ofloxacin, ethambutol, and high-dose isoniazid for 6 months. Standardized measures of adherence and adverse events were recorded poor outcome was defined as incident tuberculosis or death from any cause. One hundred eighty-six children were included, with a median age of 34 months (interquartile range, 14-47 months). Of 179 children tested for HIV, 9 (5.0%) were positive. Adherence was good in 141 (75.8%) children. Only 7 (3.7%) children developed grade 3 adverse events. One child (0.5%) died and 6 (3.2%) developed incident tuberculosis during 219 patient-years of observation time. Factors associated with poor outcome were age <1 year (rate ratio [RR], 10.1 95% confidence interval [CI], 1.65-105.8 P = .009), HIV-positive status (RR, 10.6 95% CI, 1.01-64.9 P = .049), exposure to multiple source cases (RR, 6.75 95% CI, 1.11-70.9 P = .036) and poor adherence (RR, 7.50 95% CI, 1.23-78.7 P = .026). This 3-drug preventive therapy regimen was well tolerated and few children developed tuberculosis or died if adherent to therapy. The provision of preventive therapy to vulnerable children following exposure to MDR tuberculosis should be considered.
Publisher: Oxford University Press (OUP)
Date: 10-10-2012
DOI: 10.1093/JAC/DKS389
Abstract: Current anti-tuberculosis therapeutics are not sufficiently effective against drug-resistant tuberculosis (DR-TB), and there is a need for new drugs and therapeutic approaches. It has been proposed that repurposing clofazimine for DR-TB treatment might be one way to increase therapeutic options. We conducted a systematic review of studies reporting on the efficacy and safety of clofazimine as part of combination therapy for DR-TB. Six databases and six conference abstract sites were searched from inception until April 2012. All studies involving the use of clofazimine in the treatment of DR-TB were included. Twelve studies, comprising 3489 patients across 10 countries, were included in this review. Treatment success ranged from 16.5% (95% CI 2.7%-38.7%) to 87.8% (95% CI 76.8%-95.6%), with an overall pooled proportion of 61.96% achieving treatment success (95% CI 52.79%-71.12%) (τ(2) 0.07). Mortality, treatment interruptions, defaulting and adverse events were all in line with DR-TB treatment outcomes overall. The most commonly reported adverse events were gastrointestinal disturbances and skin pigmentation. The available evidence to date suggests that clofazimine could be considered as an additional therapeutic option in the treatment of DR-TB. The optimal dose of clofazimine and duration of use require further investigation.
Publisher: International Union Against Tuberculosis and Lung Disease
Date: 04-2012
Abstract: Current treatment for drug-resistant tuberculosis (DR-TB) is inadequate, and outcomes are significantly poorer than for drug-susceptible TB, particularly for patients previously treated with second-line drugs, treatment failures or extensively drug-resistant (XDR-) TB patients (complicated DR-TB). Linezolid is not recommended for routine DR-TB treatment due to the lack of efficacy data, but is suggested for patients where adequate second-line regimens are difficult to design. To conduct a systematic review and meta-analysis to assess existing evidence of efficacy and safety of linezolid for DR-TB treatment. We searched PubMed, Embase and abstracts from World Conferences of The Union for studies published through February 2011. We included all studies in which linezolid was given systematically to DR-TB patients and where treatment outcomes were reported. A total of 11 studies were included in our review, representing 148 patients. The pooled proportion for treatment success was 67.99% (95%CI 58.00-78.99, τ2 129.42). There were no significant differences in success comparing daily linezolid dose (≤600 vs. >600 mg) and mean linezolid duration (≤7 vs. >7 months). The pooled estimate for the frequency of any adverse events was 61.48% (95%CI 40.15-82.80), with 36.23% (95%CI 20.67-51.79) discontinuing linezolid due to adverse events. Treatment success with linezolid was equal to or better than that commonly achieved for uncomplicated DR-TB, and better than previous reports for previously treated patients and those with XDR-TB. While data are limited, linezolid appears be a useful drug, albeit associated with significant adverse events, and should be considered in the treatment of complicated DR-TB.
Publisher: Oxford University Press (OUP)
Date: 28-04-2010
DOI: 10.1093/JAC/DKQ120
Abstract: Mechanisms of resistance to ethambutol in Mycobacterium tuberculosis remain inadequately described. Although there is mounting evidence that mutations of codon 306 in embB play a key role, a significant number of phenotypically ethambutol-resistant strains do not carry mutations in this codon. Here, other mutations in the embCAB operon are suggested to be involved in resistance development. The entire embCAB operon ( approximately 10 kb) was analysed in 34 phenotypically ethambutol-resistant M. tuberculosis strains without mutations in embB306 and in 12 ethambutol-susceptible strains. Furthermore, 106 control strains were investigated for the presence of particular mutations only. Overall, 18 non-synonymous mutations in 15 distinct codons of the embCAB operon were identified in ethambutol-resistant strains but not in ethambutol-susceptible isolates. The majority occurred in the embB gene (10 distinct codons), in a 570 bp region also encompassing embB306. Mutations in embC and embA were found rarely and in most cases in combination with polymorphisms in embB. One synonymous mutation (embA 228 bp) and two non-synonymous mutations (embCVal981Leu and embCArg738Gln) were found in ethambutol-susceptible strains as well as resistant strains and were confirmed to represent phylogenetic markers for strains of the Beijing, Haarlem and Delhi/CAS genotypes, respectively. Besides mutations in embB306, mutations in embB406 and embB497 were confirmed as hot spots for genomic variation in ethambutol-resistant clinical isolates. Of all resistant strains 70.6% carry a mutation in a relatively short region in embB, which therefore represents a promising target for inclusion in molecular assays for rapid detection of ethambutol resistance.
Publisher: International Union Against Tuberculosis and Lung Disease
Date: 04-2015
Abstract: Electrocardiographic (ECG) monitoring is recommended for some of the new and re-purposed drugs used in the treatment of multidrug-resistant tuberculosis (MDR-TB), as these drugs have been shown to prolong the QTc interval. ECG monitoring is relatively new in the management of TB patients, and has several implications for programs and providers. This review discusses what is known about QTc prolongation and the medications currently being studied or used to treat MDR-TB, and discusses strategies for managing QTc prolongation in the context of treating such a serious infectious disease. It also reviews some major implications of ECG monitoring in the field, including interpretation of ECGs and QTc intervals, management of patients with prolonged QTc intervals, and contextualizing the risk of QTc prolongation for patients being treated for MDR-TB.
Publisher: Oxford University Press (OUP)
Date: 06-2007
DOI: 10.1086/517536
Abstract: Data on the performance of standardized short-course directly observed treatment (DOTS) of tuberculosis (TB) in areas with high levels of drug resistance and on the potential impact of DOTS on lification of resistance are limited. Therefore, we analyzed treatment results from a cross-sectional s le of patients with TB enrolled in a DOTS program in an area with high levels of drug resistance in Uzbekistan and Turkmenistan in Central Asia. Sputum s les for testing for susceptibility to 5 first-line drugs and for molecular typing were obtained from patients starting treatment in 8 districts. Patients with sputum smear results positive for TB at the end of the intensive phase of treatment and/or at 2 months into the continuation phase were tested again. RESULTS. Among 382 patients with diagnoses of TB, 62 did not respond well to treatment and were found to be infected with an identical Mycobacterium tuberculosis strain when tested again 19 of these patients had strains that developed new or additional drug resistance. Amplification occurred in only 1.2% of patients with initially susceptible or monoresistant TB strains, but it occurred in 17% of those with polyresistant strains (but not multidrug-resistant strains, defined as strains with resistance to at least isoniazid and rif icin) and in 7% of those with multidrug-resistant strains at diagnosis. Overall, 3.5% of the patients not initially infected with multidrug-resistant TB strains developed such strains during treatment. Amplification of resistance, however, was found only in polyresistant Beijing genotype strains. High levels of lification of drug resistance demonstrated under well-established DOTS program conditions reinforce the need for implementation of DOTS-Plus for multidrug-resistant TB in areas with high levels of drug resistance. The strong association of Beijing genotype and lification in situations of preexisting resistance is striking and may underlie the strong association between this genotype and drug resistance.
Publisher: Elsevier BV
Date: 07-2023
Publisher: Elsevier BV
Date: 07-2021
Publisher: Massachusetts Medical Society
Date: 27-11-2008
DOI: 10.1056/NEJMC0805644
Publisher: Springer Science and Business Media LLC
Date: 17-01-2020
DOI: 10.1186/S12889-019-8035-Z
Abstract: Patient-centered care is pillar 1 of the “End TB” strategy, but little has been documented in the literature about what this means for people living with rif icin-resistant (RR-TB). Optimizing care for such in iduals requires a better understanding of the challenges they face and the support they need. A qualitative study was done among persons living with RR-TB and members of their support network. A purposive s le was selected from a larger study population and open-ended interviews were conducted using a semi-standard interview guide. Interviews were recorded and transcribed and the content analyzed using an iterative thematic analysis based in grounded theory. 16 participants were interviewed from three different provinces. Four distinct periods in which support was needed were identified: 1) pre-diagnosis 2) pre-treatment 3) treatment and 4) post-treatment. Challenges common in all four periods included: socioeconomic issues, centralized care, and the need for better counseling at multiple levels. Beyond being a “very humiliating illness”, RR-TB robs people of their physical, social, economic, psychological, and emotional well-being far beyond the period when treatment is being administered. Efforts to tackle these issues are as important as new drugs and diagnostics in the fight against TB.
Publisher: Oxford University Press (OUP)
Date: 21-02-2023
DOI: 10.1093/OFID/OFAD087
Abstract: Children and adolescents with household exposure to multidrug- or rif icin-resistant tuberculosis (MDR/RR-TB) are at high risk of developing TB disease. Tuberculosis preventive therapy (TPT) is recommended, but programmatic experience is limited, particularly for adolescents. We conducted a prospective cohort study to describe MDR/RR-TB diagnosis and TPT provision for in iduals aged & years with MDR/RR-TB exposure. Participants were assessed for TB either in homes or health facilities, with referral for chest x-ray or specimen collection at clinician discretion. The TPT regimens included levofloxacin, isoniazid, or delamanid monotherapy for 6 months, based on source patient drug-resistance profile. Between March 1, 2020 and July 31, 2021, 112 participants were enrolled median age was 8.5 years, 57 (51%) were female, and 6 (5%) had human immunodeficiency virus. On screening, 11 (10%) were diagnosed with TB: 10 presumptive MDR/RR-TB and 1 drug-susceptible TB. Overall, 95 (94% of 101) participants started TPT: 79 with levofloxacin, 9 with isoniazid, and 7 with delamanid. Seventy-six (80%) completed TPT, 12 (13%) were lost to follow up, and 7 (7%) stopped TPT early due to adverse events. Potential adverse events were reported for 12 (13%) participants none were serious. There were no further TB diagnoses (200 days median follow up). Post-MDR/RR-TB exposure management for children and adolescents resulted in significant MDR/RR-TB detection and both high TPT initiation and completion. Tuberculosis preventive monotherapy was well tolerated and there were no further TB diagnoses after initial assessment. Key factors supporting these outcomes included use of pediatric formulations for young children, monotherapy, and community-based options for assessment and follow up.
Publisher: International Union Against Tuberculosis and Lung Disease
Date: 03-2013
Abstract: Scaling up treatment for multidrug-resistant tuberculosis is a global health priority. However, current treatment regimens are long and associated with side effects, and default rates are consequently high. This systematic review aimed to identify strategies for reducing treatment default. We conducted a systematic search up to May 2012 to identify studies describing interventions to support patients receiving treatment for multidrug-resistant tuberculosis (MDR-TB). The potential influence of study interventions were explored through subgroup analyses. A total of 75 studies provided outcomes for 18,294 patients across 31 countries. Default rates ranged from 0.5% to 56%, with a pooled proportion of 14.8% (95%CI 12.4-17.4). Strategies identified to be associated with lower default rates included the engagement of community health workers as directly observed treatment (DOT) providers, the provision of DOT throughout treatment, smaller cohort sizes and the provision of patient education. Current interventions to support adherence and retention are poorly described and based on weak evidence. This review was able to identify a number of promising, inexpensive interventions feasible for implementation and scale-up in MDR-TB programmes. The high default rates reported from many programmes underscore the pressing need to further refine and evaluate simple intervention packages to support patients.
Publisher: International Union Against Tuberculosis and Lung Disease
Date: 2020
Abstract: SETTING: Thirteen districts in Eastern Cape (EC), KwaZulu-Natal (KZN) and Western Cape (WC) Provinces, South Africa. OBJECTIVE: To pilot a methodology for describing and visualising healthcare journeys among drug-resistant tuberculosis (DR-TB) patients using routine laboratory records. DESIGN: Laboratory records were obtained for 195 patients with laboratory-detected rif icin-resistant TB (RR-TB) during July–September 2016. Health facility visits identified from these data were plotted to visualise patient healthcare journeys. Data were verified by facility visits. RESULTS: In the 9 months after the index RR-TB s le was collected, patients visited a mean of 2.3 health facilities (95% CI 2.1–2.6), with 9% visiting ≥4 facilities. The median distance travelled by patients from rural areas (116 km, interquartile range [IQR] 50–290) was greater than for urban patients (51 km, IQR 9–140). A median of 21% of patient's time was spent under the care of primary healthcare facilities: this was respectively 6%, 37% and 39% in KZN, EC and WC. Journey patterns were generally similar within districts. Some reflected a semi-centralised model of care where patients were referred to regional hospitals other journeys showed greater involvement of primary care. CONCLUSION: Routine laboratory data can be used to explore DR-TB patient healthcare journeys and show how the use of healthcare services for DR-TB varies in different settings.
Publisher: Elsevier BV
Date: 03-2015
DOI: 10.1016/J.IJID.2014.12.012
Abstract: Multidrug-resistant tuberculosis (MDR-TB) is on the rise, and is difficult to treat. The approval of two new drugs, bedaquiline and delamanid, and growing evidence for the use of linezolid, offer renewed hope for addressing MDR-TB. However, access to these medicines remains a significant challenge. These drugs have not been registered for TB in most settings barriers to preapproval access persist and high pricing and intellectual property restrictions limit access. Many unanswered research questions about optimal use of these drugs also limit access, particularly for vulnerable populations. This review outlines challenges in accessing drugs encountered from the perspective of clinicians, patients and affected communities, and offers potential solutions.
Publisher: Public Library of Science (PLoS)
Date: 18-03-2015
Publisher: International Union Against Tuberculosis and Lung Disease
Date: 02-2015
Publisher: Public Library of Science (PLoS)
Date: 15-11-2010
Publisher: Public Library of Science (PLoS)
Date: 10-11-2015
Publisher: South African Medical Association NPC
Date: 05-11-2020
Publisher: Oxford University Press (OUP)
Date: 24-04-2022
Abstract: Data are limited on the resolution of symptoms and signs in children treated for pulmonary tuberculosis (PTB) and whether this resolution differs from children with other lower respiratory tract infections (LRTIs). A prospective study of children ≤ 15 years presenting with features suggestive of PTB was performed. Clinical, microbiological, and radiological investigations were done at enrollment. Symptoms and clinical features were measured 1, 3, and 6 months after enrollment. Participants were categorized into 3 groups based on National Institutes of Health consensus definitions: confirmed PTB, unconfirmed PTB, and unlikely PTB (children with other LRTIs). Univariable and multivariable logistic regression modeling was used to investigate predictors of persistence of symptoms or signs. Among 2019 participants, there were 427 (21%) confirmed, 810 (40%) unconfirmed, and 782 (39%) with unlikely PTB. Of 1693/2008 (84%) with cough and 1157/1997 (58%) with loss of appetite at baseline, persistence at 3 months was reported in 24/1222 (2%) and 23/886 (3%), respectively. Of 934/1884 (50%) with tachypnoea and 947/1999 (47%) with abnormal auscultatory findings at baseline, persistence at 3 months occurred in 410/723 (57%) and 216/778 (28%), respectively. HIV infection and abnormal baseline chest radiography were associated with persistence of symptoms or signs at month 3 (adjusted odds ration [aOR] 1.6 95% confidence interval [CI]: [1.1, 2.3] and aOR 2.3 95% CI: [1.5, 3.3], respectively]. The resolution of symptoms and signs was similar across categories. Symptoms resolved rapidly in most children with PTB, but signs resolved more slowly. The pattern and resolution of symptoms or signs did not distinguish children with PTB from those with other LRTIs.
Publisher: Elsevier BV
Date: 08-2010
Publisher: International Union Against Tuberculosis and Lung Disease
Date: 10-2020
Publisher: Public Library of Science (PLoS)
Date: 07-11-2007
Publisher: Elsevier BV
Date: 03-2003
Publisher: Public Library of Science (PLoS)
Date: 31-01-2013
Publisher: Elsevier BV
Date: 10-2022
Publisher: Elsevier BV
Date: 10-2008
Publisher: European Respiratory Society (ERS)
Date: 02-04-2015
Publisher: Academy of Science of South Africa
Date: 24-07-2023
DOI: 10.17159/1996-2096/2023/V23N1A2
Abstract: In 2020 the United Nations Committee on Economic, Social and Cultural Rights published its 25th General Comment on the right to enjoy the benefits of scientific progress (REBSP). The General Comment describes the normative content of the right, including the obligations of the state and the entitlements of rights holders. It addressed the major gap in the REBSP, which was the lack of internationally-accepted interpretations of what the right entails. This article aims to shed light on the REBSP, and to demonstrate how it can be applied to advance public health. The article argues that the application of the REBSP requires a balancing act between the rights of researchers or scientists and the rights of users of the scientific knowledge they generate. It further argues that, when applied to health, the REBSP has the potential to improve access to better prevention, diagnosis and treatment of diseases, and could draw attention to neglected diseases, which mostly affect developing countries.
Publisher: Public Library of Science (PLoS)
Date: 18-10-2021
DOI: 10.1371/JOURNAL.PONE.0251482
Abstract: There are few data on the on post-treatment experiences of people who have been successfully treated for rif icin-resistant (RR-)TB. To describe the experiences and impact of RR-TB disease and therapy on post-treatment life of in iduals who were successfully treated. In this qualitative study in-depth interviews were conducted among a purposively selected s le from a population of in iduals who were successfully treated for RR-TB between January 2008 and December 2018. Interview transcripts and notes were analysed using a thematic network analysis which included grounded theory and a framework for understanding pathophysiological mechanisms for post-TB morbidity and mortality. The analysis was iterative and the coding system developed focused on disease, treatment and post-treatment experiences of in iduals. This paper follows the COREQ guidelines. For all 12 participants interviewed, the development of RR-TB disease, its diagnosis and the subsequent treatment were a major disruption to their lives as well as a transformative experience. On diagnosis of RR-TB disease, participants entered a liminal period in which their lives were marked with uncertainty and dominated by physical and mental suffering. Irrespective of how long ago they had completed their treatment, they all remembered with clarity the signs and symptoms of the disease and the arduous treatment journey. Post-treatment participants reported physical, social, psychological and economic changes as consequences of their RR-TB disease and treatment. Many participants reported a diminished ability to perform physical activities and, once discharged from the RR-TB hospital, inadequate physical rehabilitation. For some, these physical limitations impacted on their social life, and ultimately on their psychological health as well as on their ability to earn money and support their families. The experiences and impact of RR-TB disease and therapy on post-treatment life of in iduals successfully treated, highlights gaps in the current health care system that need to be addressed to improve the life of in iduals post-treatment. A more holistic and long-term view of post-TB health, including the provision of comprehensive medical and social services for post-treatment care of physical ailments, social re-integration and the mitigation of the perceived fear and risk of getting TB again could be a central part of person-centred TB care.
Publisher: Elsevier BV
Date: 11-2009
DOI: 10.1016/J.TUBE.2009.09.001
Abstract: embB306 mutations are potential markers for detecting ethambutol resistance in clinical Mycobacterium tuberculosis isolates. However, more recently, embB306 mutations have been found in ethambutol susceptible isolates and an association with broad drug resistance rather than ethambutol resistance has been reported. To further investigate this question, we analyzed the association between embB306 mutations and phenotypic ethambutol resistance among 197 isolates from a drug resistance survey performed in Karakalpakstan, Uzbekistan. 39 strains had an embB306 mutation, out of which seven were ethambutol susceptible, thus, displaying discrepant test results. After re-analysis, the seven isolates were tested ethambutol resistant. All of these strains had an increased ethambutol MIC, however, three strains showed no or weak growth on the critical concentration of 2 microg/ml on Löwenstein-Jensen. In three strains we confirmed the presence of heteroresistant mixed populations which might influence conventional ethambutol testing. Final concordance between molecular and phenotypic EMB testing was high with a sensitivity of 78% and a specificity of 100%. Our results confirm that embB306 mutations are useful markers for predicting ethambutol resistance. Discrepancies between molecular and phenotypic ethambutol resistance test results are most likely caused by problems with conventional susceptibility testing.
Publisher: International Union Against Tuberculosis and Lung Disease
Date: 11-2022
Publisher: Oxford University Press (OUP)
Date: 15-05-2015
Publisher: South African Medical Association NPC
Date: 05-05-2023
DOI: 10.7196/SAMJ.2022.V113I6.16771
Abstract: -
Publisher: Oxford University Press (OUP)
Date: 15-05-2012
Abstract: Tuberculosis was declared a global emergency by the World Health Organization (WHO) in 1993. Following the declaration and the promotion in 1995 of directly observed treatment short course (DOTS), a cost-effective strategy to contain the tuberculosis epidemic, nearly 7 million lives have been saved compared with the pre-DOTS era, high cure rates have been achieved in most countries worldwide, and the global incidence of tuberculosis has been in a slow decline since the early 2000s. However, the emergence and spread of multidrug-resistant (MDR) tuberculosis, extensively drug-resistant (XDR) tuberculosis, and more recently, totally drug-resistant tuberculosis pose a threat to global tuberculosis control. Multidrug-resistant tuberculosis is a man-made problem. Laboratory facilities for drug susceptibility testing are inadequate in most tuberculosis-endemic countries, especially in Africa thus diagnosis is missed, routine surveillance is not implemented, and the actual numbers of global drug-resistant tuberculosis cases have yet to be estimated. This exposes an ominous situation and reveals an urgent need for commitment by national programs to health system improvement because the response to MDR tuberculosis requires strong health services in general. Multidrug-resistant tuberculosis and XDR tuberculosis greatly complicate patient management within resource-poor national tuberculosis programs, reducing treatment efficacy and increasing the cost of treatment to the extent that it could bankrupt healthcare financing in tuberculosis-endemic areas. Why, despite nearly 20 years of WHO-promoted activity and >12 years of MDR tuberculosis-specific activity, has the country response to the drug-resistant tuberculosis epidemic been so ineffectual? The current dilemmas, unanswered questions, operational issues, challenges, and priority needs for global drug resistance screening and surveillance, improved treatment regimens, and management of outcomes and prevention of DR tuberculosis are discussed.
Publisher: Oxford University Press (OUP)
Date: 17-05-2022
DOI: 10.1093/CID/CIAC332
Abstract: Microbiologic diagnosis of childhood tuberculosis may be difficult. Oral swab specimens are a potential noninvasive alternative to sputum specimens for diagnosis. This was a prospective diagnostic accuracy study of oral swab specimens (buccal and tongue) for pulmonary tuberculosis diagnosis in children (aged ≤ 15 years) in 2 South African hospital sites. Children with cough of any duration as well as a positive tuberculin skin test result, tuberculosis contact, loss of weight, or chest radiograph suggestive of pulmonary tuberculosis were enrolled. Two induced sputum specimens were tested with Xpert MTB/RIF (or Xpert MTB/RIF Ultra) assay and liquid culture. Oral swab specimens were obtained before sputum specimens, frozen, and later tested with Xpert MTB/RIF Ultra. Children were classified as microbiologically confirmed tuberculosis, unconfirmed tuberculosis (receipt of tuberculosis treatment), or unlikely tuberculosis according to National Institutes of Health consensus definitions based on sputum microbiologic results. Among 291 participants (median age [interquartile range], 32 [14–73] months), 57 (20%) had human immunodeficiency virus (HIV), and 87 (30%) were malnourished 90 (31%) had confirmed pulmonary tuberculosis (rif icin resistant in 6 [7%] ), 157 (54%), unconfirmed pulmonary tuberculosis, and 44 (15%), unlikely tuberculosis. A single oral swab specimen was obtained from 126 (43%) of the participants (tongue in 96 and buccal in 30) and 2 swab specimens from 165 (57%) (tongue in 110 and buccal in 55). Sensitivity was low (22% [95% confidence interval, 15%–32%]) for all swab specimens combined (with confirmed pulmonary tuberculosis as reference), but specificity was high (100% [91%–100%]). The highest sensitivity was 33% (95% confidence interval, 15%–58%) among participants with HIV. The overall yield was 6.9% with 1 oral swab specimen and 7.2% with 2. Use of the Xpert MTB/RIF Ultra assay with oral swab specimens provides poor yield for microbiologic pulmonary tuberculosis confirmation in children.
Publisher: Elsevier BV
Date: 03-2012
Publisher: Springer Science and Business Media LLC
Date: 19-01-2015
DOI: 10.1038/NG.3195
Abstract: Mycobacterium tuberculosis strains of the Beijing lineage are globally distributed and are associated with the massive spread of multidrug-resistant (MDR) tuberculosis in Eurasia. Here we reconstructed the biogeographical structure and evolutionary history of this lineage by genetic analysis of 4,987 isolates from 99 countries and whole-genome sequencing of 110 representative isolates. We show that this lineage initially originated in the Far East, from where it radiated worldwide in several waves. We detected successive increases in population size for this pathogen over the last 200 years, practically coinciding with the Industrial Revolution, the First World War and HIV epidemics. Two MDR clones of this lineage started to spread throughout central Asia and Russia concomitantly with the collapse of the public health system in the former Soviet Union. Mutations identified in genes putatively under positive selection and associated with virulence might have favored the expansion of the most successful branches of the lineage.
Publisher: Elsevier BV
Date: 03-2012
Publisher: Oxford University Press (OUP)
Date: 15-05-2012
Abstract: Tuberculosis is unique among the major infectious diseases in that it lacks accurate rapid point-of-care diagnostic tests. Failure to control the spread of tuberculosis is largely due to our inability to detect and treat all infectious cases of pulmonary tuberculosis in a timely fashion, allowing continued Mycobacterium tuberculosis transmission within communities. Currently recommended gold-standard diagnostic tests for tuberculosis are laboratory based, and multiple investigations may be necessary over a period of weeks or months before a diagnosis is made. Several new diagnostic tests have recently become available for detecting active tuberculosis disease, screening for latent M. tuberculosis infection, and identifying drug-resistant strains of M. tuberculosis. However, progress toward a robust point-of-care test has been limited, and novel biomarker discovery remains challenging. In the absence of effective prevention strategies, high rates of early case detection and subsequent cure are required for global tuberculosis control. Early case detection is dependent on test accuracy, accessibility, cost, and complexity, but also depends on the political will and funder investment to deliver optimal, sustainable care to those worst affected by the tuberculosis and human immunodeficiency virus epidemics. This review highlights unanswered questions, challenges, recent advances, unresolved operational and technical issues, needs, and opportunities related to tuberculosis diagnostics.
Publisher: Elsevier BV
Date: 04-2011
Publisher: Public Library of Science (PLoS)
Date: 11-07-2012
Publisher: Public Library of Science (PLoS)
Date: 03-10-2006
Publisher: Public Library of Science (PLoS)
Date: 12-10-2009
Publisher: Wiley
Date: 06-2015
DOI: 10.1111/TMI.12544
Publisher: International Union Against Tuberculosis and Lung Disease
Date: 12-2022
Publisher: International Union Against Tuberculosis and Lung Disease
Date: 12-2015
Publisher: Cold Spring Harbor Laboratory
Date: 08-03-2022
DOI: 10.1101/2022.03.04.22271870
Abstract: Mycobacterium tuberculosis whole-genome sequencing (WGS) using Illumina technology has been widely adopted for genotypic drug susceptibility testing (DST) and outbreak investigation. Oxford Nanopore Technologies is reported to have higher error rates but has not been thoroughly evaluated for these applications. We analyse 151 isolates from Madagascar, South Africa and England with phenotypic DST and matched Illumina and Nanopore data. Using PacBio assemblies, we select Nanopore filters for BCFtools (software) detection of single nucleotide polymorphisms (SNPs). We compare transmission clusters identified by Nanopore and the United Kingdom Health Security Agency Illumina pipeline (COMPASS). We compare Illumina and Nanopore WGS-based DST predictions using Mykrobe (software). Nanopore/BCFtools identifies SNPs with median precision/recall of 99·5/90·2% compared with 99·6/91·9% for Illumina/COMPASS. Using a threshold of 12 SNPs for putative transmission clusters, Illumina identifies 98 isolates as unrelated and 53 as belonging to 19 distinct clusters (size range 2-7). Nanopore reproduces this distribution with addition of 5 singleton isolates to distinct clusters and merging of two cluster pairs. Illumina-based clusters are also replicated using a 5 SNP threshold. Clustering accuracy is maintained using mixed Illumina/Nanopore datasets. Genotyping resistance variants is highly concordant, with 0(4) discordant SNPs (indels) across 151 isolates genotyped at (60,000) SNPs (indels). Illumina and Nanopore sequence data provide comparable cluster-identification and DST results. Academy for Medical Sciences (SGL018\\110), Oxford Wellcome Institutional Strategic Support Fund (ISSF TT17 4). Swiss South Africa Joint Research Award (Swiss national science Foundation and South African national research foundation). Two key types of information can be obtained from laboratory testing of M. tuberculosis isolates to help directly guide public health interventions: drug susceptibility testing (DST) to guide therapy, and bacterial typing to enrich understanding of the epidemiology and guide interventions to mitigate transmission. DST is typically performed by the “gold standard” culture-based phenotyping method or nucleic acid lification assays targeting specific resistance-conferring mutations. Studies over the last 7 years have shown that prediction of susceptibility profile using Illumina-technology genome sequence data is possible, and can be automated. In a key publication, the CRyPTIC consortium and UK 100,000 Genomes project evaluated the method on over 10,000 genomes including prospectively s led isolates and showed that for first-line tuberculosis (TB) drugs (isoniazid, rif icin, ethambutol, pyrazinamide) a pan-susceptibility profile is accurate enough to be used clinically. The genetic basis of resistance remains imperfectly understood for second-line TB drugs, in particular for new and repurposed drugs (bedaquiline, clofazimine, delamanid, linezolid). Prior work in the field of genotypic DST was heavily based on Illumina technology, which provides short (70-300 base pair) sequence reads of very high quality. Many different softwares (e.g. TBProfiler, Mykrobe, MTBseq, kvarq) have been designed for sequence analysis and genotypic DST. However, the increasingly used Nanopore sequencing platforms yield very different data with much longer sequence reads (frequently over 1kb) and higher error rates including systematic biases. To date, very limited evaluation of Nanopore-based drug susceptibility prediction has been performed using the only two compatible tools (Mykrobe (n=5 independent s les), TBProfiler (n=3 independent s les)). Molecular typing of M. tuberculosis allows lineage identification and detection of putative transmission clusters. In the last decade, multiple M. tuberculosis molecular epidemiology studies have shown how genomic information can complement traditional epidemiology in identifying person-to-person transmission clusters with a high level of resolution. Typically, the number of single nucleotide polymorphism (SNP) disagreements between genomes, or SNP distance, is calculated and single-linkage clustering is performed for genomes falling within retrospectively established transmission thresholds of either 5 or 12 SNPs. Just as with DST, these thresholds were established with Illumina sequencing data. The increased error rate in Nanopore sequencing is believed to lead to inflated SNP distances if standard genome analysis tools are used. Prior to this study it was unknown what impact on isolate-clustering this would incur. Full-scale adoption of genomic sequencing in tuberculosis reference laboratories has so far taken place in a limited number of settings - England, the Netherlands, and New York State - all using Illumina-based sequencing data. Building on current evidence, specific WHO technical guidance and ersification and democratisation of technology, sequencing is expected to be increasingly used in tuberculosis control globally. For the first time, our study offers 4 key deliverables intended to inform adoption of Nanopore technology as an alternative, or a complement, to Illumina. First: a systematic head-to-head comparison of Nanopore and Illumina data for M. tuberculosis drug susceptibility profiling and isolate clustering, including quantitative metrics for cluster precision and recall. Second: an assessment of the impact of mixed Illumina and Nanopore data on clustering which represents an increasingly common challenge. Third: an open-source software pipeline allowing research and reference laboratories to replicate our analytical approach. Fourth: a publicly available curated test set of 151 isolates, including matched Illumina and Nanopore sequence data, and (for a subset of seven isolates) high-quality PacBio assemblies, for method development and validation. Catalogues of drug resistance conferring mutations will keep improving, especially for new and repurposed drugs. Our data confirms that Illumina and Nanopore sequencing technologies can be used to identify those mutations equally accurately in M. tuberculosis . Bacterial molecular typing is constantly shown to support the understanding of disease transmission and tuberculosis control in new settings. The bioinformatics tools and filters we have developed, assessed, and made publicly available allow the use of Nanopore or mixed-technology data to appropriately cluster genetically related isolates. We provide a measure of the expected level of over-clustering associated with Nanopore technology. This study confirms that Illumina and Nanopore sequence data provide comparable DST results and isolate cluster-identification.
Publisher: American Society for Microbiology
Date: 18-10-2021
DOI: 10.1128/AAC.00364-21
Abstract: Rif in monoresistance (RMR rif in resistance and isoniazid susceptibility) accounts for 38% of all rif in-resistant tuberculosis (RR-TB) in South Africa and is increasing. We aimed to compare RMR-TB with multidrug-resistant TB (MDR-TB) in a setting with high TB, RR-TB, and HIV burdens.
Publisher: Elsevier BV
Date: 08-2014
Publisher: Cold Spring Harbor Laboratory
Date: 20-10-2020
DOI: 10.1101/2020.10.20.346866
Abstract: Lineage 1 (L1) and 3 (L3) are two lineages of the Mycobacterium tuberculosis complex (MTBC), causing tuberculosis (TB) in humans. L1 and L3 are endemic to the Rim of the Indian Ocean, the region that accounts for most of the world’s new TB cases. Despite their relevance for this region, L1 and L3 remain understudied. Here we analyzed 2,938 L1 and 2,030 L3 whole genome sequences originating from 69 countries. We show that South Asia played a central role in the dispersion of these two lineages to neighboring regions. Moreover, we found that L1 exhibits signatures of local adaptation at the esxH locus, a gene coding for a secreted effector that targets the human endosomal sorting complex, and is included in several vaccine candidates. Our study highlights the importance of genetic ersity in the MTBC, and sheds new light on two of the most important MTBC lineages affecting humans.
Publisher: Springer Science and Business Media LLC
Date: 30-03-2010
Publisher: Elsevier BV
Date: 2013
Publisher: Public Library of Science (PLoS)
Date: 13-02-2023
DOI: 10.1371/JOURNAL.PONE.0281097
Abstract: Updated World Health Organization (WHO) treatment guidelines prioritize all-oral drug-resistant tuberculosis (DR-TB) regimens. Several poorly tolerated drugs, such as amikacin and para-aminosalicylic acid (PAS), remain treatment options for DR-TB in WHO-recommended longer regimens as Group C drugs. Incomplete treatment with anti-TB drugs increases the risk of treatment failure, relapse, and death. We determined whether missed doses of in idual anti-TB drugs, and reasons for their discontinuation, varied in closely monitored hospital settings prior to the 2020 WHO DR-TB treatment guideline updates. We collected retrospective data on adult patients with microbiologically confirmed DR-TB between 2008 and 2015 who were selected for a study of acquired drug resistance in the Western Cape Province of South Africa. Medical records through mid-2017 were reviewed. Patients received directly observed treatment during hospitalization at specialized DR-TB hospitals. Incomplete treatment with in idual anti-TB drugs, defined as the failure to take medication as prescribed, regardless of reason, was determined by comparing percent missed doses, stratified by HIV status and DR-TB regimen. We applied a generalized mixed effects model. Among 242 patients, 131 (54%) were male, 97 (40%) were living with HIV, 175 (72%) received second-line treatment prior to first hospitalization, and 191 (79%) died during the study period. At initial hospitalization, 134 (55%) patients had Mycobacterium tuberculosis with resistance to rif icin and isoniazid (multidrug-resistant TB [MDR-TB]) without resistance to ofloxacin or amikacin, and 102 (42%) had resistance to ofloxacin and/or amikacin. Most patients (129 [53%]) had multiple hospitalizations and DST changes occurred in 146 (60%) by the end of their last hospital discharge. Incomplete treatment was significantly higher for amikacin (18%), capreomycin (18%), PAS (17%) and kanamycin (16%) than other DR-TB drugs (P .001), including ethionamide (8%), moxifloxacin (7%), terizidone (7%), ethambutol (7%), and pyrazinamide (6%). Among the most frequently prescribed drugs, second-line injectables had the highest rates of discontinuation for adverse events (range 0.56–1.02 events per year follow-up), while amikacin, PAS and ethionamide had the highest rates of discontinuation for patient refusal (range 0.51–0.68 events per year follow-up). Missed doses did not differ according to HIV status or anti-TB drug combinations. We found that incomplete treatment for second-line injectables and PAS during hospitalization was higher than for other anti-TB drugs. To maximize treatment success, interventions to improve person-centered care and mitigate adverse events may be necessary in cases when PAS or amikacin (2020 WHO recommended Group C drugs) are needed.
Publisher: Elsevier BV
Date: 10-2015
Publisher: F1000 Research Ltd
Date: 02-2021
DOI: 10.12688/F1000RESEARCH.28318.1
Abstract: Background: Lineage 1 (L1) and 3 (L3) are two lineages of the Mycobacterium tuberculosis complex (MTBC) causing tuberculosis (TB) in humans. L1 and L3 are prevalent around the rim of the Indian Ocean, the region that accounts for most of the world’s new TB cases. Despite their relevance for this region, L1 and L3 remain understudied. Methods: We analyzed 2,938 L1 and 2,030 L3 whole genome sequences originating from 69 countries. We reconstructed the evolutionary history of these two lineages and identified genes under positive selection. Results: We found a strongly asymmetric pattern of migration from South Asia toward neighboring regions, highlighting the historical role of South Asia in the dispersion of L1 and L3. Moreover, we found that several genes were under positive selection, including genes involved in virulence and resistance to antibiotics . For L1 we identified signatures of local adaptation at the esxH locus, a gene coding for a secreted effector that targets the human endosomal sorting complex, and is included in several vaccine candidates. Conclusions: Our study highlights the importance of genetic ersity in the MTBC, and sheds new light on two of the most important MTBC lineages affecting humans.
Publisher: Public Library of Science (PLoS)
Date: 06-12-2013
Publisher: Springer Science and Business Media LLC
Date: 30-08-2022
DOI: 10.1038/S41467-022-32455-1
Abstract: Transmission-driven multi-/extensively drug resistant (M/XDR) tuberculosis (TB) is the largest single contributor to human mortality due to antimicrobial resistance. A few major clades of the Mycobacterium tuberculosis complex belonging to lineage 2, responsible for high prevalence of MDR-TB in Eurasia, show outstanding transnational distributions. Here, we determined factors underlying the emergence and epidemic spread of the W148 clade by genome sequencing and Bayesian demogenetic analyses of 720 isolates from 23 countries. We dated a common ancestor around 1963 and identified two successive epidemic expansions in the late 1980s and late 1990s, coinciding with major socio-economic changes in the post-Soviet Era. These population expansions favored accumulation of resistance mutations to up to 11 anti-TB drugs, with MDR evolving toward additional resistances to fluoroquinolones and second-line injectable drugs within 20 years on average. Timescaled haplotypic density analysis revealed that widespread acquisition of compensatory mutations was associated with transmission success of XDR strains. Virtually all W148 strains harbored a hypervirulence-associated ppe38 gene locus, and incipient recurrent emergence of prpR mutation-mediated drug tolerance was detected. The outstanding genetic arsenal of this geographically widespread M/XDR strain clade represents a “perfect storm” that jeopardizes the successful introduction of new anti-M/XDR-TB antibiotic regimens.
No related grants have been discovered for Helen Cox.