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Schematic diagram of the region flanking the direct repeat (DR) region in H37Rv, nonBeijing and Beijing strains. Large arrows indicate open reading frames according to the annotation of Cole and coworkers (29). The IS6110 insertion in the DR region is indicated by a square box (note: IS6110 is inverted in the Beijing strain family). The region specifically deleted in all Beijing strains is indicated by dotted lines (18, 19). Primer positions (sets 1, 2, 3, and 4) are indicated by small arrows.
Source publication
South Africa has a high burden of drug-resistant tuberculosis (TB).
Routine drug susceptibility testing was performed prospectively over a 2-year period on Mycobacterium tuberculosis isolates in two health districts of the Western Province, South Africa. A cluster of drug-resistant strains that shared a rare mutation in katG315 was found in 64 of t...
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During 1999 to 2000, we identified HIV-infected persons with new episodes of tuberculosis (TB) at 10 hospitals in Lima, Peru, and a random sample of other Lima residents with TB. Multidrug-resistant (MDR)-TB was documented in 35 (43%) of 81 HIV-positive patients and 38 (3.9%) of 965 patients who were HIV-negative or of unknown HIV status (p<0.001)....
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Citations
... Although some MDR-M. tuberculosis strains are in fact less transmissible, several reports showed that certain strains were able to cause community-wide outbreaks involving the immunocompetent population [12,[52][53][54][55]. Because antimicrobials target essential functions of M. tuberculosis, the acquisition of drug-resistance conferring mutations has an impact in bacterial fitness, which can be defined as the ability of a certain pathogen to be transmitted and cause disease [4,51]. ...
Multidrug-resistant tuberculosis is one of the major obstacles that face the tuberculosis eradication efforts. Drug-resistant Mycobacterium tuberculosis clones were initially disregarded as a public health threat, because they were assumed to have paid a high fitness cost in exchange of resistance acquisition. However, some genotypes manage to overcome the impact of drug-resistance conferring mutations, retain transmissibility and cause large outbreaks. In Argentina, the HIV-AIDS epidemics fuelled the expansion of the so-called M strain in the early 1990s, which is responsible for the largest recorded multidrug-resistant tuberculosis cluster of Latin America. The aim of this work is to review the knowledge gathered after nearly three decades of multidisciplinary research on epidemiological, microbiological and immunological aspects of this highly successful strain. Collectively, our results indicate that the successful transmission of the M strain could be ascribed to its unaltered virulence, low Th1/Th17 response, a low fitness cost imposed by the resistance conferring mutations and a high resistance to host-related stress. In the early 2000s, the incident cases due to the M strain steadily declined and stabilized in the latest years. Improvements in the management, diagnosis and treatment of multidrug-resistant tuberculosis along with societal factors such as the low domestic and international mobility of the patients affected by this strain probably contributed to the outbreak containment. This stresses the importance of sustaining the public health interventions to avoid the resurgence of this conspicuous multidrug-resistant strain.
... The X1 cluster containing 28 isolates and X3 cluster with eight cases were identified in WC. The X strains have been reported to have caused large DR-TB outbreaks in WC historically [8,38]. ...
Background
Studies have shown that drug-resistant tuberculosis (DR-TB) in South Africa (SA) is clonal and is caused mostly by transmission. Identifying transmission chains is important in controlling DR-TB. This study reports on the sentinel molecular surveillance data of Rifampicin-Resistant (RR) TB in SA, aiming to describe the RR-TB strain population and the estimated transmission of RR-TB cases.
Method
RR-TB isolates collected between 2014 and 2018 from eight provinces were genotyped using combination of spoligotyping and 24-loci mycobacterial interspersed repetitive-units-variable-number tandem repeats (MIRU-VNTR) typing.
Results
Of the 3007 isolates genotyped, 301 clusters were identified. Cluster size ranged between 2 and 270 cases. Most of the clusters (247/301; 82.0%) were small in size (< 5 cases), 12.0% (37/301) were medium sized (5–10 cases), 3.3% (10/301) were large (11–25 cases) and 2.3% (7/301) were very large with 26–270 cases. The Beijing genotype was responsible for majority of RR-TB cases in Western and Eastern Cape, while the East-African-Indian-Somalian (EAI1_SOM) genotype accounted for a third of RR-TB cases in Mpumalanga. The overall proportion of RR-TB cases estimated to be due to transmission was 42%, with the highest transmission-rate in Western Cape (64%) and the lowest in Northern Cape (9%).
Conclusion
Large clusters contribute to the burden of RR-TB in specific geographic areas such as Western Cape, Eastern Cape and Mpumalanga, highlighting the need for community-wide interventions. Most of the clusters identified in the study were small, suggesting close contact transmission events, emphasizing the importance of contact investigations and infection control as the primary interventions in SA.
... The South African Tuberculosis Drug Resistant Tuberculosis Survey from 2012-2014 estimated that 4.3% of tuberculosis cases in the Western Cape Province were RR, a figure very close to our province-wide mean estimate of 4.6% [12]. We successfully identified areas known to have a high burden of RR-tuberculosis, such as poorer townships in Cape Town [25], communities near George [26], and an outbreak in the West Coast District (Fig 3) [27]. We also identified areas warranting further investigation for RR-tuberculosis, such as rural wine and farming regions and communities bordering the Eastern Cape Province-an area with poorer healthcare infrastructure, known higher drug-resistant tuberculosis rates, and from where drug-resistant tuberculosis cases have been linked via molecular epidemiology studies [28][29][30]. ...
Background
South Africa has the highest tuberculosis incidence globally (781/100,000), with an estimated 4.3% of cases being rifampicin resistant (RR). Control and elimination strategies will require detailed spatial information to understand where drug-resistant tuberculosis exists and why it persists in those communities. We demonstrate a method to enable drug-resistant tuberculosis monitoring by identifying high-burden communities in the Western Cape Province using routinely collected laboratory data.
Methods and findings
We retrospectively identified cases of microbiologically confirmed tuberculosis and RR-tuberculosis from all biological samples submitted for tuberculosis testing (n = 2,219,891) to the Western Cape National Health Laboratory Services (NHLS) between January 1, 2008, and June 30, 2013. Because the NHLS database lacks unique patient identifiers, we performed a series of record-linking processes to match specimen records to individual patients. We counted an individual as having a single disease episode if their positive samples came from within two years of each other. Cases were aggregated by clinic location (n = 302) to estimate the percentage of tuberculosis cases with rifampicin resistance per clinic. We used inverse distance weighting (IDW) to produce heatmaps of the RR-tuberculosis percentage across the province. Regression was used to estimate annual changes in the RR-tuberculosis percentage by clinic, and estimated average size and direction of change was mapped. We identified 799,779 individuals who had specimens submitted from mappable clinics for testing, of whom 222,735 (27.8%) had microbiologically confirmed tuberculosis. The study population was 43% female, the median age was 36 years (IQR 27–44), and 10,255 (4.6%, 95% CI: 4.6–4.7) cases had documented rifampicin resistance. Among individuals with microbiologically confirmed tuberculosis, 8,947 (4.0%) had more than one disease episode during the study period. The percentage of tuberculosis cases with rifampicin resistance documented among these individuals was 11.4% (95% CI: 10.7–12.0). Overall, the percentage of tuberculosis cases that were RR-tuberculosis was spatially heterogeneous, ranging from 0% to 25% across the province. Our maps reveal significant yearly fluctuations in RR-tuberculosis percentages at several locations. Additionally, the directions of change over time in RR-tuberculosis percentage were not uniform. The main limitation of this study is the lack of unique patient identifiers in the NHLS database, rendering findings to be estimates reliant on the accuracy of the person-matching algorithm.
Conclusions
Our maps reveal striking spatial and temporal heterogeneity in RR-tuberculosis percentages across this province. We demonstrate the potential to monitor RR-tuberculosis spatially and temporally with routinely collected laboratory data, enabling improved resource targeting and more rapid locally appropriate interventions.
... The World Health Organisation (WHO) estimates that one out of every 100 people develop active TB disease in South Africa every year (WHO 2014). As a result of poor TB control programmes and treatment strategies, M. tuberculosis strains have been found to disseminate in MDR (resistance to isoniazid and rifampicin) and XDR (MDR in addition to resistance to any fluoroquinolone and at least one injectable drug) forms in South Africa (Pillay and Sturm 2007;Victor et al. 2007;Cox et al. 2010;WHO 2014;Cohen et al. 2015). Moreover, the appearance of XDR-TB is strongly associated with specific strain genotypes (Muller et al. 2013;Cohen et al. 2015), including the F15/LAM4/KZN (KZN) genotype which caused the largest XDR-TB outbreak, in Tugela Ferry, KwaZulu-Natal (Gandhi et al. 2006). ...
While the acquisition of drug resistance is often accompanied by fitness costs, Mycobacterium tuberculosis has developed mechanisms to overcome these costs in the form of compensatory mutations. In an attempt to dissect strain-specific differences in biological fitness, 10 M. tuberculosis genomes, representing F15/LAM4/KZN, Beijing, F11 and F28 genotypes were sequenced on the Illumina MiSeq platform. Drug-susceptible F15/LAM4/KZN strains differed by 43 SNPs, demonstrating that heterogeneity exists even among closely-related strains. We found unique, nonsynonymous single-nucleotide polymorphisms (SNPs) in the sigA and grcC1 genes of multidrug resistant (MDR) and XDR F15/LAM4/KZN strains, respectively. The F28 MDR strain harboured a novel ubiA mutation in combination with its embB M306I mutation, which may be related to ethambutol resistance. In addition, it possessed a low-frequency rpoC mutation, suggesting that this strain was in the process of developing compensation. In contrast, no compensatory mutations were identified in Beijing and F11 MDR strains, corroborating its low in vitro fitness. Clinical strains also harboured unique SNPs in a number of important genes associated with virulence, highlighting the need for future studies which examine the correlation of genetic variations with phenotypic diversity. In summary, whole-genome sequencing revealed the presence of fitness-compensatory mutations in F15/LAM4/KZN and F28 genotypes which predominate in MDR and/or extensively drug resistant (XDR) forms in KwaZulu-Natal, South Africa.
... The spread of TB in immune-compromised HIV/AIDS patients has coincided with the development of multidrug resistant (MDR) and Extremely drug resistant (XDR) strains of Mtb. Immuno-compromised HIV-infected individuals more rapidly develop resistance to drugs, especially rifampicin and ethambutol, and this leads to failure of the treatment (Victor et al., 2007;Andrew et al., 2007).Multidrug-resistant (MDR) TB is in vitro resistant to at least the two front-line antitubercular drugs rifampicin (RIF) and isoniazid (INH) (WHO, 2006). Extensively drugresistant (XDR) TB is described as any Mtb strain resistant to RIF and INH, as well as to any member of the fluoroquinolone drug family (Shenoi and Friedland, 2009), and to at least any of the second-line injectable drugs (kanamycin, capreomycin or amikacin) (Shenoi and Friedland, 2009). ...
... These prisons were not only over-crowded but also characterized by inadequate ventilation and malnutrition [20]. Such conditions resulted in high transmission of TB [7][8][9][10]. Between 1991 and 1997 the mortality rate in Russian prisons more than doubled with approximately half of these deaths being attributed to TB [47] and by 1999, one-third of all TB cases in Russia were in prisons [48]. ...
Background
A systematic literature review was performed to investigate the occurrence of multidrug-resistant tuberculosis (MDR TB) in prisons located in countries formerly part of the Soviet Union.
Methods
A systematic search of published studies reporting MDR TB occurrence in prisons located in former Soviet countries was conducted by probing PubMed and Cumulative Index Nursing and Allied Health Literature for articles that met predetermined inclusion criteria.
Results
Seventeen studies were identified for systematic review. Studies were conducted in six different countries. Overall, prevalence of MDR TB among prisoners varied greatly between studies. Our findings suggest a high prevalence of MDR TB in prisons of Post-Soviet states with percentages as high as 16 times more than the worldwide prevalence estimated by the WHO in 2014.
Conclusion
All studies suggested a high prevalence of MDR TB in prison populations in Post-Soviet states.
... 77 Other studies using different typing techniques (including phenotyping) at the individual or population level have similarly suggested that INH resistance arises before RMP resistance. [78][79][80][81] Results at the population level may, however, simply reflect when the different drugs were introduced and the more rapid mutation rate to INH resistance. A recent study across five continents, however, not only indicated that in 96% of MDR strains INH resistance was observed before RMP resistance, but also that this was independent of lineage, where strains were sampled from, and the time when resistance arose i.e. ...
The drug isoniazid (INH) is a key component of global tuberculosis (TB) control programmes. It is estimated, however, that 16.1% of TB disease cases in the former Soviet Union countries and 7.5% of cases outside of these settings have non-multidrug-resistant (MDR) INH resistance. Resistance has been linked to poorer treatment outcomes, post-treatment relapse and death, at least for specific sites of disease. Multiple genetic loci are associated with phenotypic resistance; however, the relationship between genotype and phenotype is complex, and restricts the use of rapid sequencing techniques as part of the diagnostic process to determine the most appropriate treatment regimens for patients. The burden of resistance also influences the usefulness of INH preventive therapy. Despite seven decades of INH use, our knowledge in key areas such as the epidemiology of resistant strains, their clinical consequences, whether tailored treatment regimens are required and the role of INH resistance in fuelling the MDR-TB epidemic is limited. The importance of non-MDR INH resistance needs to be re-evaluated both globally and by national TB control programmes.
... For this reason, health care workers are even at a greater risk as they meet such people on a routine basis as they perform their duties. Unfortunately, a number of studies from other countries have found that health care workers do not always have sufficient knowledge and the right attitude in order to adopt acceptable practices for preventing the spread of resistant tuberculosis and treating tuberculosis adequately [2][3][4][5]. ...
Tuberculosis (TB) is a global public health concern. It is even more so as its incidence seems to be increasing in South Africa. The aim of this study was to describe and compare the tuberculosis infection control measures implemented by facilities in Ugu and Uthungulu health districts of Kwazulu-Natal province.
This was a cross-sectional survey based on a self-administered questionnaire and site visit observations. Data were collected from healthcare workers at 52 health facilities from the beginning of February to mid-March 2012. The facilities that completed the questionnaires were visited for site observations.
The mean age of participants was 44.7 ± 11.7 years of age, ranging from 22 to 66 years old; 89.1% of them were females and nurses. Overall, some 48.6% (18 out of 37) of aspects of tuberculosis infection control encompassing administrative, environmental, clinical and occupational health measures were complied with by at least 80% of facilities surveyed. The unfortunate outcome of this inadequate compliance was that 23 and 12 cases of nosocomial tuberculosis had been diagnosed among staff members respectively in Ugu and Uthungulu districts.
Overall, it appears that at the facilities surveyed, less than 50% of tuberculosis infection control measures were complied with. This finding calls for appropriate interventions to be designed and implemented. These include the purchase and installation of environmental control systems; the implementation of administrative tuberculosis infection control measures at each facility together with the training of staff members on the strict adherence to preventive measures including the use of personal protective equipment.
... Our use of RFLP spoligotyping helped to provide some resolution. The AH strains have been reported to have caused large drug-resistant outbreaks in the Western Cape of South Africa (29,39), a finding consistent with ours (Table E2). ...
HIV-associated tuberculosis remains a major health problem among the gold-mining workforce in South Africa. We postulate that high levels of recent transmission, indicated by strain clustering, are fueling the tuberculosis epidemic among gold miners.
To combine molecular and epidemiologic data to describe Mycobacterium tuberculosis genetic diversity, estimate levels of transmission, and examine risk factors for clustering.
We conducted a cross-sectional study of culture-positive M. tuberculosis isolates in 15 gold mine shafts across three provinces in South Africa. All isolates were subject IS6110-based restriction fragment length polymorphisms, and we performed spoligotyping analysis and combined it with basic demographic and clinical information.
Of the 1,602 M. tuberculosis patient isolates, 1,240 (78%) had genotyping data available for analysis. A highly diverse bacillary population was identified, comprising a total of 730 discrete genotypes. Four genotypic families (Latin American Mediterranean spoligotype family; W-Beijing; AH or X; and T1-T4) accounted for over 50% of all strains. Overall, 45% (560/1,240) of strains were genotypically clustered. The minimum estimate for recent transmission (n - 1 method) was 32% (range, 27-34%). There were no individual-level risk factors for clustering, apart from borderline evidence for being non-South African and having self-reported HIV infection.
The high M. tuberculosis genetic diversity and lack of risk factors for clustering are indicative of a universal risk for disease among gold miners and likely mixing with nonmining populations. Our results underscore the urgent need to intensify interventions to interrupt transmission across the entire gold-mining workforce in South Africa.
... Although some of the in-vitro data show conflicting results [45,46], current thinking is that virulent strains subvert the immune system by causing a reduced inflammatory response, which in turn results in impaired bacterial control by the host, more rapidly progressive disease, and enhanced transmission. Strain virulence also can be inferred from the capacity of MTB clones to spread in human populations, as measured by the identification of strain clusters using genotyping techniques [11,15,19,47]. However, it remains unclear whether there is a microbial basis to explain why some clinical isolates cause widespread disease and other closely related strains remain limited in spread [46,48,49]. ...
The degree to which tuberculosis (TB) is transmitted between persons is variable. Identifying the factors that contribute to transmission could provide new opportunities for TB control. Transmission is influenced by host, bacterial and environmental factors. However, distinguishing their individual effects is problematic because measures of disease severity are tightly correlated, and assessing the virulence of Mycobacterium tuberculosis isolates is complicated by epidemiological and clinical confounders.To overcome these problems, we investigated factors potentially associated with TB transmission within households.We evaluated patients with smear-positive (≥2+), pulmonary TB and classified M. tuberculosis strains into single nucleotide polymorphism genetic cluster groups (SCG). We recorded index case, household contact, and environmental characteristics and tested contacts with tuberculin skin test (TST) and interferon-gamma release assay. Households were classified as high (≥70% of contacts with TST≥10 mm) and low (≤40%) transmission. We used logistic regression to determine independent predictors.From March 2008 to June 2012, we screened 293 TB patients to enroll 124 index cases and their 731 contacts. There were 23 low and 73 high transmission households. Index case factors associated with high transmission were severity of cough as measured by a visual analog cough scale (VACS) and the Leicester Cough Questionnaire (LCQ), and cavitation on chest radiograph. SCG 3b strains tended to be more prevalent in low (27.3%) than in high (12.5%) transmission households (p = 0.11). In adjusted models, only VACS (p
