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Abstract Background Drug-resistant tuberculosis (DR-TB) epidemic is driven mainly by the effect of ongoing transmission. In high-burden settings such as South Africa (SA), considerable demographic and geographic heterogeneity in DR-TB transmission exists. Thus, a better understanding of risk-factors for clustering can help to prioritise resources to specifically targeted high-risk groups as well as areas that contribute disproportionately to transmission. Methods The study analyzed potential risk-factors for recent transmission in SA, using data collected from a sentinel molecular surveillance of DR-TB, by comparing demographic, clinical and epidemiologic characteristics with clustering and cluster sizes. A genotypic cluster was defined as two or more patients having identical patterns by the two genotyping methods used. Clustering was used as a proxy for recent transmission. Descriptive statistics and multinomial logistic regression were used. Result The study identified 277 clusters, with cluster size ranging between 2 and 259 cases. The majority (81.6%) of the clusters were small (2–5 cases) with few large (11–25 cases) and very large (≥ 26 cases) clusters identified mainly in Western Cape (WC), Eastern Cape (EC) and Mpumalanga (MP). In a multivariable model, patients in clusters including 11–25 and ≥ 26 individuals were more likely to be infected by Beijing family, have XDR-TB, living in Nelson Mandela Metro in EC or Umgungunglovo in Kwa-Zulu Natal (KZN) provinces, and having history of imprisonment. Individuals belonging in a small genotypic cluster were more likely to infected with Rifampicin resistant TB (RR-TB) and more likely to reside in Frances Baard in Northern Cape (NC). Conclusion Sociodemographic, clinical and bacterial risk-factors influenced rate of Mycobacterium tuberculosis (M. tuberculosis) genotypic clustering. Hence, high-risk groups and hotspot areas for clustering in EC, WC, KZN and MP should be prioritized for targeted intervention to prevent ongoing DR-TB transmission.

Tuberculosis (TB) and non-communicable diseases (NCD) share predisposing risk factors. TB-associated NCD might cluster within households affected with TB requiring shared prevention and care strategies. We conducted an individual participant data meta-analysis of national TB prevalence surveys to determine whether NCD cluster in members of households with TB. We identified eligible surveys that reported at least one NCD or NCD risk factor through the archive maintained by the World Health Organization and searching in Medline and Embase from 1 January 2000 to 10 August 2021, which was updated on 23 March 2023. We compared the prevalence of NCD and their risk factors between people who do not have TB living in households with at least one person with TB (members of households with TB), and members of households without TB. We included 16 surveys (n = 740,815) from Asia and Africa. In a multivariable model adjusted for age and gender, the odds of smoking was higher among members of households with TB (adjusted odds ratio (aOR) 1.23; 95% CI: 1.11-1.38), compared with members of households without TB. The analysis did not find a significant difference in the prevalence of alcohol drinking, diabetes, hypertension, or BMI between members of households with and without TB. Studies evaluating household-wide interventions for smoking to reduce its dual impact on TB and NCD may be warranted. Systematically screening for NCD using objective diagnostic methods is needed to understand the actual burden of NCD and inform comprehensive interventions.

OBJECTIVES/GOALS: DR-TB care in South Africa includes decentralized treatment with shorter, all-oral regimens. Treatment guidelines direct regular clinical and laboratory evaluation to assess patient improvement. We therefore measured sputum collection frequency and follow-up time to assess fidelity to these guidelines in Gauteng Province, South Africa. METHODS/STUDY POPULATION: We included Rifampicin-resistant (RR) sputum specimens from the South African National Health Laboratory Service, which provides pathology services to 80% of the population, submitted between August 2022-September 2023. Patient data were obtained from a DR-TB registry and additional sputum specimen data were collected from follow-up laboratory worksheets. Follow-up spanned from first sputum collection date (baseline) to patient outcome date (e.g., completion, lost) or study closure date (if still on treatment). Monthly sputum submission rate was measured for those with ≥1 additional sputum submitted. We compared patient data by treatment site: at the specialized hospital vs. any other site, using Wilcoxon ranksum and χ2 tests. RESULTS/ANTICIPATED RESULTS: Baseline RR-TB specimens were available for 142 patients, of whom 28 (20%) had specimens submitted from the specialized hospital. Patients at the specialized hospital were older (median age 41 vs. 35.5 years, p=0.03), had higher baseline fluoroquinolone resistance (10% vs. 1%, p=0.01), and longer follow-up (median 5.2 vs. 3.5 months, p=0.01) compared to patients elsewhere. Further, 43 (30%) patients had ≥1 additional sputum submitted during follow-up. Among these, monthly sputum collection rates did not differ by site (0.3 vs. 0.3 sputum per month, p=0.89). We anticipate that increased sputum frequency will be associated with successful TB treatment outcomes based on preliminary findings. DISCUSSION/SIGNIFICANCE: These findings highlight ongoing challenges with routine laboratory follow-up according to DR-TB guidelines across treatment sites in South Africa. Future research is needed to determine reasons for low sputum collection rates, such as low patient adherence, variation in practice of healthcare workers, loss to follow-up, and clinical challenges.

Summary: Background: Non-communicable diseases (NCDs) and NCD risk factors, such as smoking, increase the risk for tuberculosis (TB). Data are scarce on the risk of prevalent TB associated with these factors in the context of population-wide systematic screening and on the association between NCDs and NCD risk factors with different manifestations of TB, where ∼50% being asymptomatic but bacteriologically positive (subclinical). We did an individual participant data (IPD) meta-analysis of national and sub-national TB prevalence surveys to synthesise the evidence on the risk of symptomatic and subclinical TB in people with NCDs or risk factors, which could help countries to plan screening activities. Methods: In this systematic review and IPD meta-analysis, we identified eligible prevalence surveys in low-income and middle-income countries that reported at least one NCD (e.g., diabetes) or NCD risk factor (e.g., smoking, alcohol use) through the archive maintained by the World Health Organization and by searching in Medline and Embase from January 1, 2000 to August 10, 2021. The search was updated on March 23, 2023. We performed a one-stage meta-analysis using multivariable multinomial models. We estimated the proportion of and the odds ratio for subclinical and symptomatic TB compared to people without TB for current smoking, alcohol use, and self-reported diabetes, adjusted for age and gender. Subclinical TB was defined as microbiologically confirmed TB without symptoms of current cough, fever, night sweats, or weight loss and symptomatic TB with at least one of these symptoms. We assessed heterogeneity using forest plots and I2 statistic. Missing variables were imputed through multi-level multiple imputation. This study is registered with PROSPERO (CRD42021272679). Findings: We obtained IPD from 16 national surveys out of 21 national and five sub-national surveys identified (five in Asia and 11 in Africa, N = 740,815). Across surveys, 15.1%–56.7% of TB were subclinical (median: 38.1%). In the multivariable model, current smoking was associated with both subclinical (OR 1.67, 95% CI 1.27–2.40) and symptomatic TB (OR 1.49, 95% CI 1.34–1.66). Self-reported diabetes was associated with symptomatic TB (OR 1.67, 95% CI 1.17–2.40) but not with subclinical TB (OR 0.92, 95% CI 0.55–1.55). For alcohol drinking ≥ twice per week vs no alcohol drinking, the estimates were imprecise (OR 1.59, 95% CI 0.70–3.62) for subclinical TB and OR 1.43, 95% CI 0.59–3.46 for symptomatic TB). For the association between current smoking and symptomatic TB, I2 was high (76.5% (95% CI 62.0–85.4), while the direction of the point estimates was consistent except for three surveys with wide CIs. Interpretation: Our findings suggest that current smokers are more likely to have both symptomatic and subclinical TB. These individuals can, therefore, be prioritised for intensified screening, such as the use of chest X-ray in the context of community-based screening. People with self-reported diabetes are also more likely to have symptomatic TB, but the association is unclear for subclinical TB. Funding: None.

BackgroundAlthough tuberculosis (TB) symptoms have limited sensitivity they remain an important entry point into the TB care cascade.ObjectivesTo investigate self-reported healthcare seeking for TB symptoms in participants in a community-based survey.MethodsWe compared reasons for not seeking care in participants reporting ≥1 of four TB screening symptoms (cough, weight loss, night sweats, fever) in the first South African national TB prevalence survey (2017-2019). We used logistic regression analyses to identify sociodemographic and clinical characteristics associated with healthcare seeking.Results5,168/35,191 (14.7%) survey participants reported TB symptoms and 3,442/5168 had not sought healthcare. 2,064/3,442(60.0%) participants intended to seek care, 912 (26.5%) regarded symptoms as benign, 399 (11.6%) reported access barriers(distance and cost), 36 (1.0%) took other medications and 20(0.6%) reported health system barriers. Of the 57/98 symptomatic participants diagnosed with bacteriologically confirmed TB who had not sought care: 38(66.7%) intended to do so, 8(14.0%) regarded symptoms as benign, and 6(10.5%) reported access barriers. Among these 98, those with unknown HIV status(OR 0.16 95% CI 0.03-0.82), p = 0.03 and those who smoked tobacco products(OR 0.39, 95% CI 0.17-0.89, p = 0.03) were significantly less likely to seek care.ConclusionsPeople with TB symptoms delayed seeking healthcare, many regarded symptoms as benign while others faced access barriers. Those with unknown HIV status were significantly less likely to seek care. Strengthening community-based TB awareness and screening programmes together with self-screening models could increase awareness of the significance of TB symptoms and contribute to improving healthcare seeking and enable many people with TB to enter the TB care cascade.

Abstract 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 (

Abstract Background We aimed to describe an outbreak of cutaneous abscesses caused by Panton-Valentine leukocidin (PVL)-producing methicillin-susceptible Staphylococcus aureus (MSSA) among gold mine workers. Methods In February 2018, we retrospectively reviewed a random sample of 50 medical records from 243 cases and conducted face-to-face interviews using a structured questionnaire. Pus aspirates were sent to the National Institute for Communicable Diseases from prospectively-identified cases (November 2017–March 2018). Nasopharyngeal swabs were collected during a colonisation survey in February 2018. Staphylococcus aureus isolates were screened with a conventional PCR for lukS/F-PV. Pulsed-field gel electrophoresis (PFGE) was performed to determine the genetic relatedness among the isolates. A sample of isolates were selected for whole genome sequencing (WGS). We conducted an assessment on biological risks associated with mining activities. Results From January 2017 to February 2018, 10% (350/3582) of mine workers sought care for cutaneous abscesses. Forty-seven medical files were available for review, 96% were male (n = 45) with a mean age of 43 years (SD = 7). About 52% (24/46) were involved in stoping and 28% (13/47) worked on a particular level. We cultured S. aureus from 79% (30/38) of cases with a submitted specimen and 14% (12/83) from colonisation swabs. All isolates were susceptible to cloxacillin. Seventy-one percent of S. aureus isolates (30/42) were PVL-PCR-positive. Six PFGE clusters were identified, 57% (21/37) were closely related. WGS analysis found nine different sequence types. PFGE and WGS analysis showed more than one cluster of S. aureus infections involving closely related isolates. Test reports for feed and product water of the mine showed that total plate counts were above the limits of 1000 cfu/ml, coliform counts > 10 cfu/100 ml and presence of faecal coliforms. Best practices were poorly implemented as some mine workers washed protective clothing with untreated water and hung them for drying at the underground surface. Conclusions PVL-producing MSSA caused an outbreak of cutaneous abscesses among underground workers at a gold mining company. To our knowledge, no other outbreaks of PVL-producing S. aureus involving skin and soft tissue infections have been reported in mining facilities in South Africa. We recommend that worker awareness of infection prevention and control practices be strengthened.

Abstract Background Ralstonia species are Gram-negative bacilli of low virulence. These organisms are capable of causing healthcare associated infections through contaminated solutions. In this study, we aimed to determine the source of Ralstonia mannitolilytica bacteraemia in affected patients in a haemodialysis unit. Methods Our laboratory noted an increase in cases of bacteraemia caused by Ralstonia mannitililytica between May and June 2016. All affected patients underwent haemodialysis at the haemodialysis unit of an academic hospital. The reverse osmosis filter of the haemodialysis water system was found to be dysfunctional. We collected water for culture at various points of the dialysis system to determine the source of the organism implicated. ERIC-PCR was used to determine relatedness of patient and environmental isolates. Results Sixteen patients were found to have Ralstonia mannitolilytica bacteraemia during the outbreak period. We cultured Ralstonia spp. from water collected in the dialysis system. This isolate and patient isolates were found to have the identical molecular banding pattern. Conclusions All patients were septic and received directed antibiotic therapy. There was 1 mortality. The source of the R. mannitolilytica infection in these patients was most likely the dialysis water as the identical organism was cultured from the dialysis water and the patients. The hospital management intervened and repaired the dialysis water system following which no further cases of R. mannitolilytca infections were detected. A multidisciplinary approach is required to control healthcare associated infections such as these. Routine maintenance of water systems in the hospital is essential to prevent clinical infections with R.mannitolilytica.

No abstract available.

Introduction: Brucella spp. are rarely encountered organisms in the medical microbiology laboratory and, when encountered, can cause concern in laboratory workers. Laboratory personnel may in fact develop serious disease as a result of this exposure. This case highlights shortcomings in recognition of Brucella spp. from a patient presenting atypically as well as the follow-up and management of an infected patient. Case presentation: The patient was an 8-year-old boy from a rural area of South Africa who presented to an academic hospital with a bladder mass and history of enuresis in September 2016. Brucella melitensis was isolated from a blood culture submitted to the laboratory. The child was subsequently treated for brucellosis in November 2016. Management and outcome: The source of infection in the patient was traced to consumption of unpasteurised milk from a local farmer. The patient was treated with doxycycline 100 mg twice daily and rifampicin 600 mg daily for 6 weeks and completed treatment, however he was not followed up at our hospital. The laboratory personnel, however, did not handle the specimen as a Biosafety Level 3 pathogen as this organism is not commonly encountered; they were provided with prophylaxis for brucellosis (rifampicin and doxycycline). Conclusion: Brucella spp. is a dangerous pathogen, easily capable of causing significant exposure in an unsuspecting and unprepared laboratory. The case discusses the management of brucellosis in the infected patient as well as the management of laboratory exposure to Brucella spp. Our case also describes the public health response to a case of brucellosis.

Background: Bedaquiline (BDQ) is a novel agent approved for use in combination treatment of multi-drug resistant tuberculosis (MDR-TB). We sought to determine BDQ epidemiological cut-off values (ECVs), define and assess interpretive criteria against putative resistance associated variants (RAVs), microbiological outcomes and cross resistance with clofazimine (CFZ). Methods: A retrospective cohort study was conducted. Minimal inhibitory concentrations (MIC) to BDQ were determined using 7H9 broth microdilution (BMD) and MGIT960. RAVs were genetically characterised using whole genome sequencing. BDQ ECVs were determined using ECOFFinder and compared with 6-month culture conversion status and CFZ MICs. Findings: A total of 391 isolates were analysed. Susceptible and intermediate categories were determined to have MICs of ≤0.125 μg/ml and 0.25 μg/ml using BMD and ≤1 μg/ml and 2 μg/ml using MGIT960 respectively. Microbiological failures occurred among BDQ exposed patients with a non-susceptible BDQ MIC, an Rv0678 mutation and ≤2 active drug classes. The Rv0678 RAVs were not the dominant mechanism of CFZ resistance and cross resistance was limited to isolates with an Rv0678 mutation. Interpretation: Criteria for BDQ susceptibility are defined and will facilitate improved early detection of resistance. Cross- resistance between BDQ and CFZ is an emerging concern but in this study was primarily among those with an Rv0678 mutation.

South Africa remains challenged with a high tuberculosis burden accompanied by an increase in drug resistant cases. We assessed the use of the Illumina MiSeq, a next-generation sequencing platform for whole genome sequencing, followed by bioinformatic analysis using a commercial software package to determine resistance to selected drugs used for Mycobacterium tuberculosis treatment in our setting. Whole genome sequencing shows potential as a diagnostic platform for the detection of drug resistance in Mycobacterium tuberculosis with the provision of information for several drugs simultaneously.

Background: The World Health Organization End TB Strategy targets for 2035 are ambitious and drug resistant tuberculosis is an important barrier, particularly in Africa, home to over a billion people. Objective: We sought to review the current status of drug resistant tuberculosis in Africa and highlight key areas requiring improvement. Methods: Available data from 2016 World Health Organization global tuberculosis database were extracted and analysed using descriptive statistics. Results: The true burden of drug resistant tuberculosis on the continent is poorly described with only 51% of countries having a formal survey completed. In the absence of this data, modelled estimates were used and reported 92 629 drug resistant tuberculosis cases with 42% of these occurring in just two countries: Nigeria and South Africa. Of the cases estimated, the majority of patients (70%) were not notified, representing ‘missed cases’. Mortality among patients with multi-drug resistant tuberculosis was 21%, and was 43% among those with extensively drug resistant tuberculosis. Policies on the adoption of new diagnostic tools was poor and implementation was lacking. A rifampicin result was available for less than 10% of tuberculosis cases in 23 of 47 countries. Second-line drug resistance testing was available in only 60% of countries. The introduction of the short multi-drug resistant tuberculosis regimen was a welcome development, with 40% of countries having implemented it in 2016. Bedaquiline has also been introduced in several countries. Conclusion: Drug resistant tuberculosis is largely missed in Africa and this threatens prospects to achieve the 2035 targets. Urgent efforts are required to confirm the true burden of drug resistant tuberculosis in Africa. Adoption of new tools and drugs is essential if the 2035 targets are to be met.

Acinetobacter baumannii is an opportunistic pathogen that is increasingly responsible for hospital-acquired infections. The increasing prevalence of carbapenem resistant A. baumannii has left clinicians with limited treatment options. Last line antimicrobials (i.e., polymyxins and glycylcyclines) are often used as treatment options. The aim of this study was to determine the prevalence of selected β-lactamase genes from A. baumannii isolates obtained from patients with hospital-acquired infections and to determine the genetic relationship and epidemiological profiles among clinical A. baumannii isolates collected from two tertiary academic hospitals in the Tshwane region, South Africa (SA). Multiplex-PCR (M-PCR) assays were performed to detect selected resistance genes. The collected isolates’ genetic relatedness was determined by using pulsed field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). The acquired oxacillinase (OXA) genes, notably blaOXA-23-like were prevalent in the A. baumannii isolates. The M-PCR assays showed that the isolates collected from hospital A contained the OXA-23-like (96%; n = 69/72) genes and the isolates collected from hospital B contained the OXA-23-like (91%; n = 63/69) and OXA-58-like (4%; n = 3/69) genes. Colistin resistance was found in 1% of the isolates (n = 2/141) and tigecycline intermediate resistance was found in 6% of the isolates (n = 8/141). The A. baumannii isolates were genetically diverse. Molecular epidemiological data showed that specific sequence types (STs) (ST106, ST229, ST258 and ST208) were established in both hospitals, while ST848 was established in hospital A and ST502, ST339 and the novel ST1552 were established in hospital B. ST848 (established in hospital A) was predominately detected in ICU wards whereas ST208, ST339 and the novel ST1552 (established in hospital B) were detected in ICUs and the general wards. The origin of the A. baumannii isolates in the hospitals may be due to the dissemination and adaptation of a diverse group of successful clones. Poor infection control and prevention strategies and possibly the overuse of antimicrobials contributed to the establishment of these A. baumannii clones in the studied hospitals.