Singapore tuberculosis (TB) clinical management guidelines 2024: A modified Delphi adaptation of international guidelines for drug-susceptible TB infection and pulmonary disease.

Introduction: Tuberculosis (TB) remains endemic in Singapore. Singapore's clinical practice guidelines for the management of tuberculosis were first published in 2016. Since then, there have been major new advances in the clinical management of TB, ranging from diagnostics to new drugs and treatment regimens. The National TB Programme convened a multidisciplinary panel to update guidelines for the clinical management of drug-susceptible TB infection and disease in Singapore, contextualising current evidence for local practice. Method: Following the ADAPTE framework, the panel systematically reviewed, scored and synthesised English-language national and international TB clinical guidelines published from 2016, adapting recommendations for a prioritised list of clinical decisions. For questions related to more recent advances, an additional primary literature review was conducted via a targeted search approach. A 2-round modified Delphi process was implemented to achieve consensus for each recommendation, with a final round of edits after consultation with external stakeholders. Results: Recommendations for 25 clinical questions spanning screening, diagnosis, selection of drug regimen, monitoring and follow-up of TB infection and disease were formulated. The availability of results from recent clinical trials led to the inclusion of shorter treatment regimens for TB infection and disease, as well as consensus positions on the role of newer technologies, such as computer-aided detection-artificial intelligence products for radiological screening of TB disease, next-generation sequencing for drug-susceptibility testing, and video observation of treatment. Conclusion: The panel updated recommendations on the management of drug-susceptible TB infection and disease in Singapore.

Impact of COVID-19 pandemic on carbapenem-resistant Enterobacterales incidence in the South-East Asia region: an observational study.

The COVID-19 pandemic led to an initial increase in the incidence of carbapenem-resistant Enterobacterales (CRE) from clinical cultures in South-East Asia hospitals, which was unsustained as the pandemic progressed. Conversely, there was a decrease in CRE incidence from surveillance cultures and overall combined incidence. Further studies are needed for future pandemic preparedness.

Implementation of national whole-genome sequencing of Mycobacterium tuberculosis, National Public Health Laboratory, Singapore, 2019-2022.

The National Tuberculosis Programme (NTBP) monitors the occurrence and spread of tuberculosis (TB) and multidrug-resistant TB (MDR-TB) in Singapore. Since 2020, whole-genome sequencing (WGS) of Mycobacterium tuberculosis isolates has been performed at the National Public Health Laboratory (NPHL) for genomic surveillance, replacing spoligotyping and mycobacterial interspersed repetitive unit-variable number tandem repeats analysis (MIRU-VNTR). Four thousand three hundred and seven samples were sequenced from 2014 to January 2023, initially as research projects and later developed into a comprehensive public health surveillance programme. Currently, all newly diagnosed culture-positive cases of TB in Singapore are prospectively sent for WGS, which is used to perform lineage classification, predict drug resistance profiles and infer genetic relationships between TB isolates. This paper describes NPHL's operational and technical experiences with implementing the WGS service in an urban TB-endemic setting, focusing on cluster detection and genomic drug susceptibility testing (DST). Cluster detection: WGS has been used to guide contact tracing by detecting clusters and discovering unknown transmission networks. Examples have been clusters in a daycare centre, housing apartment blocks and a horse-racing betting centre. Genomic DST: genomic DST prediction (gDST) identifies mutations in core genes known to be associated with TB drug resistance catalogued in the TBProfiler drug resistance mutation database. Mutations are reported with confidence scores according to a standardized approach referencing NPHL's internal gDST confidence database, which is adapted from the World Health Organization (WHO) TB drug mutation catalogue. Phenotypic-genomic concordance was observed for the first-line drugs ranging from 2959/2998 (98.7 %) (ethambutol) to 2983/2996 (99.6 %) (rifampicin). Aspects of internal database management, reporting standards and caveats in results interpretation are discussed.

Whole genome sequencing reveals hidden transmission of carbapenemase-producing Enterobacterales.

Carbapenemase-producing Enterobacterales (CPE) infection control practices are based on the paradigm that detected carriers in the hospital transmit to other patients who stay in the same ward. The role of plasmid-mediated transmission at population level remains largely unknown. In this retrospective cohort study over 4.7 years involving all multi-disciplinary public hospitals in Singapore, we analysed 779 patients who acquired CPE (1215 CPE isolates) detected by clinical or surveillance cultures. 42.0% met putative clonal transmission criteria, 44.8% met putative plasmid-mediated transmission criteria and 13.2% were unlinked. Only putative clonal transmissions associated with direct ward contact decreased in the second half of the study. Both putative clonal and plasmid-mediated transmission associated with indirect (no temporal overlap in patients' admission period) ward and hospital contact did not decrease during the study period. Indirect ward and hospital contact were identified as independent risk factors associated with clonal transmission. In conclusion, undetected CPE reservoirs continue to evade hospital infection prevention measures. New measures are needed to address plasmid-mediated transmission, which accounted for 50% of CPE dissemination.

Serotype distribution and incidence of invasive early onset and late onset group B streptococcal disease amongst infants in Singapore.

BACKGROUND: The current group B streptococcal (GBS) preventive measures had reduced invasive GBS early onset disease (EOD) incidences worldwide, but the late onset disease (LOD) incidences had remained unchanged. Administration of a safe and effective GBS vaccine in addition to the current strategies were thought to be the next steps in reducing the incidences of invasive GBS infection especially LOD. In this study, we aimed to examine the causative GBS serotypes in invasive GBS disease, determine the incidences of EOD and LOD, and compare the risk factors between EOD and LOD. METHODS: A retrospective study of infants ≤ 90-day-old over an 8-year period (2010-2017). The incidences of EOD and LOD were obtained by using patients with EOD and LOD who were born in our institution as the numerator and the live births in our institution per year of the study period as the denominator. Available GBS isolates were serotyped by the National Public Health Laboratory using capsular serotyping methods. The risk factors of EOD and LOD were compared. RESULTS: A total of 71 infants were identified; 16 (22.5%) and 55 (77.5%) of them had EOD and LOD, respectively. Serotype III (n = 42, 71.2%) was the most common serotype amongst the 59 isolates available for serotyping. Serotypes Ia, Ib, II, III, and V accounted for 98.3% (n = 58) of the invasive GBS diseases. The overall incidence was 0.42 per 1000 live births. The mean incidences of EOD and LOD were 0.13 per 1000 live births and 0.29 per 1000 live births, respectively. On multivariate analysis, risk factors for LOD as compared to EOD were: Chinese ethnicity (OR 27.1, 95% CI 3.0-243.1, p = 0.003) and negative/unknown maternal GBS status (OR 20.0, 95% CI 2.0-250.0, p = 0.012). Prematurity and intrapartum risk factors (peripartum maternal pyrexia, prolonged rupture of membrane) of EOD were not associated with LOD. CONCLUSIONS: The LOD incidence had remained higher than EOD incidence in our cohort. A GBS vaccine that covers the major causative serotypes found in our cohort can potentially reduce the overall GBS disease burden in the country.

Serotype Distribution of Remaining Pneumococcal Meningitis in the Mature PCV10/13 Period: Findings from the PSERENADE Project.

Pneumococcal conjugate vaccine (PCV) introduction has reduced pneumococcal meningitis incidence. The Pneumococcal Serotype Replacement and Distribution Estimation (PSERENADE) project described the serotype distribution of remaining pneumococcal meningitis in countries using PCV10/13 for least 5-7 years with primary series uptake above 70%. The distribution was estimated using a multinomial Dirichlet regression model, stratified by PCV product and age. In PCV10-using sites (N = 8; cases = 1141), PCV10 types caused 5% of cases <5 years of age and 15% among ≥5 years; the top serotypes were 19A, 6C, and 3, together causing 42% of cases <5 years and 37% ≥5 years. In PCV13-using sites (N = 32; cases = 4503), PCV13 types caused 14% in <5 and 26% in ≥5 years; 4% and 13%, respectively, were serotype 3. Among the top serotypes are five (15BC, 8, 12F, 10A, and 22F) included in higher-valency PCVs under evaluation. Other top serotypes (24F, 23B, and 23A) are not in any known investigational product. In countries with mature vaccination programs, the proportion of pneumococcal meningitis caused by vaccine-in-use serotypes is lower (≤26% across all ages) than pre-PCV (≥70% in children). Higher-valency PCVs under evaluation target over half of remaining pneumococcal meningitis cases, but questions remain regarding generalizability to the African meningitis belt where additional data are needed.

A Cost-Utility Analysis of Magnetic Resonance (MR) Guided Brachytherapy Versus Two-Dimensional and Computed Tomography (CT) Guided Brachytherapy for Locally Advanced Cervical Cancer.

PURPOSE: The standard treatment for locally advanced cervical cancer is external beam radiation therapy and concurrent cisplatin followed by brachytherapy. Traditionally, 2-dimensional brachytherapy (2DBT) or computed tomography guided brachytherapy (CTgBT) has been used, but magnetic resonance guided brachytherapy (MRgBT) improves clinical outcomes and has become the new standard of care. This cost-utility analysis was undertaken to compare MRgBT to CTgBT and 2DBT. METHODS AND MATERIALS: A Markov model was constructed to evaluate the cost-utility from the perspective of the public health care payer in Ontario. Treatment effectiveness, expressed as quality-adjusted life years, and costs, expressed in 2016 Canadian dollars, were evaluated for MRgBT, CTgBT, and 2DBT. Results were reported as incremental cost-effectiveness ratios for all patients and separately for low and high-risk subgroups. Sensitivity analyses were performed to assess the impact of uncertainty in model parameters. RESULTS: MRgBT improved tumor control, reduced side effects, and was less costly compared with either CTgBT or 2DBT for all patients and in low- and high-risk prognostic subgroups separately. Sensitivity analysis supported the robustness of the findings and identified the cost of treating cancer recurrence to be the single most influential model parameter. CONCLUSIONS: MRgBT is more effective and less costly than CTgBT or 2DBT by avoiding downstream costs of treating cancer recurrence and managing side effects. These findings will assist health care providers and policymakers with future infrastructure and human resource planning to ensure optimal care of women with this disease.

Antecedent Carbapenem Exposure as a Risk Factor for Non-Carbapenemase-Producing Carbapenem-Resistant Enterobacteriaceae and Carbapenemase-Producing Enterobacteriaceae.

Carbapenem-resistant Enterobacteriaceae (CRE) can be mechanistically classified into carbapenemase-producing Enterobacteriaceae (CPE) and non-carbapenemase-producing carbapenem nonsusceptible Enterobacteriaceae (NCPCRE). We sought to investigate the effect of antecedent carbapenem exposure as a risk factor for NCPCRE versus CPE. Among all patients with CRE colonization and infection, we conducted a case-control study comparing patients with NCPCRE (cases) and patients with CPE (controls). The presence of carbapenemases was investigated with phenotypic tests followed by PCR for predominant carbapenemase genes. We included 843 unique patients with first-episode CRE, including 387 (45.9%) NCPCRE and 456 (54.1%) CPE. The resistance genes detected in CPEs were blaNDM (42.8%), blaKPC (38.4%), and blaOXA-48-like (12.1%). After adjusting for confounders and clustering at the institutional level, the odds of prior 30-day carbapenem exposure was three times higher among NCPCRE than CPE patients (adjusted odds ratio [aOR], 3.48; 95% confidence interval [CI], 2.39 to 5.09; P < 0.001). The odds of prior carbapenem exposure and NCPCRE detection persisted in stratified analyses by Enterobacteriaceae species (Klebsiella pneumoniae and Escherichia coli) and carbapenemase gene (blaNDM and blaKPC). CPE was associated with male gender (aOR, 1.45; 95% CI, 1.07 to 1.97; P = 0.02), intensive care unit stay (aOR, 1.84; 95% CI, 1.24 to 2.74; P = 0.003), and hospitalization in the preceding 1 year (aOR, 1.42; 95% CI, 1.01 to 2.02; P = 0.05). In a large nationwide study, antecedent carbapenem exposure was a significant risk factor for NCPCRE versus CPE, suggesting a differential effect of antibiotic selection pressure.

Improving Quality of Radiation Therapy Care Across Ontario using a Community-of-Practice Approach.

PURPOSE: In 2003 and 2004, Cancer Care Ontario (CCO) divested its assets and staff to regional hospitals, leading to decreased contact between radiation therapy departments across Ontario's Regional Cancer Centres (RCCs). The Radiation Treatment Program (RTP) at CCO developed a communities-of-practice (CoPs) program to rebuild the provincial radiation therapy community to facilitate collaboration among centers, with the goals of decreasing variation in practice and improving the quality of patient care. RTP's CoPs are led and driven by volunteer frontline health care practitioners who identify and prioritize key quality issues and select corresponding projects to pursue. METHODS AND MATERIALS: An evaluation of RTP's CoPs was conducted to assess whether they were successful in knowledge creation, knowledge transfer and exchange, and community building. The framework was developed based on the Centers for Disease Control and Prevention CoP evaluation framework and tools. Data were collected using prospectively administered member surveys (257 surveys), publications, and semistructured interviews (18 participants). RESULTS: A total of 95% of participants reported that CoP projects were very relevant to their practice, and 50% reported changes in their practice stemming from CoP involvement. In addition, 90% of participants reported growth of their professional network as a result of CoPs. Overall, 93% of participants and 100% of interviewees reported that CoPs are a worthwhile initiative. The largest challenge of CoPs was the time commitment required to participate. CONCLUSIONS: This approach of member-driven CoPs should be explored and modeled in other health care settings as a means to develop and share knowledge to reduce variation in care and improve the quality of radiation therapy care.

Fatal Case of Diphtheria and Risk for Reemergence, Singapore.

We report a fatal autochthonous diphtheria case in a migrant worker in Singapore. This case highlights the risk for individual cases in undervaccinated subpopulations, despite high vaccination coverage in the general population. Prompt implementation of public health measures and maintaining immunization coverage are critical to prevent reemergence of diphtheria.

Diagnostic Accuracy of BD Phoenix CPO Detect for Carbapenemase Production in 190 Enterobacteriaceae Isolates.

The rapid and accurate detection of carbapenemase-producing Enterobacteriaceae (CPE) is necessary for patient management and infection control measures. We compared the performance of the BD Phoenix CPO Detect with that of a homemade Carba NP assay and a modified carbapenem inactivation method (mCIM) by challenging all 3 assays with 190 isolates of Enterobacteriaceae with meropenem MICs of >0.125 mg/liter. A total of 160 isolates produced KPC-, IMI-1-, NDM-, IMP-, and OXA-type carbapenemases, while 30 isolates were negative for carbapenemase production. The sensitivity and specificity were 90.6% (95% confidence interval [CI], 85.0% to 94.7%) and 100.0% (95% CI, 88.4% to 100.0%), respectively, for the Carba NP; 100.0% (95% CI, 97.7% to 100.0%) and 96.7% (95% CI, 82.7% to 99.9%), respectively, for the mCIM; and 89.4% (95% CI, 83.5% to 93.7%) and 66.7% (95% CI, 47.2% to 82.7%), respectively, for the BD Phoenix CPO Detect. In particular, the BD CPO Detect failed to detect a significant number of CPE with IMI-1. While the BD Phoenix CPO Detect is able to classify carbapenemases and is built into routine susceptibility testing with the potential to reduce the time to CPE detection, its low specificity means that a positive result will need confirmatory testing by another method.

The Clinical Specialist Radiation Therapist (CSRT): A case study exploring the effectiveness of a new advanced practice role in Canada.

INTRODUCTION: The Clinical Specialist Radiation Therapist (CSRT), is a new advanced practice (AP) role for radiation therapists (RTTs). Following training, education and evaluation, the CSRT performs specific duties in autonomous ways, making advanced clinical decisions in their area of specialization. This case study examines the CSRT's impact on quantity (i.e., increasing capacity), improving quality and stimulating research and innovation. METHODS: Between 2007 and 2016, 23 CSRTs worked in 10 cancer centres in various AP position. A standardised metrics package, focusing on wait-times, patient volumes, patient throughput, time-savings, quality initiatives, satisfaction, research and innovation was developed and used to collect qualitative and quantitative data. Data were self-reported by the CSRTs but electronic databases, pre/post-studies, surveys and interviews were also used. RESULTS: Quantity projects (n = 76) related to patient volumes, wait-times, patient throughput and time-savings increased capacity and allowed more patients to enter the system. The presence of a CSRT allowed, on average, 13 additional patients (either new or re-treated) to be seen, at their respective cancer centre, per month. An average of 1.4 yearly quality improvement initiatives were led by each CSRT, which contributed to improvements in quality of care and satisfaction. CSRTs demonstrated a high level of involvement in research, innovation and knowledge translation activities, either as leaders or part of interprofessional teams. CONCLUSION: CSRTs positively impact quantity (capacity of the system), quality, research and innovation. Future efforts include permanent and sustainable team integration, practice standards, formal and comprehensive educational preparation, and approaches to consistent, valid assessment of AP in radiation therapy.

Retrospective genome-wide comparisons of Salmonella enterica serovar Enteritidis from suspected outbreaks in Singapore.

The number of salmonellosis cases in Singapore has increased over the years. Salmonella enterica serovar Enteritidis has always been the most predominant serovar in the last five years. The National Public Health Laboratory assisted outbreak investigations by performing multilocus variable number tandem repeat analysis (MLVA) on isolates that were collected at the time of the investigations. Isolates were defined as belonging to a particular cluster if they had identical MLVA patterns. Whilst MLVA has been instrumental in outbreak investigations, it may not be useful when outbreaks are caused by an endemic MLVA type. In this study, we analysed 67 isolates from 12 suspected outbreaks with known epidemiological links to explore the use of next-generation sequencing (NGS) for defining outbreaks. We found that NGS can confidently group isolates into their respective outbreaks. The isolates from each suspected outbreak were closely related and differed by a maximum of 3 single nucleotide polymorphisms (SNPs). They were also clearly separated from isolates that belonged to different suspected outbreaks. This study provides an important insight and further evidence on the value of NGS for routine surveillance and outbreak detection of S. Enteritidis.

Moving toward uniform and evidence-based practice of radiotherapy for management of cervical cancer in Ontario, Canada.

PURPOSE: To recognize the practice of radiotherapy for management of cervical cancer in Ontario, Canada, and to use the results of the survey to harmonize and standardize practice across the province. METHODS AND MATERIALS: An electronic survey (SurveyMonkey) was sent to all 14 provincial cancer centers by Cancer Care Ontario Gynecology Community of Practice (CoP) in 2013. The survey included 72 questions in four different categories: general/demographic, pretreatment assessment, external beam radiotherapy (EBRT), and brachytherapy (BT). RESULTS: Ten of 14 centers treated cervical cancer patients and had a dedicated BT suite. All 10 centers had a peer review process for quality assurance. EBRT technique was a 4-field box in eight of 10 centers. The dose/fractionation for pelvic EBRT was 45-50 Gy in 1.8-2 Gy/fraction in all but one center. Nine of 10 centers used high-dose-rate BT. Only one center offered interstitial BT. For treatment planning, two centers used CT and MRI, five centers used CT, and three centers used orthogonal x-rays. Groupe Européen de Curiethérapie and the European Society for Radiotherapy & Oncology guidelines were used in four of seven of the centers for target volume delineation and in five of seven centers for organs at risk dose constraints. All but one center prescribed and reported dose to Point A. CONCLUSIONS: The survey identified areas where practice varied across the province. Gynecology CoP used this information to identify priorities for practice change and implemented several strategies to harmonize the care of women with cervical cancer. This highlights the value of interdisciplinary, grass-roots initiatives such as CoPs to standardize practice in a practical manner that directly benefits patients.

Persistent and Non-Persistent High-Users of Acute Care Resources: A Deeper Dive into the Patient and System Factors.

A small population of patients are responsible for the majority of Ontario's acute healthcare costs ߝ high-users of acute care. At our institution, high-users were divided into those who persisted in their high use across more than six months and those who did not. Persistent users were more likely to live alone, have more than three comorbidities, take more than five medications and be admitted for chronic diseases. In a survey of their family physicians, 58% believed no interventions could have prevented readmissions; however, useful strategies such as patient education, surgical rapid access clinics and increased mental health supports were proposed.

Exploiting the synthetic lethality between terminal respiratory oxidases to kill Mycobacterium tuberculosis and clear host infection.

The recent discovery of small molecules targeting the cytochrome bc1 :aa3 in Mycobacterium tuberculosis triggered interest in the terminal respiratory oxidases for antituberculosis drug development. The mycobacterial cytochrome bc1 :aa3 consists of a menaquinone:cytochrome c reductase (bc1 ) and a cytochrome aa3 -type oxidase. The clinical-stage drug candidate Q203 interferes with the function of the subunit b of the menaquinone:cytochrome c reductase. Despite the affinity of Q203 for the bc1 :aa3 complex, the drug is only bacteriostatic and does not kill drug-tolerant persisters. This raises the possibility that the alternate terminal bd-type oxidase (cytochrome bd oxidase) is capable of maintaining a membrane potential and menaquinol oxidation in the presence of Q203. Here, we show that the electron flow through the cytochrome bd oxidase is sufficient to maintain respiration and ATP synthesis at a level high enough to protect M. tuberculosis from Q203-induced bacterial death. Upon genetic deletion of the cytochrome bd oxidase-encoding genes cydAB, Q203 inhibited mycobacterial respiration completely, became bactericidal, killed drug-tolerant mycobacterial persisters, and rapidly cleared M. tuberculosis infection in vivo. These results indicate a synthetic lethal interaction between the two terminal respiratory oxidases that can be exploited for anti-TB drug development. Our findings should be considered in the clinical development of drugs targeting the cytochrome bc1 :aa3 , as well as for the development of a drug combination targeting oxidative phosphorylation in M. tuberculosis.

EthA/R-Independent Killing of Mycobacterium tuberculosis by Ethionamide.

Ethionamide (ETH) is part of the drug arsenal available to treat multi-drug resistant tuberculosis. The current paradigm of this pro-drug activation involves the mycobacterial enzyme EthA and the transcriptional repressor, EthR. However, several lines of evidence suggest the involvement of additional players. The ethA/R locus was deleted in Mycobacterium bovis BCG and three Mycobacterium tuberculosis (MTB) strains. While complete resistance to ETH was observed with BCG ethA/R KO, drug susceptibility and dose-dependent killing were retained in the ethA/R KO MTB mutants, suggesting the existence of an alternative pathway of ETH bio-activation in MTB. We further demonstrated that this alternative pathway is EthR-independent, whereby re-introduction of ethR in ethA/R KO MTB did not lead to increased resistance to ETH. Consistently, ethA KO MTB (with intact ethR expression) displayed similar ETH susceptibility profile as their ethA/R KO counterparts. To identify the alternative ETH bio-activator, spontaneous ETH-resistant mutants were obtained from ethA/R KO MTB and whole genome sequencing identified single nucleotide polymorphisms in mshA, involved in mycothiol biosynthesis and previously linked to ETH resistance. Deletion of mshA in ethA/R KO MTB led to complete ETH resistance, supporting that the role of MshA in ETH killing is EthA/R-independent. Furthermore mshA single KO MTB displayed levels of ETH resistance similar or greater than those obtained with ethA/R KO strains, supporting that mshA is as critical as ethA/R for ETH killing efficacy.

Role and contribution of pulmonary CD103+ dendritic cells in the adaptive immune response to Mycobacterium tuberculosis.

Despite international control programmes, the global burden of tuberculosis remains enormous. Efforts to discover novel drugs have largely focused on targeting the bacterium directly. Alternatively, manipulating the host immune response may represent a valuable approach to enhance immunological clearance of the bacilli, but necessitates a deeper understanding of the immune mechanisms associated with protection against Mycobacterium tuberculosis infection. Here, we examined the various dendritic cells (DC) subsets present in the lung and draining lymph nodes (LN) from mice intra-tracheally infected with M. tuberculosis. We showed that although limited in number, pulmonary CD103+ DCs appeared to be involved in the initial transport of mycobacteria to the draining mediastinal LN and subsequent activation of T cells. Using CLEC9A-DTR transgenic mice enabling the inducible depletion of CD103+ DCs, we established that this DC subset contributes to the control of mycobacterial burden and plays a role in the early activation of T cells, in particular CD8+ T cells. Our findings thus support a previously unidentified role for pulmonary CD103+ DCs in the rapid mobilization of mycobacteria from the lungs to the draining LN soon after exposure to M. tuberculosis, which is a critical step for the development of the host adaptive immune response.