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Background: Current antimicrobial resistance surveillance (AMR) is mainly laboratory based. This approach can have inherent biases given the potential for selective specimen submission for microbiological analysis and for its inability to map antibiotic susceptibility test results to a clinical syndrome., Objectives: To discuss the need for population-based surveillance of AMR, and highlight the pros and cons of threshold surveys., Sources: Studies on methodology for AMR surveillance published in the last 10 years, obtained through a PubMed search on antimicrobial resistance (all fields) and surveillance/method (MeSH term)., Content: We discuss the use of threshold surveys to overcome the challenge of sample size in population-bases AMR surveys, which are a suitable approach in both low- and high-resource settings., Implications: Scale up in the use of population-based threshold survey on the prevalence of AMR will provide necessary information to triangulate the data from routinely-reported laboratory-based AMR surveillance at the local, national, and global level., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Drug-resistant tuberculosis is a substantial health-care concern worldwide. Despite culture-based methods being considered the gold standard for drug susceptibility testing, molecular methods provide rapid information about the Mycobacterium tuberculosis mutations associated with resistance to anti-tuberculosis drugs. This consensus document was developed on the basis of a comprehensive literature search, by the TBnet and RESIST-TB networks, about reporting standards for the clinical use of molecular drug susceptibility testing. Review and the search for evidence included hand-searching journals and searching electronic databases. The panel identified studies that linked mutations in genomic regions of M tuberculosis with treatment outcome data. Implementation of molecular testing for the prediction of drug resistance in M tuberculosis is key. Detection of mutations in clinical isolates has implications for the clinical management of patients with multidrug-resistant or rifampicin-resistant tuberculosis, especially in situations when phenotypic drug susceptibility testing is not available. A multidisciplinary team including clinicians, microbiologists, and laboratory scientists reached a consensus on key questions relevant to molecular prediction of drug susceptibility or resistance to M tuberculosis, and their implications for clinical practice. This consensus document should help clinicians in the management of patients with tuberculosis, providing guidance for the design of treatment regimens and optimising outcomes., Competing Interests: Declaration of interests JD reports a technology licence to GenID (Germany), and honoraria for lectures from Oxford Immunotec (UK). EC reports support for attendance, accommodation, and travel for ECCMID 2022, Lisboa from European Society of Clinical Microbiology and Infectious Diseases (ESCMID), for annual ERL-TB net meetings from ERL-TB net (Network of National Reference Centers for Tuberculosis in Europe), and for the annual congress 2022, Bologna, from the European Society for Mycobacteriology; is a member of the Executive committee of ESCMID; and is chair of the subcommittee for antimycobacterial agents of EUCAST (European Committee on Antimicrobial Susceptibility Testing). MRF reports grants or contracts from NIH/NIAID (5R01AI155765 and 5R21AI154089) and consulting fees (paid to them) from FIND. LG is a member (unpaid) of the data safety monitoring board for the XACT-19 clinical trial in University of Cape Town, Cape Town, South Africa, and is co-principal investigator of two phase 3 clinical trials on shorter treatment for MDR-TB (endTB and endTB-Q), funded by Unitaid. BL reports grants or contracts from European Union, German Ministry for Education and Research (BMBF), Kultusministerkonferenz, German Centre for Infection Research, and Helmholtz Association, and unpaid leadership or fiduciary roles for DZIF IAB, DZIF Steering Committee transplant Cohort, and TBnet chair Epidemiology. SN reports support for this manuscript (eg, funding, provision of study materials, medical writing, and article processing charges) from BMBF (German Center for Infection Research), DFG (Excellenz Cluster Precision Medicine in Chronic Inflammation EXC 2167), and Leibniz Science Campus Evolutionary Medicine of the LUNG (EvoLUNG), and consulting fees from Illumina advisory board in 2022. NV reports grants or contracts for a study on bedaquiline from Janssen. CRH reports grants or contracts from NIH/NIAID (R01AI134430, DAA3-19-65672, R01AI147316 U01AI152980, and R01AI146555), and Centers for Disease Control and Prevention (NU38PS004651); consulting fees from Otsuka Pharmaceuticals; participation on a data safety monitoring board for SODUCU (PanACEA Sutezolid Dose-finding and Combination Evaluation), BEAT-Tuberculosis (Building Evidence for Advancing New treatment for tuberculosis), DECODE (PanACEA Delpazolid Dose-finding and Combination Development), and Médecins Sans Frontières; and a leadership or fiduciary role from the International Union Against Tuberculosis and Lung Diseases. CLa reports support for the present manuscript (eg, funding, provision of study materials, medical writing, and article processing charges) from DZIF (German Center of Infection Research); consulting fees from a consultation service to INSMED, a company that produced liposomal amikacin as an inhalative suspension for the treatment of non-tuberculous mycobacteria pulmonary disease (outside of the scope of this work); speakers' honoraria from Insmed, Gilead, and Janssen (all outside of the scope of this work); is a member of the data safety board of trials from Médecins Sans Frontières (outside of the scope of this work); is supported by the German Center for Infection Research (DZIF); and acknowledges funding from the European Commission (anTBiotic EU-H2020 733079, ClicTB EDCTP2 RIA2017T-2030, stool4TB EDCTP2 RIAD2018-2511, and UNITE4TB EU-IMI 101007873). All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Diabetes and hypertension are increasingly important population health challenges in Eswatini. Prior to this project, healthcare for these conditions was primarily provided through physician-led teams at tertiary care facilities and accessed by only a small fraction of people living with diabetes or hypertension. This trial tests and evaluates two community-based healthcare service models implemented at the national level, which involve health care personnel at primary care facilities and utilize the country's public sector community health worker cadre (the rural health motivators [RHMs]) to help generate demand for care., Methods: This study is a cluster-randomized controlled trial with two treatment arms and one control arm. The unit of randomization is a primary healthcare facility along with all RHMs (and their corresponding service areas) assigned to the facility. A total of 84 primary healthcare facilities were randomized in a 1:1:1 ratio to the three study arms. The first treatment arm implements differentiated service delivery (DSD) models at the clinic and community levels with the objective of improving treatment uptake and adherence among clients with diabetes or hypertension. In the second treatment arm, community distribution points (CDPs), which previously targeted clients living with human immunodeficiency virus, extend their services to clients with diabetes or hypertension by allowing them to pick up medications and obtain routine nurse-led follow-up visits in their community rather than at the healthcare facility. In both treatment arms, RHMs visit households regularly, screen clients at risk, provide personalized counseling, and refer clients to either primary care clinics or the nearest CDP. In the control arm, primary care clinics provide diabetes and hypertension care services but without the involvement of RHMs and the implementation of DSD models or CDPs. The primary endpoints are mean glycated hemoglobin (HbA1c) and systolic blood pressure among adults aged 40 years and older living with diabetes or hypertension, respectively. These endpoints will be assessed through a household survey in the RHM service areas. In addition to the health impact evaluation, we will conduct studies on cost-effectiveness, syndemics, and the intervention's implementation processes., Discussion: This study has the ambition to assist the Eswatini government in selecting the most effective delivery model for diabetes and hypertension care. The evidence generated with this national-level cluster-randomized controlled trial may also prove useful to policy makers in the wider Sub-Saharan African region., Trial Registration: NCT04183413. Trial registration date: December 3, 2019., (© 2023. The Author(s).)

Background: Evidence on the comparative performance of purified protein derivative tuberculin skin tests (TST) and interferon-gamma release assays (IGRA) for predicting incident active tuberculosis (TB) remains conflicting. We conducted an individual participant data meta-analysis to directly compare the predictive performance for incident TB disease between TST and IGRA to inform policy., Methods: We searched Medline and Embase from 1 January 2002 to 4 September 2020, and studies that were included in previous systematic reviews. We included prospective longitudinal studies in which participants received both TST and IGRA and estimated performance as hazard ratios (HR) for the development of all diagnoses of TB in participants with dichotomised positive test results compared to negative results, using different thresholds of positivity for TST. Secondary analyses included an evaluation of the impact of background TB incidence. We also estimated the sensitivity and specificity for predicting TB. We explored heterogeneity through pre-defined sub-group analyses (e.g. country-level TB incidence). Publication bias was assessed using funnel plots and Egger's test. This review is registered with PROSPERO, CRD42020205667., Findings: We obtained data from 13 studies out of 40 that were considered eligible (N = 32,034 participants: 36% from countries with TB incidence rate ≥100 per 100,000 population). All reported data on TST and QuantiFERON Gold in-Tube (QFT-GIT). The point estimate for the TST was highest with higher cut-offs for positivity and particularly when stratified by bacillus Calmette-Guérin vaccine (BCG) status (15 mm if BCG vaccinated and 5 mm if not [TST 5/15 mm ]) at 2.88 (95% CI 1.69-4.90). The pooled HR for QFT-GIT was higher than for TST at 4.15 (95% CI 1.97-8.75). The difference was large in countries with TB incidence rate <100 per 100,000 population (HR 10.38, 95% CI 4.17-25.87 for QFT-GIT VS. HR 5.36, 95% CI 3.82-7.51 for TST 5/15 mm ) but much of this difference was driven by a single study (HR 5.13, 95% CI 3.58-7.35 for TST 5/15 mm VS. 7.18, 95% CI 4.48-11.51 for QFT-GIT, when excluding the study, in which all 19 TB cases had positive QFT-GIT results). The comparative performance was similar in the higher burden countries (HR 1.61, 95% CI 1.23-2.10 for QFT-GIT VS. HR 1.72, 95% CI 0.98-3.01 for TST 5/15 mm ). The predictive performance of both tests was higher in countries with TB incidence rate <100 per 100,000 population. In the lower TB incidence countries, the specificity of TST (76% for TST 5/15 mm ) and QFT-GIT (74%) for predicting active TB approached the minimum World Health Organization target (≥75%), but the sensitivity was below the target of ≥75% (63% for TST 5/15 mm and 65% for QFT-GIT). The absolute differences in positive and negative predictive values between TST 15 mm and QFT-GIT were small (positive predictive values 2.74% VS. 2.46%; negative predictive values 99.42% VS. 99.52% in low-incidence countries). Egger's test did not show evidence of publication bias (0.74 for TST 15 mm and p = 0.68 for QFT-GIT)., Interpretation: IGRA appears to have higher predictive performance than the TST in low TB incidence countries, but the difference was driven by a single study. Any advantage in clinical performance may be small, given the numerically similar positive and negative predictive values. Both IGRA and TST had lower performance in countries with high TB incidence. Test choice should be contextual and made considering operational and likely clinical impact of test results., Funding: YH, IA, and MXR were supported by the National Institute for Health and Care Research (NIHR), United Kingdom (RP-PG-0217-20009). MQ was supported by the Medical Research Council [MC&#95;UU&#95;00004/07]., Competing Interests: YH and MXR report donation of QIAreach, an IGRA, by QIAGEN for a LTBI infection survey. YH, MXR, and IA report donations of Cy-TB, a TB-specific skin test for detection of LTBI, by the Serum Institute of India for a study on the feasibility and patient-important outcomes. They had no role in the submitted work. RD declared the receipt of payment for lectures from Qiagen and Oxford Immunotec. JD declared honoraria for lectures from Oxford Immunotec. AG declared receipt of research grants from the US National Institute of Health (NIH) and membership in NIH Council and IndoUS Science Technology Forum. CL provided consultation service to INSMED and received speakers honoraria from INSMED, GILEAD, JANSSEN and is a member of the Data Safety Board of trials from Medicines sans Frontiers, all outside of the submitted work. ILR has a patent (PCT/EP2019/064885), in vitro method for the diagnosis or detection of non-tuberculous mycobacteria. MS reports receipt of test kits free of charge from Qiagen and Oxford Immunotec. MS also reports receipt of research grants from Biotest and Astellas, consulting fees and honoraria from Biotest, Moderna, Qiagen, and Takeda, support for travel from Biotest, and participation on advisory board for Biotest and Moderna, all outside of this work. GS reports receipt of consulting fees from Pfizer, Diasorin, and INSMED. All other authors declare no competing interests., (© 2022 The Author(s).)

Objectives: To evaluate the access to comprehensive diagnostics and novel antituberculosis medicines in European countries., Methods: We investigated the access to genotypic and phenotypic Mycobacterium tuberculosis drug susceptibility testing and the availability of antituberculosis drugs and calculated the cost of drugs and treatment regimens at major tuberculosis treatment centres in countries of the WHO European region where rates of drug-resistant tuberculosis are the highest among all WHO regions. Results were stratified by middle-income and high-income countries., Results: Overall, 43 treatment centres from 43 countries participated in the study. For WHO group A drugs, the frequency of countries with the availability of phenotypic drug susceptibility testing was as follows: (a) 75% (30/40) for levofloxacin, (b) 82% (33/40) for moxifloxacin, (c) 48% (19/40) for bedaquiline, and (d) 72% (29/40) for linezolid. Overall, of the 43 countries, 36 (84%) and 24 (56%) countries had access to bedaquiline and delamanid, respectively, whereas only 6 (14%) countries had access to rifapentine. The treatment of patients with extensively drug-resistant tuberculosis with a regimen including a carbapenem was available only in 17 (40%) of the 43 countries. The median cost of regimens for drug-susceptible tuberculosis, multidrug-resistant/rifampicin-resistant tuberculosis (shorter regimen, including bedaquiline for 6 months), and extensively drug-resistant tuberculosis (including bedaquiline, delamanid, and a carbapenem) were €44 (minimum-maximum, €15-152), €764 (minimum-maximum, €542-15152), and €8709 (minimum-maximum, €7965-11759) in middle-income countries (n = 12) and €280 (minimum-maximum, €78-1084), €29765 (minimum-maximum, €11116-40584), and €217591 (minimum-maximum, €82827-320146) in high-income countries (n = 29), respectively., Discussion: In countries of the WHO European region, there is a widespread lack of drug susceptibility testing capacity to new and repurposed antituberculosis drugs, lack of access to essential medications in several countries, and a high cost for the treatment of drug-resistant tuberculosis., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Individuals with a history of tuberculosis (TB) disease are at higher risk of developing a subsequent episode than those without. Considering the role of social and environmental factors in tuberculosis, we assessed neighbourhood-level risk factors associated with recurrent tuberculosis in Cape Town, South Africa., Methods: This cohort consisted of patients who completed treatment for their first drug-sensitive TB episode between 2003 and 2015. Addresses were geocoded at neighbourhood level. Data on neighbourhood-level factors were obtained from the Census 2011 (household size, population density) and the City of Cape Town (Socio-Economic Index). Neighbourhood-level TB burden was calculated annually by dividing the number of notified TB episodes by the population in that neighbourhood. Multilevel survival analysis was performed with the outcome recurrent TB, defined as a second episode of TB, and controlling for individual-level risk factors (age, gender and time since first episode in years). Follow-up ended at the second episode, or on 31 December 2015, whichever came first., Results: The study included 173 421 patients from 700 neighbourhoods. Higher Socio-Economic Index was associated with a lower risk of recurrence compared with average Socio-Economic Index. An increased risk was found for higher household size and TB burden, with an increase of 20% for every additional person in mean household size and 10% for every additional TB episode/100 inhabitants. No association was found with population density., Conclusion: Recurrent TB was associated with increased household size and TB burden at neighbourhood level. These findings could be used to target TB screening activities., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

BACKGROUND: In high TB burden countries, delayed diagnosis remains a big challenge in TB control. The objective of this study is to assess the role of distance between residence and healthcare facility (HCF) on care-seeking among individuals with symptoms associated with pulmonary TB in Tanzania. METHODS: In this cross-sectional study, using data from a national TB survey, coordinates of 300 (residential) sites within 62 clusters were obtained through Google searches and average distances to HCF were calculated per cluster. Univariable and multivariable logistic regression analyses were conducted, with care-seeking behaviour being the primary outcome variable. RESULTS: Distance from residence to HCF had no effect on care-seeking behaviour of individuals with TB-related symptoms in this study (OR 1.00, 95% CI 1.00-1.00). Over 85% of HCFs where care has been sought lack TB diagnostic capacity, mostly comprising dispensaries with staff less educated in TB-related symptoms. CONCLUSION: Care-seeking behaviour among individuals with TB-related symptoms in Tanzania was not found to be associated with distance to HCF. First-line diagnostics should be improved 1) by equipping local dispensaries with basic TB diagnostic capacity, and 2) by educating staff of local dispensaries more thoroughly about basic TB symptoms and the importance of swift referrals.

Background: Antiretroviral therapy (ART) is known to reduce tuberculosis (TB) incidence among people living with HIV (PLWH). However, studies describing the impact of long-term ART and CD4 count recovery on TB incidence remain scarce due to limited follow up in previous studies. We evaluated TB incidence in a long-term cohort of PLWH on ART in Thailand., Methods: We conducted an analysis of PLWH aged ≥ 18 years who started ART between 1996 and December 2020. Participants were followed up every 6 months for routine HIV care. TB risk factors, body mass index (BMI), physical examination and full differential blood counts were evaluated at each clinic visit, and CD4 cell counts and HIV RNA every 12 months. Participants diagnosed with TB > 3 months after starting ART were classified as incident cases. Time to event models with death as a competing risk, were used to derive the TB cumulative incidence function (CIF) after ART initiation, and assess time-updated factors associated with incident TB using a six month lag., Results: A total of 2,636 PLWH contributing 24,229 person years (PY) of follow-up on ART were analysed. Median age was 32.0 (IQR 27.4-37.6) years; 67.5% were male. Median CD4 cell count at ART initiation was 264 (IQR 167-379) cells/mm 3 and median follow-up duration was 7.6 (IQR 1.9-15.7) years. During follow-up, 113 PLWH developed TB. The probability of incident TB was 0.7%, 1.7%, 3.3% and 4.3%, at 1, 2, 5 and 7 years after ART initiation, respectively. TB CIF was highest among participants with CD4 < 50 cells/mm 3 . The overall crude incidence of TB was 4.66 (95% CI 3.87-5.60) per 1000 PY. Low CD4 count, BMI < 18 kg/m 2 , and substance use in the previous six months were significantly associated with incident TB. Incidence declined with time on suppressive ART, but remained higher than the Thai general population 7 years after ART initiation (2.2 vs 1.5/1000 PY, respectively)., Conclusion: Despite a marked reduction in TB incidence following ART, ongoing TB risk remains high among PLWH, despite long-term suppressive ART. Those with low CD4 cell counts, who are underweight, or currently having substance abuse should be carefully monitored., (© 2022. The Author(s).)

Background: Diagnosing urinary tract infections (UTIs) in nursing home residents is complex, as specific urinary symptoms are often absent and asymptomatic bacteriuria (ASB) is prevalent. The aim of this study was to assess the sensitivity of blood C-reactive protein (CRP) and procalcitonin (PCT), measured by point-of-care tests (PoCTs), to diagnose UTIs in this setting., Methods: Elderly residents (≥65 years old) with a suspected UTI were recruited from psychogeriatric, somatic, or rehabilitation wards across 13 participating nursing homes. CRP and PCT were tested simultaneously in the same study participants. To assess the tests' sensitivities, a stringent definition of "true" UTI was used that included the presence of symptoms, urinary leucocytes, a positive urine culture, and symptom resolution during antibiotic treatment covering isolated uropathogen(s). The original sample size was 440 suspected UTI episodes, in order to detect a clinically relevant sensitivity of at least 65% when calculated using the matched analysis approach to compare both PoCTs., Results: After enrollment of 302 episodes (68.6% of the planned sample size), an unplanned and funder-mandated interim analysis was done, resulting in premature discontinuation of the study for futility. For 247 of 266 eligible episodes, all mandatory items required for the true UTI definition (92.9%) were available. In total, 49 episodes fulfilled our stringent UTI definition (19.8%). The sensitivities of CRP (cut-off, 6.5 mg/L) and PCT (cut-off, 0.025 ng/mL) were 52.3% (95% confidence interval [CI], 36.7-67.5%) and 37.0% (95% CI, 23.2-52.5%), respectively., Conclusions: Our results indicate that CRP and PCT are not suitable tests for distinguishing UTI and ASB in nursing home residents., Clinical Trials Registration: Netherlands Trial Registry NL6293., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

BACKGROUND: Diagnostic tools to identify incipient or subclinical TB stages will be helpful for preventive intervention. A simple biomarker to predict TB may be the monocytes to lymphocytes ratio (ML ratio) in peripheral blood. METHODS: We assessed the relationship between multiple time-updated ML ratio measurements and incidence of TB in people living with HIV (PLWH) after antiretroviral therapy (ART) was initiated. The ML ratio was updated at least every 6 months. TB incidence with corresponding 95% confidence intervals stratified according to time-updated ML ratio was calculated using ML ratio in quartiles. RESULTS: A total of 1305 PLWH were included in the analyses: 46 had incident TB and 1259 remained TB-free. The TB incidence rate was 10.3 (95% CI 7.1-14.9) cases/1000 patient-years (PYR) among participants with ML ratio ≥0.25 compared with 1.1/1000 PYR (95% CI 0.4-2.9) among those with ML ratio <0.15. At cut-point 0.23, the ML ratio provided a diagnostic area under the receiver operating characteristics curve (AROC) of 0.849 (95% CI 0.784-0.914) and a sensitivity of 85% and specificity of 71%. CONCLUSION: Increased ML ratio was predictive of incident TB among PLWH on or after ART. The ML ratio can be a simple tool to stratify the risk of TB in PLWH.

Background: The World Health Organization recommends standardised treatment durations for patients with tuberculosis (TB). We identified and validated a host-RNA signature as a biomarker for individualised therapy durations for patients with drug-susceptible (DS)- and multidrug-resistant (MDR)-TB., Methods: Adult patients with pulmonary TB were prospectively enrolled into five independent cohorts in Germany and Romania. Clinical and microbiological data and whole blood for RNA transcriptomic analysis were collected at pre-defined time points throughout therapy. Treatment outcomes were ascertained by TBnet criteria (6-month culture status/1-year follow-up). A whole-blood RNA therapy-end model was developed in a multistep process involving a machine-learning algorithm to identify hypothetical individual end-of-treatment time points., Results: 50 patients with DS-TB and 30 patients with MDR-TB were recruited in the German identification cohorts (DS-GIC and MDR-GIC, respectively); 28 patients with DS-TB and 32 patients with MDR-TB in the German validation cohorts (DS-GVC and MDR-GVC, respectively); and 52 patients with MDR-TB in the Romanian validation cohort (MDR-RVC). A 22-gene RNA model (TB22) that defined cure-associated end-of-therapy time points was derived from the DS- and MDR-GIC data. The TB22 model was superior to other published signatures to accurately predict clinical outcomes for patients in the DS-GVC (area under the curve 0.94, 95% CI 0.9-0.98) and suggests that cure may be achieved with shorter treatment durations for TB patients in the MDR-GIC (mean reduction 218.0 days, 34.2%; p<0.001), the MDR-GVC (mean reduction 211.0 days, 32.9%; p<0.001) and the MDR-RVC (mean reduction of 161.0 days, 23.4%; p=0.001)., Conclusion: Biomarker-guided management may substantially shorten the duration of therapy for many patients with MDR-TB., Competing Interests: Conflict of interest: J. Heyckendorf reports no conflicts of interest; the Research Center Borstel has a patent EP20158652.6. Conflict of interest: S. Marwitz has nothing to disclose. Conflict of interest: M. Reimann has nothing to disclose. Conflict of interest: K. Avsar has nothing to disclose. Conflict of interest: A.R. DiNardo has nothing to disclose. Conflict of interest: G. Günther has nothing to disclose. Conflict of interest: M. Hoelscher has nothing to disclose. Conflict of interest: E. Ibraim reports grants, personal fees and non-financial support from Deutsches Zentrum fur Infektionsforschung (DZIF), during the conduct of the study. Conflict of interest: B. Kalsdorf has nothing to disclose. Conflict of interest: S.H.E. Kaufmann has nothing to disclose. Conflict of interest: I. Kontsevaya reports grants from German Center for Infectious Research (DZIF) and German Center for Lung Research (DZL), during the conduct of the study; grants from EU Horizon 2020 AnTBiotic (733079) and CARE (825673), outside the submitted work. Conflict of interest: F. van Leth has nothing to disclose. Conflict of interest: A.M. Mandalakas has nothing to disclose. Conflict of interest: F.P. Maurer has nothing to disclose. Conflict of interest: M. Müller has nothing to disclose. Conflict of interest: D. Nitschkowski has nothing to disclose. Conflict of interest: I.D. Olaru has nothing to disclose. Conflict of interest: C. Popa has nothing to disclose. Conflict of interest: A. Rachow has nothing to disclose. Conflict of interest: T. Rolling has nothing to disclose. Conflict of interest: J. Rybniker has nothing to disclose. Conflict of interest: H.J.F. Salzer has nothing to disclose. Conflict of interest: P. Sanchez-Carballo has nothing to disclose. Conflict of interest: M. Schuhmann has nothing to disclose. Conflict of interest: D. Schaub has nothing to disclose. Conflict of interest: V. Spinu reports grants, personal fees and non-financial support from Deutsches Zentrum fur Infektionsforschung (DZIF), during the conduct of the study. Conflict of interest: I. Suárez has nothing to disclose. Conflict of interest: E. Terhalle has nothing to disclose. Conflict of interest: M. Unnewehr has nothing to disclose. Conflict of interest: J. Weiner 3rd has nothing to disclose. Conflict of interest: T. Goldmann has a patent pending. Conflict of interest: C. Lange reports personal fees for lectures from Chiesi, Gilead, Janssen, Lucane, Novartis, Oxoid, Berlin Chemie and Thermofisher, and personal fees for meeting attendance from Oxford Immunotec, outside the submitted work., (Copyright ©The authors 2021. For reproduction rights and permissions contact permissions@ersnet.org.)

Objective: To evaluate the diagnostic and antibiotic treatment strategies for patients suspected of sepsis, in a tertiary hospital in Indonesia. This can identify areas for improvement in care provided, and inform diagnostic and antimicrobial stewardship activities within the hospital., Methods: Retrospective review of medical records with regards to the diagnosis and management of adult patients with sepsis admitted to a tertiary hospital in Indonesia. We assessed the diagnostic process, and whether or not the antibiotic treatment provided was appropriate for the diagnosis. Appropriateness of antibiotic treatment was classified as being definite appropriate, probable appropriate, inappropriate, or unknown., Results: The study included 535 adult patients, of whom 295 (55%) were diagnosed with a community-acquired sepsis, and 240 (45%) with a hospital-acquired sepsis. A specimen for culture and antimicrobial susceptibility testing was collected from three out of four patients (392/535). All but 10 patients had information on antibiotic treatment at the time of sepsis diagnosis. Of those, nearly 50% (257/525) of the patients received antibiotic treatment with unknown appropriateness because no cultures were taken (n = 141) or all cultures were negative (n = 116). Just 3.4% and 9.1% of the patients received definite or probable appropriate antibiotic treatment, respectively., Conclusions: There is a clear need in encouraging attending physicians to obtain the much-required blood cultures, or cultures from the suspected source of infection before empirical antibiotic treatment is started. This will improve the use of appropriate antibiotic treatment strategies, and contribute to antimicrobial stewardship.

Objective: There is unmet need for an easy, noninvasive urine collection method to diagnose urinary tract infections (UTIs) in nursing home residents suffering from urinary incontinence or cognitive impairments. UTIs are highly prevalent in nursing home residents, and urine specimen collection can be difficult. The objective of this study was to assess if urine specimens collected from super-absorbing incontinence pads (adult diapers) are a reliable collection method for UTI diagnosis., Design: This was a paired noninferiority laboratory study, in which pairing refers to UTI diagnostics performed directly using clinical urine specimens (reference specimen) and indirectly using urine extracted from diapers (diaper specimen)., Setting and Participants: In this study, remnants of 250 clinical urine specimens were used to assess noninferiority in diagnosing UTIs, based on a 1-sided type I error of 2.5%, a power of 90%, and a noninferiority margin of 15%., Methods: Urine specimens were poured on super-absorbing disposable adult diapers and extracted after 3 hours, to use for dipstick urinalysis and bacterial culture. UTIs were defined as presence of leukocytes and a positive bacterial culture. Noninferiority was assessed by calculating a Wald-type test statistic., Results: Noninferiority was established for diagnosing UTIs in diaper specimens, and for each of its components (dipstick leukocyte detection and bacterial culture positivity). Positive bacterial cultures were found in 72 (29.0%) diaper specimens compared with 65 (26.2%) reference specimens (difference -2.8%, 97.5% CI -7.1% to 1.5%). Leukocytes were present in 162 (64.8%) diaper specimens, compared with 175 (70.0%) reference specimens (difference -5.7%, 97.5% CI: -10.6% to -0.7%)., Conclusion and Implications: Our results on diagnosing UTIs, by dipstick analysis and bacterial cultures, using super-absorbing adult diapers are promising. Before translation into clinical practice, further studies are needed to evaluate the risk of bacterial contamination by wearing adult diapers, possibly resulting in overdiagnosis of UTI., (Copyright © 2020 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Antimicrobial resistance (AMR) in urinary tract infections (UTI) is a global public health problem. However, estimates of the prevalence of AMR, required for empirical treatment guidelines, are lacking for many regions., Objectives: To perform a systematic review and summarize the available information about AMR prevalence among urinary Escherichia coli and Klebsiella pneumoniae , the two priority uropathogens, in the Asia-Pacific region (APAC)., Methods: PubMed, EBSCO and Web of Science databases were searched for articles (2008-20), following PRISMA guidelines. The prevalence of resistance was calculated and reported as point estimate with 95% CI for antimicrobial drugs recommended in WHO treatment guidelines. Data were stratified by country and surveillance approach (laboratory- or population-based surveillance). The quality of included articles was assessed using a modified Newcastle-Ottawa Quality Assessment Scale., Results: Out of 2400 identified articles, 24 studies, reporting on 11 (26.8%) of the 41 APAC countries, met the inclusion criteria. Prevalence of resistance against trimethoprim/sulfamethoxazole, ciprofloxacin, and ceftriaxone ranged between 33% and 90%, with highest prevalence reported from Bangladesh, India, Sri Lanka and Indonesia. Resistance against nitrofurantoin ranged between 2.7% and 31.4%. Two studies reported data on fosfomycin resistance (1.8% and 1.7%). Quality of reporting was moderate., Conclusions: We show very high prevalence estimates of AMR against antibiotics commonly used for the empirical treatment of UTI, in the limited number of countries in the APAC for which data are available. Novel feasible and affordable approaches that facilitate population-based AMR surveillance are needed to increase knowledge on AMR prevalence across the region., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.)

Untreated active tuberculosis (TB) has a very high long-term mortality. Treatment of TB reduces mortality dramatically and should maximize cure, preventing ongoing transmission and TB sequelae. However, predicting the risk of failure and relapse is crucial for the management of individual patients and for the evaluation of effectiveness of programs. Various outcome definitions for drug-sensitive and drug-resistant TB were developed, implemented, and endorsed since introduction of TB chemotherapy by the World Health Organization (WHO), mostly based on culture and smear results. They should be applicable for individual patient care, surveillance, and research. Definitions with focus on program evaluation differ from definitions to evaluate the efficacy and effectiveness of regimens. Lack of sputum production at the later stage of treatment reduces the easy applicability of current definitions. Definitions of failure and cure are sometimes difficult to apply. Alternative approaches suggest culture positivity at 6 months or more of treatment as an indicator for failure. New definitions for cure including a relapse-free period posttreatment and reduced number of culture and smear results are considered. Increasing variation and individualization of treatment and its duration urgently require new approaches using pathogen- or host-specific biomarkers, which indicate risk of failure and define cure. Such biomarkers are under evaluation but still far from translation in clinical routine practice., (© 2021 S. Karger AG, Basel.)

The risk of tuberculosis (TB) is variable among individuals with latent Mycobacterium tuberculosis infection (LTBI), but validated estimates of personalized risk are lacking. In pooled data from 18 systematically identified cohort studies from 20 countries, including 80,468 individuals tested for LTBI, 5-year cumulative incident TB risk among people with untreated LTBI was 15.6% (95% confidence interval (CI), 8.0-29.2%) among child contacts, 4.8% (95% CI, 3.0-7.7%) among adult contacts, 5.0% (95% CI, 1.6-14.5%) among migrants and 4.8% (95% CI, 1.5-14.3%) among immunocompromised groups. We confirmed highly variable estimates within risk groups, necessitating an individualized approach to risk stratification. Therefore, we developed a personalized risk predictor for incident TB (PERISKOPE-TB) that combines a quantitative measure of T cell sensitization and clinical covariates. Internal-external cross-validation of the model demonstrated a random effects meta-analysis C-statistic of 0.88 (95% CI, 0.82-0.93) for incident TB. In decision curve analysis, the model demonstrated clinical utility for targeting preventative treatment, compared to treating all, or no, people with LTBI. We challenge the current crude approach to TB risk estimation among people with LTBI in favor of our evidence-based and patient-centered method, in settings aiming for pre-elimination worldwide.

Background: Diagnosing urinary tract infections (UTI) in nursing home residents is complex, due to frequent non-specific symptomatology and asymptomatic bacteriuria. The objective of this study was to explore health care professionals' perceptions of the proposed use of inflammatory marker Point-Of-Care Testing (POCT) in this respect., Methods: We conducted a qualitative inquiry (2018-2019) alongside the multicenter PROGRESS study (NL6293), which assessed the sensitivity of C-reactive protein and procalcitonin POCT in UTI. We used semi-structured face-to-face interviews. The participants were physicians (n = 12) and nurses (n = 6) from 13 nursing homes in the Netherlands. Most respondents were not familiar with inflammatory marker POCT, while some used POCT for respiratory tract infections. Both the interview guide and the analysis of the interview transcripts were based on the Consolidated Framework for Implementation Research., Results: All respondents acknowledged that sufficiently sensitive POCT could decrease diagnostic uncertainty to some extent in residents presenting with non-specific symptoms. They primarily thought that negative test results would rule out UTI and justify withholding antibiotic treatment. Secondly, they described how positive test results could rule in UTI and justify antimicrobial treatment. However, most respondents also expected new diagnostic uncertainties to arise. Firstly, in case of negative test results, they were not sure how to deal with residents' persisting non-specific symptoms. Secondly, in case of positive test results, they feared overlooking infections other than UTI. These new uncertainties could lead to inappropriate antibiotics use. Therefore, POCT was thought to create a false sense of confidence., Conclusions: Our study suggests that inflammatory marker POCT will only improve UTI management in nursing homes to some extent. To realize the expected added value, any implementation of POCT requires thorough guidance to ensure appropriate use. Developing UTI markers with high negative and positive predictive values may offer greater potential to improve UTI management in nursing homes.

Surveillance of antimicrobial resistance (AMR) enables monitoring of trends in AMR prevalence. WHO recommends laboratory-based surveillance to obtain actionable AMR data at local or national level. However, laboratory-based surveillance may lead to overestimation of the prevalence of AMR due to bias. The objective of this study is to assess the difference in resistance prevalence between laboratory-based and population-based surveillance (PBS) among uropathogens in Indonesia. We included all urine samples submitted to the laboratory growing Escherichia coli and Klebsiella pneumoniae in the laboratory-based surveillance. Population-based surveillance data were collected in a cross-sectional survey of AMR in E. coli and K. pneumoniae isolated from urine samples among consecutive patients with symptoms of UTI, attending outpatient clinics and hospital wards. Data were collected between 1 April 2014 until 31 May 2015. The difference in percentage resistance (95% confidence intervals) between laboratory- and population-based surveillance was calculated for relevant antibiotics. A difference larger than +/- 5 percent points was defined as a biased result, precluding laboratory-based surveillance for guiding empirical treatment. We observed high prevalence of AMR ranging between 63.1% (piperacillin-tazobactam) and 85% (ceftriaxone) in laboratory-based surveillance and 41.3% (piperacillin-tazobactam) and 74.2% (ceftriaxone) in population-based surveillance, except for amikacin and meropenem (5.7%/9.8%; 10.8%/5.9%; [laboratory-/population-based surveillance], respectively). Laboratory-based surveillance yielded significantly higher AMR prevalence estimates than population-based surveillance. This difference was much larger when comparing surveillance data from outpatients than from inpatients. All point estimates of the difference between the two surveillance systems were larger than 5 percent points, except for amikacin and meropenem. Laboratory-based AMR surveillance of uropathogens, is not adequate to guide empirical treatment for community-based settings in Indonesia., Competing Interests: The authors have declared that no competing interests exist.

Background: Mass administrations of antimalarial drugs (MDA) have reduced the incidence and prevalence of P. falciparum infections in a trial in the Greater Mekong Subregion. Here we assess the impact of the MDA on P. vivax infections., Methods: Between May 2013 and July 2017, four villages in each Myanmar, Vietnam, Cambodia and Lao PDR were selected based on high prevalence of P. falciparum infections. Eight of the 16 villages were randomly assigned to receive MDA consisting of three-monthly rounds of three-day courses of dihydroartemisinin-piperaquine and, except in Cambodia, a single low-dose of primaquine. Cross-sectional surveys were conducted at quarterly intervals to detect Plasmodium infections using ultrasensitive qPCR. The difference in the cumulative incidence between the groups was assessed through a discrete time survival approach, the difference in prevalence through a difference-in-difference analysis, and the difference in the number of participants with a recurrence of P. vivax infection through a mixed-effect logistic regression., Results: 3,790 (86%) residents in the intervention villages participated in at least one MDA round, of whom 2,520 (57%) participated in three rounds. The prevalence of P. vivax infections fell from 9.31% to 0.89% at month 3 but rebounded by six months to 5.81%. There was no evidence that the intervention reduced the cumulative incidence of P.vivax infections (95% confidence interval [CI] Odds ratio (OR): 0.29 to 1.36). Similarly, there was no evidence of MDA related reduction in the number of participants with at least one recurrent infection (OR: 0.34; 95% CI: 0.08 to 1.42)., Conclusion: MDA with schizontocidal drugs had a lasting effect on P. falciparum infections but only a transient effect on the prevalence of P. vivax infections. Radical cure with an 8-aminoquinoline will be needed for the rapid elimination of vivax malaria., Competing Interests: We declare no competing of interests in any form related to employment, consultancy, patents, products in development, or marketed product, etc. None of our authors is affiliated with a commercial entity.

Following publication of the original article [1], it was brought to the authors' attention that one of the names in the author list had been provided with the incorrect spelling.

Background: Trials to assess the efficacy of the radical cure of Plasmodium vivax malaria with 8-aminoquinolines require that most post-treatment relapses are identified, but there is no consensus on the optimal duration of follow-up in either symptomatic or asymptomatic vivax malaria. The efficacy of a 14-day course of primaquine on the cumulative incidence of recurrent asymptomatic P. vivax infections detected by ultrasensitive quantitative PCR (uPCR) as a primary endpoint was assessed., Methods: A randomized, placebo-controlled, single-blind trial was conducted in four villages of the Lao PDR during 2016-2018 nested in a larger project evaluating mass drug administrations (MDA) with dihydroartemisinin-piperaquine (DP) and a single low-dose primaquine to clear Plasmodium falciparum infections. In the nested sub-study, eligible participants with mono- or mixed P. vivax infections detected by uPCR were randomized to receive either 14 days of primaquine (0.5 mg/kg/day) or placebo during the last round of MDA (round 3) through directly observed therapy. Participants were checked monthly for 12 months for parasitaemia using uPCR. The primary outcome was cumulative incidence of participants with at least one recurrent episode of P. vivax infection., Results: 20 G6PD-normal participants were randomized in each arm. 5 (29%) of 20 participants in the placebo arm experienced asymptomatic, recurrent P. vivax infections, resulting in a cumulative incidence at month 12 of 29%. None of the 20 participants in the intervention arm had recurrent infections (p = 0.047 Fisher's exact test). Participants with recurrent P. vivax infections were found to be parasitaemic for between one and five sequential monthly tests. The median time to recurrence of P. vivax parasitaemia was 178 days (range 62-243 days)., Conclusions: A 14-day course of primaquine in addition to a DP-MDA was safe, well-tolerated, and prevented recurrent asymptomatic P. vivax infections. Long follow-up for up to 12 months is required to capture all recurrences following the treatment of asymptomatic vivax infection. To eliminate all malarias in settings where P. vivax is endemic, a full-course of an 8-aminoquinolines should be added to MDA to eliminate all malarias. Trial registration This study was registered with ClinicalTrials.gov under NCT02802813 on 16th June 2016. https://clinicaltrials.gov/ct2/show/NCT02802813.

Background: Mycobacterium tuberculosis rapid diagnostic tests (RDTs) are widely employed in routine laboratories and national surveys for detection of rifampicin-resistant (RR)-TB. However, as next-generation sequencing technologies have become more commonplace in research and surveillance programs, RDTs are being increasingly complemented by whole genome sequencing (WGS). While comparison between RDTs is difficult, all RDT results can be derived from WGS data. This can facilitate continuous analysis of RR-TB burden regardless of the data generation technology employed. By converting WGS to RDT results, we enable comparison of data with different formats and sources particularly for low- and middle-income high TB-burden countries that employ different diagnostic algorithms for drug resistance surveys. This allows national TB control programs (NTPs) and epidemiologists to utilize all available data in the setting for improved RR-TB surveillance., Methods: We developed the Python-based MycTB Genome to Test (MTBGT) tool that transforms WGS-derived data into laboratory-validated results of the primary RDTs-Xpert MTB/RIF, XpertMTB/RIF Ultra, GenoType MDRTB plus v2.0, and GenoscholarNTM+MDRTB II. The tool was validated through RDT results of RR-TB strains with diverse resistance patterns and geographic origins and applied on routine-derived WGS data., Results: The MTBGT tool correctly transformed the single nucleotide polymorphism (SNP) data into the RDT results and generated tabulated frequencies of the RDT probes as well as rifampicin-susceptible cases. The tool supplemented the RDT probe reactions output with the RR-conferring mutation based on identified SNPs. The MTBGT tool facilitated continuous analysis of RR-TB and Xpert probe reactions from different platforms and collection periods in Rwanda., Conclusion: Overall, the MTBGT tool allows low- and middle-income countries to make sense of the increasingly generated WGS in light of the readily available RDT results, and assess whether currently implemented RDTs adequately detect RR-TB in their setting. With its feature to transform WGS to RDT results and facilitate continuous RR-TB data analysis, the MTBGT tool may bridge the gap between and among data from periodic surveys, continuous surveillance, research, and routine tests, and may be integrated within the national information system for use by the NTP and epidemiologists to improve setting-specific RR-TB control. The MTBGT source code and accompanying documentation are available at https://github.com/KamelaNg/MTBGT., Competing Interests: The authors declare that they have no competing interests.

Introduction: Suspected urinary tract infection (UTI) ranks among the most common reasons for antibiotic use in nursing homes. However, diagnosing UTI in this setting is challenging because UTI often presents with non-specific symptomatology. Moreover asymptomatic bacteriuria is common in elderly, which complicates attribution of causality to detection of bacteria in urine. These diagnostic challenges contribute to overuse of antibiotics and emergence of antimicrobial resistance in nursing homes. Given the diagnostic challenges, there is a need for point-of-care (POC) diagnostic tests to support clinical rules for diagnosing UTI. Procalcitonin (PCT) and C reactive protein (CRP) are inflammatory blood markers that have been proven useful to support diagnosis and monitoring of (bacterial) respiratory tract infections and sepsis. While limited studies suggest their usefulness in supporting UTI diagnosis, their utility has not been studied in elderly populations for this purpose., Methods and Analysis: In a 24-month matched prospective study, 'PROGRESS' will assess and compare the sensitivity of rapid POC measurements of blood CRP and PCT levels to support clinical rules for diagnosing UTI in nursing home residents. The primary outcome measure is sensitivity of the POC tests to identify patients with true UTI based on the predefined definition, as derived from receiver operating curves., Ethics and Dissemination: This study will be conducted in accordance with Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. The study protocol is approved by the Medical Ethical Committee of Amsterdam UMC location VUmc with reference number 2017.350 and National Central Committee on Research involving Human Subjects with reference number NL62067.029.17., Trial Registration Number: NTR6467., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

The emergence of multidrug-resistant tuberculosis (MDR-TB; defined as resistance to at least rifampicin and isoniazid) represents a growing threat to public health and economic growth. Never before in the history of mankind have more patients been affected by MDR-TB than is the case today. The World Health Organization reports that MDR-TB outcomes are poor despite staggeringly high management costs. Moreover, treatment is prolonged, adverse events are common, and the majority of affected patients do not receive adequate treatment. As MDR-TB strains are often resistant to one or more second-line anti-TB drugs, in-depth genotypic and phenotypic drug susceptibility testing is needed to construct personalised treatment regimens to improve treatment outcomes. For the first time in decades, the availability of novel drugs such as bedaquiline allow us to design potent and well-tolerated personalised MDR-TB treatment regimens based solely on oral drugs. In this article, we present management guidance to optimise the diagnosis, algorithm-based treatment, drug dosing and therapeutic drug monitoring, and the management of adverse events and comorbidities, associated with MDR-TB. We also discuss the role of surgery, physiotherapy, rehabilitation, palliative care and smoking cessation in patients with MDR-TB. We hope that incorporating these recommendations into patient care will be helpful in optimising treatment outcomes, and lead to more MDR-TB patients achieving a relapse-free cure.

Introduction: There are concerns that immediate ART initiation (regardless of CD4 count) negatively affects HIV status disclosure, ART adherence and healthcare interactions. We assessed changes in these factors after the 'Early access to ART for all' intervention, a universal test-and-treat study in Swaziland., Methods: We recruited two samples of participants between 2014 and 2017. The first group was interviewed before the intervention (control); the second group at the implementation and 6 months thereafter (intervention)., Results: High levels of disclosure to partners (controls and intervention: 94%) and family members (controls: 78%, intervention: 79%) were reported, and high levels of adherence (85% did not miss a dose among the controls, 84% in the intervention group). There were no changes in patients reporting feeling pressured to initiate ART (controls: 10%, intervention: 11%). The quality of interaction with healthcare workers improved after the intervention; healthcare workers explained more often the choice of ART initiation (controls: 88%, intervention: 93%) and the meaning of both CD4 and viral load test results (controls: 15%, intervention: 47%). More patients in the intervention group reported receiving test results (controls: 13%, intervention: 46%). We observed no changes in disclosure, adherence or patient experiences 6 months into the intervention compared to its start., Conclusion: Our results suggest that both reported adherence and disclosure levels remain high after the introduction of immediate ART in Swaziland. We observed an improvement in the healthcare interactions, possibly due to training at participating facilities, which will be an important element for a successful roll-out of immediate ART., (© 2019 The Authors. Tropical Medicine & International Health Published by John Wiley & Sons Ltd.)

Global surveillance of antimicrobial resistance (AMR) is a key component of the 68th World Health Assembly Global Action Plan on AMR. Laboratory-based surveillance is inherently biased and lacks local relevance due to aggregation of data. We assessed the feasibility, sensitivity, and affordability of a population-based AMR survey using lot quality assurance sampling (LQAS), which classifies a population as having a high or low prevalence of AMR based on a priori defined criteria. Three studies were carried out in Medan and Bandung, Indonesia, between April 2014 and June 2017. LQAS classifications for 15 antibiotics were compared with AMR estimates from a conventional population-based survey, with an assessment of the cost of a single LQAS classification using microcosting methodology, among patients suspected of urinary tract infection at 11 sites in Indonesia. The sensitivity of LQAS was above 98%. The approach detected local variation in the prevalence of AMR across sites. Time to reach LQAS results ranged from 47 to 138 days. The average cost of an LQAS classification in a single facility was US$466. The findings indicate that LQAS-based AMR survey is a feasible, sensitive, and affordable strategy for population-based AMR surveys, providing essential data to inform local empirical treatment guidelines and antimicrobial stewardship efforts., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Background: Access to quality hypertension care is often poor in sub-Saharan Africa. Some community pharmacies offer hypertension monitoring services, with and without involvement of medical doctors. To directly connect pharmacy staff and cardiologists a care model including a mobile application (mHealth) for remote patient monitoring was implemented and pilot tested in Lagos, Nigeria. Pharmacists provided blood pressure measurements and counselling. Cardiologists enrolled patients in the pilot program and remotely monitored them, for which patients paid a monthly fee. We evaluated the feasibility of this care model at five private community pharmacies. Outcome measures were retention in care, blood pressure change, quality of care, and patients' and healthcare providers' satisfaction with the care model., Methods: Patients participated in the care model's pilot at one of the five pharmacies for approximately 6-8 months from February 2016. We conducted structured patient interviews and blood pressure measurements at pilot entry and exit, and used exports of the mHealth-application, in-depth interviews and focus group discussions with patients, pharmacists and cardiologists., Results: Of 336 enrolled patients, 236 (72%) were interviewed at pilot entry and exit. According to the mHealth data 71% returned to the pharmacy after enrollment, with 3.3 months (IQR: 2.2-5.4) median duration of activity in the mHealth-application. Patients self-reported more visits than recorded in the mHealth data. Pharmacists mentioned use of paper records, understaffing, the application not being user-friendly, and patients' unwillingness to pay as reasons for underreporting. Mean systolic blood pressure decreased 9.9 mmHg (SD: 18). Blood pressure on target increased from 24 to 56% and an additional 10% had an improved blood pressure at endline, however this was not associated with duration of mHealth activity. Patients were satisfied because of accessibility, attention, adherence and information provision., Conclusion: Patients, pharmacists and cardiologists adopted the care model, albeit with gaps in mHealth data. Most patients were satisfied, and their mean blood pressure significantly reduced. Usage of the mHealth application, pharmacy incentives, and a modified financing model are opportunities for improvement. In addition, costs of implementation and availability of involved healthcare providers need to be investigated before such a care model can be further implemented.

Objective: To assess the test characteristics of a urine dipstick test in predicting a positive urine culture in an outpatient setting in Indonesia., Design: Cross-sectional study., Setting: Two outpatient clinics in Medan, Indonesia., Participants: 616 consecutively enrolled participants suspected of having a urinary tract infection., Outcome Measures: The primary outcome is the estimates of accuracy (sensitivity, specificity, predictive values) where urine culture is the reference test. The secondary outcome is the post-test probability of a positive urine culture., Results: The optimal test characteristics were obtained when index test positivity was defined as any leucocyte esterase reaction and/or a nitrite reaction and reference test positivity was defined as a urine culture with a growth of at least 10 3 colony-forming units/mL (sensitivity: 88.2% (95% CI 81.6 to 93.1), negative predictive value: 93.0% (95% CI 88.9 to 95.9)). The post-test probability of a positive urine culture after a negative urinary dipstick test was 7% in the obstetric/gynaecology clinic and 8% in the internal medicine clinic., Conclusion: The use of a urine dipstick test in a rule-out strategy can reduce the need for urine culture and avoid the prescription of (ineffective) antibiotics in a non-urology outpatient setting., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Rationale: Multidrug-resistant tuberculosis (MDR-TB) is a major burden to public health in Europe. Reported treatment success rates are around 50% or less, and cure rates are even lower., Objectives: To document the management and treatment outcome in patients with MDR-TB in Europe., Methods: We performed a prospective cohort study, analyzing management and treatment outcomes stratified by incidence of patients with MDR-TB in Europe. Treatment outcomes were compared by World Health Organization and alternative simplified definitions by the Tuberculosis Network European Trialsgroup (TBNET)., Measurements and Main Results: A total of 380 patients with MDR-TB were recruited and followed up between 2010 and 2014 in 16 European countries. Patients in high-incidence countries compared with low-incidence countries were treated more frequently with standardized regimen (83.2% vs. 9.9%), had delayed treatment initiation (median, 111 vs. 28 d), developed more additional drug resistance (23% vs. 5.8%), and had increased mortality (9.4% vs. 1.9%). Only 20.1% of patients using pyrazinamide had proven susceptibility to the drug. Applying World Health Organization outcome definitions, frequency of cure (38.7% vs. 9.7%) was higher in high-incidence countries. Simplified outcome definitions that include 1 year of follow-up after the end of treatment showed similar frequency of relapse-free cure in low- (58.3%), intermediate- (55.8%), and high-incidence (57.1%) countries, but highest frequency of failure in high-incidence countries (24.1% vs. 14.6%)., Conclusions: Conventional standard MDR-TB treatment regimens resulted in a higher frequency of failure compared with individualized treatments. Overall, cure from MDR-TB is substantially more frequent than previously anticipated, and poorly reflected by World Health Organization outcome definitions.

Background: Excellent treatment outcomes have recently been reported for patients with multi/extensively drug-resistant tuberculosis (M/XDR-TB) in settings where optimal resources for individualised therapy are available., Objective: To ascertain whether differences remain in treatment responses between patients with M/XDR-TB and those with non-M/XDR-TB., Method: Patients with TB were prospectively enrolled between March 2013 and March 2016 at five hospitals in Germany. Treatment was conducted following current guidelines and individualised on the basis of drug susceptibility testing. Two-month and 6-month sputum smear and sputum culture conversion rates were assessed. A clinical and radiological score were used to assess response to anti-tuberculosis treatment., Results: Non-M/XDR-TB (n = 29) and M/XDR-TB (n = 46) patients showed similar rates of microbiological conversion: 2-month smear conversion rate, 90% vs. 78%; culture conversion rate, 67% vs. 61%; time to smear conversion, 19 days (IQR 10-32) vs. 31 days (IQR 14-56) (P = 0.066); time to culture conversion, 39 days (IQR 17-67) vs. 39 days (IQR 6-85) (P = 0.191). Both clinical and radiological scores decreased after the introduction of anti-tuberculosis treatment., Conclusion: There were no significant differences in scores between the two groups until 6 months of treatment. Under optimal clinical conditions, with the availability of novel diagnostics and a wide range of therapeutic options for individualised treatment, patients with M/XDR-TB achieved 6-month culture conversion rates that were compatible with those in patients with non-M/XDR-TB.

Background: No guidelines exist on assessing ventilation through air changes per hour (ACH) using a vaneometer. The objective of the study was to evaluate the position and frequency for measuring air velocity using a vaneometer to assess ventilation with ACH; and to assess influence of ambient temperature and weather on ACH., Methods: Cross-sectional survey in six urban health facilities in Kampala, Uganda. Measurements consisted of taking air velocity on nine separate moments in five positions in each opening of the TB clinic, laboratory, outpatient consultation and outpatient waiting room using a vaneometer. We assessed in addition the ventilation with the "20% rule", and compared this estimation with the ventilation in ACH assessed using the vaneometer., Results: A total of 189 measurements showed no influence on air velocity of the position and moment of the measurement. No significant influence existed of ambient temperature and a small but significant influence of sunny weather. Ventilation was adequate in 17/24 (71%) of all measurements. Using the "20% rule", ventilation was adequate in 50% of rooms assessed. Agreement between both methods existed in 13/23 (56%) of the rooms assessed., Conclusion: Most rooms had adequate ventilation when assessed using a vaneometer for measuring air velocity. A single vaneometer measurement of air velocity is adequate to assess ventilation in this setting. These findings provide practical input for clear guidelines on assessing ventilation using a vaneometer. Assessing ventilation with a vaneometer differs substantially from applying the "20% rule".

Background: Multidrug-resistant tuberculosis (MDR-TB) is considered to be less transmissible due to the fitness cost associated with drug resistance-conferring mutations in essential genes., Objective: To test the hypothesis that TB drug resistance-conferring mutations with fitness cost are more frequent among human immunodeficiency virus (HIV) positive than among HIV-negative patients., Design: We analysed all strains from the two TB drug resistance surveys conducted in Uganda between 2008 and 2011. Strains phenotypically susceptible to rifampicin and/or isoniazid were assumed to be wild-type; in all other cases, we performed whole-genome sequencing. Mutations at the rpoB531 and katG315 codons were considered without fitness loss, whereas other rpoB codons and non-katG were considered with fitness loss., Results: Of the 897 TB patients, 286 (32.1%) were HIV-positive. Mutations with fitness loss in HIV-positive and HIV-negative patients were respectively as follows: non-531 rpoB: 1.03% (n = 3), 0.71% (n = 4) (OR 1.46, 95%CI 0.58-3.68); non-katG: 0.40% (n = 1), 1.0% (n = 6) (OR 0.40, 95%CI 0.07-2.20); rpoB531: 1.49% (n = 4), 0.69% (n = 4) (OR 2.29, 95%CI 0.83-5.77); katG315: 3.86% (n = 11), 2.55% (n = 15) (OR 1.54, 95%CI 0.81-2.90). The odds of mutations with and without fitness cost were higher for patients with a history of previous anti-tuberculosis treatment., Conclusions: Our data do not support the hypothesis that resistance-conferring mutations with fitness cost are likely to be often present in HIV-positive individuals.

Objectives: Urinary tract infections (UTIs) are a common reason for empirical treatment with broad-spectrum antibiotics worldwide. However, population-based antimicrobial resistance (AMR) prevalence data to inform empirical treatment choice are lacking in many regions, because of limited surveillance capacity. We aimed to assess the prevalence of AMR to commonly used antimicrobial drugs in Escherichia coli and Klebsiella pneumoniae isolated from patients with community- or healthcare-associated UTIs on two islands of Indonesia., Methods: We performed a cross-sectional patient-based study in public and private hospitals and clinics between April 2014 and May 2015. We screened patients for symptoms of UTIs and through urine dipstick analysis. Urine culture and susceptibility testing were supported by telemicrobiology and interactive virtual laboratory rounds. Surveillance data were entered in forms on mobile phones., Results: Of 3424 eligible patients, 3380 (98.7%) were included in the final analysis, and yielded 840 positive cultures and antimicrobial susceptibility data for 657 E. coli and K. pneumoniae isolates. Fosfomycin was the single oral treatment option with resistance prevalence <20% in both E. coli and K. pneumoniae in community settings. Tigecycline and fosfomycin were the only options for treatment of catheter-associated UTIs with resistance prevalence <20%, whilst the prevalence of resistance to meropenem was 21.3% in K. pneumoniae ., Conclusions: Patient-based surveillance of AMR in E. coli and K. pneumoniae causing UTIs indicates that resistance to the commonly available empirical treatment options is high in Indonesia. Smart AMR surveillance strategies are needed to inform policy makers and to guide interventions., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.)

Aim: Increasing antimicrobial resistance (AMR) requires rapid surveillance tools, such as Lot Quality Assurance Sampling (LQAS)., Materials & Methods: LQAS classifies AMR as high or low based on set parameters. We compared classifications with the underlying true AMR prevalence using data on 1335 Escherichia coli isolates from surveys of community-acquired urinary tract infection in women, by assessing operating curves, sensitivity and specificity., Results: Sensitivity and specificity of any set of LQAS parameters was above 99% and between 79 and 90%, respectively. Operating curves showed high concordance of the LQAS classification with true AMR prevalence estimates., Conclusion: LQAS-based AMR surveillance is a feasible approach that provides timely and locally relevant estimates, and the necessary information to formulate and evaluate guidelines for empirical treatment.

Human immunodeficiency virus (HIV)-infected individuals successfully treated for tuberculosis (TB) remain at risk of recurrence of the disease, especially in high TB incidence settings. We performed a systematic review, investigating whether secondary preventive therapy (sPT) with anti-TB drugs (preventive therapy in former TB patients with treatment success) is an effective strategy to prevent recurrence of TB in this patient group. We searched the databases PubMed, Cochrane Library, EMBASE, Web of Science and Google Scholar using the keywords HIV-infections, HIV, human immunodeficiency virus, AIDS, isoniazid, isoniazid preventive therapy (IPT), tuberculosis, TB, recurrence and recurrent disease, resulting in 253 potential publications. We identified eight publications for full text assessment, after which four articles qualified for inclusion in this systematic review. The quality of the included articles was rated using the GRADE system. All but one study were rated as having a high quality. In all included studies, sPT significantly decreased the incidence of recurrent TB in HIV-infected individuals to a substantial degree in comparison to non-treatment or placebo. Relative reductions varied from 55.0% to 82.1%. These data showed that the use of sPT to prevent recurrent TB in HIV-infected individuals was highly beneficial. These findings need to be confirmed in prospective studies with an adequate assessment of the effect of antiretroviral therapy (ART) and the occurrence of drug resistance.

Early mortality after initiation of antiretroviral therapy (ART) occurs in 9-39% of patients in sub-Saharan Africa. A significant proportion of deaths are attributable to tuberculosis (TB). Low baseline CD4 T-cell count and low body mass index (BMI) are strongly associated with early mortality. We hypothesized that initiation of ART concurrent with presumptive anti-TB chemotherapy in high-risk patients would reduce mortality within the first 6 months by treating unrecognized TB. From October 2011 to December 2012, ART-naive, smear-negative participants with a CD4 T-cell count < 50 cells/μL and BMI < 18 kg/m 2 were randomly assigned to undergo either empiric four-drug anti-TB treatment followed 2 weeks later by efavirenz-based ART (N = 23) (ART + TB) or ART only (N = 20). This open-label, 1:1 randomized, controlled trial took place in Uganda, Mozambique, and Gabon and was stopped prematurely by the sponsor for slow recruitment. Overall, the 43 participants had a median CD4 of 22 (interquartile range [IQR]: 9-35) cells/μL and a median BMI of 17.5 (IQR: 16.6-18.0) kg/m 2 The mortality was 14% (95% confidence interval [CI]: 5.3-27.9); two (10.0%) participants (ART-only group), and four (17.4%; ART + TB group). The associated hazard ratio (HR) for all-cause mortality was 1.6 (95% CI: 0.30-8.90). Despite limited enrollment, the study did not suggest that empiric TB treatment in severely immunosuppressed patients with low BMI decreased mortality and, had an HR in the opposite direction than expected. Notably, two participants in the ART + TB group died with autopsy-confirmed drug-induced hepatotoxicity. Improved TB diagnostics sensitive in immunosuppressed patients presenting late to care are urgently needed for more targeted interventions., (© The American Society of Tropical Medicine and Hygiene.)

Setting: Tanzania has an estimated tuberculosis (TB) prevalence of 295 per 100 000 adult population. There is currently no nationally representative information on factors associated with TB in Tanzania., Objective: To determine the demographic and clinical factors associated with bacteriologically confirmed TB in the adult general population of Tanzania., Design: A case-control study nested in a nationally representative TB prevalence survey. All patients with bacteriologically confirmed pulmonary TB (PTB) constituted cases and a representative sample of people without bacteriologically confirmed PTB constituted controls. We calculated adjusted odds ratios (aORs) to identify factors associated with TB., Results: Age groups 25-34 years (aOR 3.7, 95%CI 1.5-8.8) and 55-64 years (aOR 2.5, 95%CI 1.1-5.5), male sex (aOR 1.6, 95%CI 1.1-2.3) and low body mass index (BMI) (aOR 1.7, 95%CI 1.1-2.8) were significantly associated with TB. Association with human immunodeficiency virus (HIV) and diabetes mellitus (DM) was not statistically significant. The population attributable fraction (PAF) was 2% (95%CI -2 to 5) for DM and 3% (95%CI -2 to 8) for HIV., Conclusion: Being in an older age group, being male and having a low BMI were associated with bacteriologically confirmed PTB. On the population level, classic risk factors for TB have no major effect on prevalent TB from which future transmission may occur.