Tuberculosis control at a South African correctional centre: Diagnosis, treatment and strain characterisation.

BACKGROUND: Correctional centres provide ideal conditions for tuberculosis (TB) transmission and disease progression. Despite the high TB incidence and incarceration rate in South Africa, data from South African correctional centres are scarce. Thus, the study evaluated TB diagnosis, treatment initiation and completion, and identified prevalent Mycobacterium tuberculosis strains among detainees entering a South African correctional centre. METHODS: This study was a prospective observational study that enrolled participants between February and September 2017 from a correctional centre located in the Western Cape, South Africa. All adult male detainees who tested positive for TB during admission screening were eligible to participate in the study. Sputum samples from enrolled participants underwent smear microscopy and culture. Strain typing was performed on culture-positive samples. The time between specimen collection and diagnosis, the time between diagnosis and treatment initiation, and the proportion of detainees completing TB treatment at the correctional centre were calculated. RESULTS: During the study period, 130 TB cases were detected through routine admission screening (126 male, 2 female, 2 juvenile). Out of the 126 eligible male detainees, 102 were enrolled in the study (81%, 102/126). All TB cases were detected within 30 hrs of admission screening. The majority (78%, 80/102) of participants started treatment within 48 hrs of TB diagnosis. However, only 8% (9/102) of participants completed treatment at the correction centre. Sputa from 90 of the 102 participants were available for smear and culture. There was a high smear positivity, with 49% (44/90) of isolates being smear positive. The Beijing family was the most frequent lineage (55.2%) in the study. CONCLUSION: The strengths of the current TB control efforts at the correctional centre include rapid detection of cases through admission screening and prompt treatment initiation. However, a high number of detainees exiting before treatment completion highlights the need to strengthen links between correctional TB services and community TB services to ensure detainees complete TB treatment after release and prevent TB transmission.

Feasibility of using postal and web-based surveys to estimate the prevalence of tuberculosis among health care workers in South Africa.

INTRODUCTION: Health Care Workers (HCWs) are among the highest risk groups for contracting tuberculosis (TB), which is ranked the third most common occupational health disease in South Africa. Little is known about the true extent of the burden of TB among South African HCWs and current surveillance approaches are inadequate. The study aimed to determine the feasibility of using postal and web-based surveys accessed through registries of registered professionals to estimate the prevalence of TB among HCWs in South Africa. MATERIALS AND METHODS: We conducted a cross sectional survey on a sample of professional nurses and doctors (general practitioners) registered on the Medpages database platform; a subscription based registry for practising health care professionals. The survey included professionals who were actively involved in the clinical management of patients, either in public or private health care facilities. The paper based survey, including pre-paid return envelopes, was distributed via the post office and web-based surveys were distributed via e-mail through a hyperlink. Descriptive statistics were used to summarize the data and the Chi-square test to determine associations between categorical variables. Active TB was defined as any history of TB. RESULTS: Out of a total of 3,400 health care professionals contacted, 596 (18%) responses were received: 401 (67%) web-based and 195 (33%) postal. A significantly higher percentage of complete forms were from postal compared to web-based (97% [189/195] versus 87% [348/401], p<0.001). Younger (<60 years) professionals were more likely to use the web-based compared to postal (87% [236/270] versus 71% [134/189], p<0.001). Overall, the prevalence of active TB infection was 8.7%, (95%CI: 6.3%-11.7%) and there was no difference observed between doctors and nurses (10.8% [18/167] versus 7.5% [22/292], p = 0.236). CONCLUSION: This novel approach demonstrated the feasibility of using an existing registry of professionals to conduct surveys to estimate the prevalence of TB. Our findings showed a high TB prevalence; however the estimate might have been biased by the low response rate. Further research to optimise our approach could lead to a viable option in improving surveillance among health care professionals.

Drug resistant tuberculosis in Africa: Current status, gaps and opportunities.

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.

Defining Bedaquiline Susceptibility, Resistance, Cross-Resistance and Associated Genetic Determinants: A Retrospective Cohort Study.

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 ≤0.125µg/ml and 0.25µg/ml using BMD and ≤1µg/ml and 2µg/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.

Relapse, re-infection and mixed infections in tuberculosis disease.

Tuberculosis (TB) disease can be characterized by genotypic and phenotypic complexity in Mycobacterium tuberculosis bacilli within a single patient. This microbiological heterogeneity has become an area of intense study due its perceived importance in drug tolerance, drug resistance and as a surrogate measure of transmission rates. This review presents a descriptive analysis of research describing the prevalence of mixed-strain TB infections in geographically distinct locations. Despite significant variation in disease burden and a rampant human immunodeficiency virus (HIV)-TB co-epidemic, there was no difference in the prevalence range of mixed infections reported in African countries when compared to the rest of the world. The occurrence of recurrent TB was associated with a higher prevalence of mixed-strain infections, but this difference was not reported as statistically significant. These interpretations were limited by differences in the design and overall size of the studies assessed. Factors such as sputum quality, culture media, number of repeated culture steps, molecular typing methods and HIV-infection status can affect the detection of mixed-strain infection. It is recommended that future clinical studies should focus on settings with varying TB burdens, with a common sample processing protocol to gain further insight into these phenomena and develop novel transmission blocking strategies.

Laboratory information system for reporting antimicrobial resistant isolates from academic hospitals, South Africa.

INTRODUCTION: We aimed to evaluate the appropriateness of Digital Innovation South Africa (DISA)-based laboratory information system (LIS) for assessing the prevalence, patterns and trends of antimicrobial resistance, and associated demographic factors. METHODOLOGY: A retrospective analysis was conducted on routine data of blood culture isolates of Staphylococcus aureus, Klebsiella pneumoniae, and Pseudomonas aeruginosa. These isolates were collected by the National Health Laboratory Services between July 1, 2005 and December 31, 2009 at seven tertiary public hospitals. Factors associated with antimicrobial resistance were analysed using multivariate logistic regression. RESULTS: Information on 9969 isolates was available, of which 3942 (39.5%), 4466 (44.8%) and 1561 (15.7%) were Staphylococcus aureus, Klebsiella pneumoniae, and Pseudomonas aeruginosa, respectively. Reporting of resistance across antibiotics tested was highest in patient age group less than 5 years old. Methicillin resistant Staphylococcus aureus was 39% on average. There was a significant increasing trend of Klebsiella pneumoniae resistance to ciprofloxacin (32.6% to 64.9%, p < 0.001), cotrimoxazole (67.5% to 81.6%, p < 0.001) and cefotaxime-ceftriaxone (55.5% to 73.2%, p < 0.001) over the study period. Pseudomonas aeruginosa resistance to meropenem showed a significant increasing trend from 2006 (27.5%) to 2009 (53.9%) (p < 0.001). Age group < 5 years, female gender, hospital location, year of infection were significantly associated with antimicrobial resistance. CONCLUSIONS: The percentages of antimicrobial resistance were high and showed a significant increasing trend among individual agents over the duration of the study e.g. ciprofloxacin, cotrimoxazole among others. Continued surveillance of antimicrobial resistance among bloodstream hospital-acquired infections should be strengthened.

Correlation of rpoB Mutations with Minimal Inhibitory Concentration of Rifampin and Rifabutin in Mycobacterium tuberculosis in an HIV/AIDS Endemic Setting, South Africa.

Treatment of tuberculosis (TB) and HIV co-infections is often complicated by drug-to-drug interactions between anti-mycobacterial and anti-retroviral agents. Rifabutin (RFB) is an alternative to rifampin (RIF) for TB regimens and is recommended for HIV patients concurrently receiving protease inhibitors because of reduced induction of CYP3A4. This study sought to determine the proportion of RFB susceptible isolates among RIF-resistant strains in a high HIV prevalence setting in South Africa. In addition, the study explored the association between rpoB mutations and minimum inhibitory concentrations (MIC) of RIF and RFB. A total of 189 multidrug resistant (MDR) Mycobacterium tuberculosis isolates from the Centre for Tuberculosis repository were analyzed. The MICs were determined using a MYCOTB Sensititre plate method and the rpoB gene was sequenced. Of the 189 MDR isolates, 138 (73%) showed resistance to both RIF and RFB, while 51 (27%) isolates were resistant to RIF but retained susceptibility to RFB. The S531L was the most frequent rpoB point mutation in 105/189 (56%) isolates, followed by H526Y in 27/189 (14%) isolates. Resistance to both RIF and RFB was found predominantly in association with mutations S531L (91/105, 87%), H526Y (20/27, 74%), and H526D (15/19, 79%), while D516V (15/17, 88%), and L533P (3/4, 75%) were found in RIF-resistant, RFB-susceptible isolates. This study has shown that up to 27% of MDR-TB patients in South Africa may benefit from a treatment regimen that includes RFB.

A Novel Molecular Strategy for Surveillance of Multidrug Resistant Tuberculosis in High Burden Settings.

BACKGROUND: In South Africa and other high prevalence countries, transmission is a significant contributor to rising rates of multidrug resistant tuberculosis (MDR-TB). Thus, there is a need to develop an early detection system for transmission clusters suitable for high burden settings. We have evaluated the discriminatory power and clustering concordance of a novel and simple genotyping approach, combining spoligotyping with pncA sequencing (SpoNC), against two well-established methods: IS6110-RFLP and 24-loci MIRU-VNTR. METHODS: A total of 216 MDR-TB isolates collected from January to June 2010 from the NHLS Central TB referral laboratory in Braamfontein, Johannesburg, representing a diversity of strains from South Africa, were included. The isolates were submitted for genotyping, pncA sequencing and analysis to the Centre for Tuberculosis in South Africa and the Public Health Research Institute Tuberculosis Center at Rutgers University in the United States. Clustering rates, Hunter-Gaston Discriminatory Indexes (HGI) and Wallace coefficients were compared between the methods. RESULTS: Overall clustering rates were high by both IS6110-RFLP (52.8%) and MIRU-VNTR (45.8%), indicative of on-going transmission. Both 24-loci MIRU-VNTR and IS6110-RFLP had similar HGI (0.972 and 0.973, respectively), with close numbers of unique profiles (87 vs. 70), clustered isolates (129 vs. 146), and cluster sizes (2 to 26 vs. 2 to 25 isolates). Spoligotyping alone was the least discriminatory (80.1% clustering, HGI 0.903), with 28 unique types. However, the discriminatory power of spoligotyping was improved when combined with pncA sequencing using the SpoNC approach (61.8% clustering, HGI 0.958). A high proportion of MDR-TB isolates had mutations in pncA (68%, n = 145), and pncA mutations were significantly associated with clustering (p = 0.007 and p = 0.0013 by 24-loci MIRU-VNTR and IS6110-RFLP, respectively), suggesting high rates of resistance to pyrazinamide among all MDR-TB cases and particularly among clustered cases. CONCLUSION: We conclude that SpoNC provides good discrimination for MDR-TB surveillance and early identification of outbreaks in South Africa, with 24-loci MIRU-VNTR applied for pncA wild-type strains as needed.

The impact of expanded testing for multidrug resistant tuberculosis using genotype [correction of geontype] MTBDRplus in South Africa: an observational cohort study.

INTRODUCTION: Globally, multidrug resistant tuberculosis (MDR-TB) remains underdiagnosed. The Genotype MTBDRplus®, a rapid drug susceptibility testing (DST) assay used to detect resistance to isoniazid and rifampicin in the diagnosis of MDR-TB, has good diagnostic accuracy, but its impact on patient outcomes in routine practice is unproven. We assessed the clinical impact of routine DST using MTBDRplus in a single health district in South Africa. METHODS: Data were collected on all adult pulmonary TB patients registered at 25 public health clinics in the periods before and after introduction of an expanded DST algorithm using MTBDRplus version 1.0. RESULTS: We collected data on 1176 TB patients before implementation and 1177 patients afterwards. In the before period, measured MDR-TB prevalence among new cases was 0.7% (95% CI1.4-3.1%), and among retreatment cases 6.2% (95% CI:3.5-8.8%), versus 3.7% (95% CI:2.4-5.0, p<0.01) and 6.6% (95% CI:3.8-9.4%, p = 0.83) respectively after MTBDRplus introduction. The median times from sputum collection to MDR treatment in the before and after periods were 78 days (IQR:52-93) and 62 days (IQR:32-86, p = 0.05), respectively. Among MDR-TB cases, 27% (95%CI:10-44) in the before period converted sputum cultures to negative by 8 months following treatment initiation, while 52% (95%CI:38-66) converted in the intervention period (p = 0.04). CONCLUSIONS: The expanded use of MTBDRplus DST resulted in a substantial increase in the proportion of new cases identified as MDR-TB; though time to MDR treatment was reduced, it was still over two months. Culture conversion for MDR-TB patients improved after introduction of MTBDRplus. This work illustrates the mixture of successes and challenges resulting from increased access to rapid DST in a setting with a high TB burden.

Staphylococcus aureus bacteraemia at two academic hospitals in Johannesburg.

OBJECTIVES AND METHODS: Staphylococcus aureus bacteraemia (SAB) remains a major problem worldwide. A retrospective study of patients with SAB seen from November 1999 to October 2002 was conducted at two academic hospitals in Johannesburg to determine mortality rates (death within 14 days of submission of blood culture) in patients bacteraemic with methicillin-sensitive (MSSA) and resistant S. aureus (MRSA) and to identify risk factors associated with mortality. RESULTS: Of 449 patients with SAB, 104 (23.2%) died within 14 days of clinically suspected SAB. Of the 204 patients who acquired SAB in hospital, 6 patients died within 2 days, 39 between 2 and 14 days, and 41 more than 14 days after onset of SAB. One hundred and five patients (23.4%) had MRSA bacteraemia, 21 (20%) originating from the community. The MRSA bacteraemia rate among patients with hospital-acquired infection was 41.1%, significantly higher (p < 0.0001) than the 10.3% community-acquired MRSA bacteraemia. Thirty-five (33.3%) of the 105 patients with MRSA bacteraemia died within 14 days, compared with 69 (20.1%) of 344 MSSA patients (p = 0.0048). Admission to the intensive care unit (ICU) was significantly associated with mortality (p < 0.001)--30 of 79 patients admitted to ICU died (38%). Among 222 patients whose HIV status was known, 117 (52.7%) were positive, and of these 32 died (27.4%), a rate not significantly higher than that among HIV-seronegative patients (18 of 105 patients, p = 0.69). CONCLUSIONS: Compared with MSSA, MRSA was shown to be significantly associated with mortality. Stay in ICU and infection with strains resistant to oxacillin, ofloxacin and rifampicin were highly significant predictors for mortality.