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Call for Papers: PLOS Medicine Special Issue on Bacterial Antimicrobial Resistance - Surveillance and Prevention The guest editors and I PLOS Medicine i editors seek high-quality and high-impact research submissions related to the main drivers, surveillance and prevention of bacterial antimicrobial resistance, particularly in low- and middle-income settings. The editors of I PLOS Medicine i , together with guest editors Timothy Walsh, Ramanan Laxminarayan and Ana Cristina Gales, announce a forthcoming Special Issue dedicated to bacterial antimicrobial resistance (AMR). [Extracted from the article]

Background: India has 23% of the global burden of active tuberculosis (TB) patients and 27% of the world's "missing" patients, which includes those who may not have received effective TB care and could potentially spread TB to others. The "cascade of care" is a useful model for visualizing deficiencies in case detection and retention in care, in order to prioritize interventions.Methods and Findings: The care cascade constructed in this paper focuses on the Revised National TB Control Programme (RNTCP), which treats about half of India's TB patients. We define the TB cascade as including the following patient populations: total prevalent active TB patients in India, TB patients who reach and undergo evaluation at RNTCP diagnostic facilities, patients successfully diagnosed with TB, patients who start treatment, patients retained to treatment completion, and patients who achieve 1-y recurrence-free survival. We estimate each step of the cascade for 2013 using data from two World Health Organization (WHO) reports (2014-2015), one WHO dataset (2015), and three RNTCP reports (2014-2016). In addition, we conduct three targeted systematic reviews of the scientific literature to identify 39 unique articles published from 2000-2015 that provide additional data on five indicators that help estimate different steps of the TB cascade. We construct separate care cascades for the overall population of patients with active TB and for patients with specific forms of TB-including new smear-positive, new smear-negative, retreatment smear-positive, and multidrug-resistant (MDR) TB. The WHO estimated that there were 2,700,000 (95%CI: 1,800,000-3,800,000) prevalent TB patients in India in 2013. Of these patients, we estimate that 1,938,027 (72%) TB patients were evaluated at RNTCP facilities; 1,629,906 (60%) were successfully diagnosed; 1,417,838 (53%) got registered for treatment; 1,221,764 (45%) completed treatment; and 1,049,237 (95%CI: 1,008,775-1,083,243), or 39%, of 2,700,000 TB patients achieved the optimal outcome of 1-y recurrence-free survival. The separate cascades for different forms of TB highlight different patterns of patient attrition. Pretreatment loss to follow-up of diagnosed patients and post-treatment TB recurrence were major points of attrition in the new smear-positive TB cascade. In the new smear-negative and MDR TB cascades, a substantial proportion of patients who were evaluated at RNTCP diagnostic facilities were not successfully diagnosed. Retreatment smear-positive and MDR TB patients had poorer treatment outcomes than the general TB population. Limitations of our analysis include the lack of available data on the cascade of care in the private sector and substantial uncertainty regarding the 1-y period prevalence of TB in India.Conclusions: Increasing case detection is critical to improving outcomes in India's TB cascade of care, especially for smear-negative and MDR TB patients. For new smear-positive patients, pretreatment loss to follow-up and post-treatment TB recurrence are considerable points of attrition that may contribute to ongoing TB transmission. Future multisite studies providing more accurate information on key steps in the public sector TB cascade and extension of this analysis to private sector patients may help to better target interventions and resources for TB control in India. [ABSTRACT FROM AUTHOR]

Background: Excellent adherence to tuberculosis (TB) treatment is critical to cure TB and avoid the emergence of resistance. Wirelessly observed therapy (WOT) is a novel patient self-management system consisting of an edible ingestion sensor (IS), external wearable patch, and paired mobile device that can detect and digitally record medication ingestions. Our study determined the accuracy of ingestion detection in clinical and home settings using WOT and subsequently compared, in a randomized control trial (RCT), confirmed daily adherence to medication in persons using WOT or directly observed therapy (DOT) during TB treatment.Methods and Findings: We evaluated WOT in persons with active Mycobacterium tuberculosis complex disease using IS-enabled combination isoniazid 150 mg/rifampin 300 mg (IS-Rifamate). Seventy-seven participants with drug-susceptible TB in the continuation phase of treatment, prescribed daily isoniazid 300 mg and rifampin 600 mg, used IS-Rifamate. The primary endpoints of the trial were determination of the positive detection accuracy (PDA) of WOT, defined as the percentage of ingestions detected by WOT administered under direct observation, and subsequently the proportion of prescribed doses confirmed by WOT compared to DOT. Initially participants received DOT and WOT simultaneously for 2-3 weeks to allow calculation of WOT PDA, and the 95% confidence interval (CI) was estimated using the bootstrap method with 10,000 samples. Sixty-one participants subsequently participated in an RCT to compare the proportion of prescribed doses confirmed by WOT and DOT. Participants were randomized 2:1 to receive WOT or maximal in-person DOT. In the WOT arm, if ingestions were not remotely confirmed, the participant was contacted within 24 hours by text or cell phone to provide support. The number of doses confirmed was collected, and nonparametric methods were used for group and individual comparisons to estimate the proportions of confirmed doses in each randomized arm with 95% CIs. Sensitivity analyses, not prespecified in the trial registration, were also performed, removing all nonworking (weekend and public holiday) and held-dose days. Participants, recruited from San Diego (SD) and Orange County (OC) Divisions of TB Control and Refugee Health, were 43.1 (range 18-80) years old, 57% male, 42% Asian, and 39% white with 49% Hispanic ethnicity. The PDA of WOT was 99.3% (CI 98.1; 100). Intent-to-treat (ITT) analysis within the RCT showed WOT confirmed 93% versus 63% DOT (p < 0.001) of daily doses prescribed. Secondary analysis removing all nonworking days (weekends and public holidays) and held doses from each arm showed WOT confirmed 95.6% versus 92.7% (p = 0.31); WOT was non-inferior to DOT (difference 2.8% CI [-1.8%, 9.1%]). One hundred percent of participants preferred using WOT. WOT associated adverse events were <10%, consisting of minor skin rash and pruritus associated with the patch. WOT provided longitudinal digital reporting in near real time, supporting patient self-management and allowing rapid remote identification of those who needed more support to maintain adherence. This study was conducted during the continuation phase of TB treatment, limiting its generalizability to the entire TB treatment course.Conclusions: In terms of accuracy, WOT was equivalent to DOT. WOT was superior to DOT in supporting confirmed daily adherence to TB medications during the continuation phase of TB treatment and was overwhelmingly preferred by participants. WOT should be tested in high-burden TB settings, where it may substantially support low- and middle-income country (LMIC) TB programs.Trial Registration: ClinicalTrials.gov NCT01960257. [ABSTRACT FROM AUTHOR]

Geraint Davies and colleagues discuss the potential for innovative early-phase clinical trial methods and technologies to reduce risk and speed up drug development for tuberculosis. [ABSTRACT FROM AUTHOR]

Background: India has the highest burden of tuberculosis (TB). Although most patients with TB in India seek care from the private sector, there is limited evidence on quality of TB care or its correlates. Following our validation study on the standardized patient (SP) method for TB, we utilized SPs to examine quality of adult TB care among health providers with different qualifications in 2 Indian cities.Methods and Findings: During 2014-2017, pilot programs engaged the private health sector to improve TB management in Mumbai and Patna. Nested within these projects, to obtain representative, baseline measures of quality of TB care at the city level, we recruited 24 adults to be SPs. They were trained to portray 4 TB "case scenarios" representing various stages of disease and diagnostic progression. Between November 2014 and August 2015, the SPs visited representatively sampled private providers stratified by qualification: (1) allopathic providers with Bachelor of Medicine, Bachelor of Surgery (MBBS) degrees or higher and (2) non-MBBS providers with alternative medicine, minimal, or no qualifications. Our main outcome was case-specific correct management benchmarked against the Standards for TB Care in India (STCI). Using ANOVA, we assessed variation in correct management and quality outcomes across (a) cities, (b) qualifications, and (c) case scenarios. Additionally, 2 micro-experiments identified sources of variation: first, quality in the presence of diagnostic test results certainty and second, provider consistency for different patients presenting the same case. A total of 2,652 SP-provider interactions across 1,203 health facilities were analyzed. Based on our sampling strategy and after removing 50 micro-experiment interactions, 2,602 interactions were weighted for city-representative interpretation. After weighting, the 473 Patna providers receiving SPs represent 3,179 eligible providers in Patna; in Mumbai, the 730 providers represent 7,115 eligible providers. Correct management was observed in 959 out of 2,602 interactions (37%; 35% weighted; 95% CI 32%-37%), primarily from referrals and ordering chest X-rays (CXRs). Unnecessary medicines were given to nearly all SPs, and antibiotic use was common. Anti-TB drugs were prescribed in 118 interactions (4.5%; 5% weighted), of which 45 were given in the case in which such treatment is considered correct management. MBBS and more qualified providers had higher odds of correctly managing cases than non-MBBS providers (odds ratio [OR] 2.80; 95% CI 2.05-3.82; p < 0.0001). Mumbai non-MBBS providers had higher odds of correct management than non-MBBS in Patna (OR 1.79; 95% CI 1.06-3.03), and MBBS providers' quality of care did not vary between cities (OR 1.15; 95% CI 0.79-1.68; p = 0.4642). In the micro-experiments, improving diagnostic certainty had a positive effect on correct management but not across all quality dimensions. Also, providers delivered idiosyncratically consistent care, repeating all observed actions, including mistakes, approximately 75% of the time. The SP method has limitations: it cannot account for patient mix or care-management practices reflecting more than one patient-provider interaction.Conclusions: Quality of TB care is suboptimal and variable in urban India's private health sector. Addressing this is critical for India's plans to end TB by 2025. For the first time, we have rich measures on representative levels of care quality from 2 cities, which can inform private-sector TB interventions and quality-improvement efforts. [ABSTRACT FROM AUTHOR]

Background: Cholera prevention and control interventions targeted to neighbors of cholera cases (case-area targeted interventions [CATIs]), including improved water, sanitation, and hygiene, oral cholera vaccine (OCV), and prophylactic antibiotics, may be able to efficiently avert cholera cases and deaths while saving scarce resources during epidemics. Efforts to quickly target interventions to neighbors of cases have been made in recent outbreaks, but little empirical evidence related to the effectiveness, efficiency, or ideal design of this approach exists. Here, we aim to provide practical guidance on how CATIs might be used by exploring key determinants of intervention impact, including the mix of interventions, "ring" size, and timing, in simulated cholera epidemics fit to data from an urban cholera epidemic in Africa.Methods and Findings: We developed a micro-simulation model and calibrated it to both the epidemic curve and the small-scale spatiotemporal clustering pattern of case households from a large 2011 cholera outbreak in N'Djamena, Chad (4,352 reported cases over 232 days), and explored the potential impact of CATIs in simulated epidemics. CATIs were implemented with realistic logistical delays after cases presented for care using different combinations of prophylactic antibiotics, OCV, and/or point-of-use water treatment (POUWT) starting at different points during the epidemics and targeting rings of various radii around incident case households. Our findings suggest that CATIs shorten the duration of epidemics and are more resource-efficient than mass campaigns. OCV was predicted to be the most effective single intervention, followed by POUWT and antibiotics. CATIs with OCV started early in an epidemic focusing on a 100-m radius around case households were estimated to shorten epidemics by 68% (IQR 62% to 72%), with an 81% (IQR 69% to 87%) reduction in cases compared to uncontrolled epidemics. These same targeted interventions with OCV led to a 44-fold (IQR 27 to 78) reduction in the number of people needed to target to avert a single case of cholera, compared to mass campaigns in high-cholera-risk neighborhoods. The optimal radius to target around incident case households differed by intervention type, with antibiotics having an optimal radius of 30 m to 45 m compared to 70 m to 100 m for OCV and POUWT. Adding POUWT or antibiotics to OCV provided only marginal impact and efficiency improvements. Starting CATIs early in an epidemic with OCV and POUWT targeting those within 100 m of an incident case household reduced epidemic durations by 70% (IQR 65% to 75%) and the number of cases by 82% (IQR 71% to 88%) compared to uncontrolled epidemics. CATIs used late in epidemics, even after the peak, were estimated to avert relatively few cases but substantially reduced the number of epidemic days (e.g., by 28% [IQR 15% to 45%] for OCV in a 100-m radius). While this study is based on a rigorous, data-driven approach, the relatively high uncertainty about the ways in which POUWT and antibiotic interventions reduce cholera risk, as well as the heterogeneity in outbreak dynamics from place to place, limits the precision and generalizability of our quantitative estimates.Conclusions: In this study, we found that CATIs using OCV, antibiotics, and water treatment interventions at an appropriate radius around cases could be an effective and efficient way to fight cholera epidemics. They can provide a complementary and efficient approach to mass intervention campaigns and may prove particularly useful during the initial phase of an outbreak, when there are few cases and few available resources, or in order to shorten the often protracted tails of cholera epidemics. [ABSTRACT FROM AUTHOR]

Background: Sexually transmitted infections (STIs) and bacterial vaginosis (BV) are associated with increased transmission of HIV, and poor reproductive and sexual health. The burden of STIs/BV among young people is unknown in many high HIV prevalence settings. We conducted an acceptability, feasibility, and prevalence study of home-based sampling for STIs/BV among young men and women aged 15-24 years old in a health and demographic surveillance site (HDSS) in rural KwaZulu-Natal, South Africa.Methods and Findings: A total of 1,342 young people, stratified by age (15-19 and 20-24 years) and sex were selected from the HDSS sampling frame; 1,171/1,342 (87%) individuals had ≥1 attempted home visit between 4 October 2016 and 31 January 2017, of whom 790 (67%) were successfully contacted. Among the 645 who were contacted and eligible, 447 (69%) enrolled. Consenting/assenting participants were interviewed, and blood, self-collected urine (men), and vaginal swabs (women) were tested for herpes simplex virus type 2 (HSV-2), chlamydia, gonorrhoea, syphilis, trichomoniasis, and BV. Both men and women reported that sample collection was easy. Participants disagreed that sampling was painful; more than half of the participants disagreed that they felt anxious or embarrassed. The weighted prevalence of STIs/BV among men and women, respectively, was 5.3% and 11.2% for chlamydia, 1.5% and 1.8% for gonorrhoea, 0% and 0.4% for active syphilis, 0.6% and 4.6% for trichomoniasis, 16.8% and 28.7% for HSV-2, and 42.1% for BV (women only). Of the women with ≥1 curable STI, 75% reported no symptoms. Factors associated with STIs/BV included having older age, being female, and not being in school or working. Among those who participated in the 2016 HIV serosurvey, the prevalence of HIV was 5.6% among men and 19% among women. Feasibility was impacted by the short study duration and the difficulty finding men at home.Conclusions: A high prevalence of STIs/BV was found in this rural setting with high HIV prevalence in South Africa. Most STIs and HIV infections were asymptomatic and would not have been identified or treated under national syndromic management guidelines. A nested STI/BV survey within a HDSS proved acceptable and feasible. This is a proof of concept for population-based STI surveillance in low- and middle-income countries that could be utilised in the evaluation of STI/HIV prevention and control programmes. [ABSTRACT FROM AUTHOR]

How do we spot the next sexually transmitted infection? Kyle Bernstein and colleagues look for lessons from past discovery. [ABSTRACT FROM AUTHOR]

Background: The existing estimate of the global burden of latent TB infection (LTBI) as "one-third" of the world population is nearly 20 y old. Given the importance of controlling LTBI as part of the End TB Strategy for eliminating TB by 2050, changes in demography and scientific understanding, and progress in TB control, it is important to re-assess the global burden of LTBI.Methods and Findings: We constructed trends in annual risk in infection (ARI) for countries between 1934 and 2014 using a combination of direct estimates of ARI from LTBI surveys (131 surveys from 1950 to 2011) and indirect estimates of ARI calculated from World Health Organisation (WHO) estimates of smear positive TB prevalence from 1990 to 2014. Gaussian process regression was used to generate ARIs for country-years without data and to represent uncertainty. Estimated ARI time-series were applied to the demography in each country to calculate the number and proportions of individuals infected, recently infected (infected within 2 y), and recently infected with isoniazid (INH)-resistant strains. Resulting estimates were aggregated by WHO region. We estimated the contribution of existing infections to TB incidence in 2035 and 2050. In 2014, the global burden of LTBI was 23.0% (95% uncertainty interval [UI]: 20.4%-26.4%), amounting to approximately 1.7 billion people. WHO South-East Asia, Western-Pacific, and Africa regions had the highest prevalence and accounted for around 80% of those with LTBI. Prevalence of recent infection was 0.8% (95% UI: 0.7%-0.9%) of the global population, amounting to 55.5 (95% UI: 48.2-63.8) million individuals currently at high risk of TB disease, of which 10.9% (95% UI:10.2%-11.8%) was isoniazid-resistant. Current LTBI alone, assuming no additional infections from 2015 onwards, would be expected to generate TB incidences in the region of 16.5 per 100,000 per year in 2035 and 8.3 per 100,000 per year in 2050. Limitations included the quantity and methodological heterogeneity of direct ARI data, and limited evidence to inform on potential clearance of LTBI.Conclusions: We estimate that approximately 1.7 billion individuals were latently infected with Mycobacterium tuberculosis (M.tb) globally in 2014, just under a quarter of the global population. Investment in new tools to improve diagnosis and treatment of those with LTBI at risk of progressing to disease is urgently needed to address this latent reservoir if the 2050 target of eliminating TB is to be reached. [ABSTRACT FROM AUTHOR]

Background: Tuberculosis (TB) case notification rates are usually higher in men than in women, but notification data are insufficient to measure sex differences in disease burden. This review set out to systematically investigate whether sex ratios in case notifications reflect differences in disease prevalence and to identify gaps in access to and/or utilisation of diagnostic services.Methods and Findings: In accordance with the published protocol (CRD42015022163), TB prevalence surveys in nationally representative and sub-national adult populations (age ≥ 15 y) in low- and middle-income countries published between 1 January 1993 and 15 March 2016 were identified through searches of PubMed, Embase, Global Health, and the Cochrane Database of Systematic Reviews; review of abstracts; and correspondence with the World Health Organization. Random-effects meta-analyses examined male-to-female (M:F) ratios in TB prevalence and prevalence-to-notification (P:N) ratios for smear-positive TB. Meta-regression was done to identify factors associated with higher M:F ratios in prevalence and higher P:N ratios. Eighty-three publications describing 88 surveys with over 3.1 million participants in 28 countries were identified (36 surveys in Africa, three in the Americas, four in the Eastern Mediterranean, 28 in South-East Asia and 17 in the Western Pacific). Fifty-six surveys reported in 53 publications were included in quantitative analyses. Overall random-effects weighted M:F prevalence ratios were 2.21 (95% CI 1.92-2.54; 56 surveys) for bacteriologically positive TB and 2.51 (95% CI 2.07-3.04; 40 surveys) for smear-positive TB. M:F prevalence ratios were highest in South-East Asia and in surveys that did not require self-report of signs/symptoms in initial screening procedures. The summary random-effects weighted M:F ratio for P:N ratios was 1.55 (95% CI 1.25-1.91; 34 surveys). We intended to stratify the analyses by age, HIV status, and rural or urban setting; however, few studies reported such data.Conclusions: TB prevalence is significantly higher among men than women in low- and middle-income countries, with strong evidence that men are disadvantaged in seeking and/or accessing TB care in many settings. Global strategies and national TB programmes should recognise men as an underserved high-risk group and improve men's access to diagnostic and screening services to reduce the overall burden of TB more effectively and ensure gender equity in TB care. [ABSTRACT FROM AUTHOR]

Ramanan Laxminarayan and Ranjit Roy Chaudhury examine the factors encouraging the emergence of antibiotic resistance in India, the implications nationally and internationally, and what might be done to help. [ABSTRACT FROM AUTHOR]

Background: Identifying and tackling the social determinants of infectious diseases has become a public health priority following the recognition that individuals with lower socioeconomic status are disproportionately affected by infectious diseases. In many parts of the world, epidemiologically and genotypically defined community-associated (CA) methicillin-resistant Staphylococcus aureus (MRSA) strains have emerged to become frequent causes of hospital infection. The aim of this study was to use spatial models with adjustment for area-level hospital attendance to determine the transmission niche of genotypically defined CA- and health-care-associated (HA)-MRSA strains across a diverse region of South East London and to explore a potential link between MRSA carriage and markers of social and material deprivation.Methods and Findings: This study involved spatial analysis of cross-sectional data linked with all MRSA isolates identified by three National Health Service (NHS) microbiology laboratories between 1 November 2011 and 29 February 2012. The cohort of hospital-based NHS microbiology diagnostic services serves 867,254 usual residents in the Lambeth, Southwark, and Lewisham boroughs in South East London, United Kingdom (UK). Isolates were classified as HA- or CA-MRSA based on whole genome sequencing. All MRSA cases identified over 4 mo within the three-borough catchment area (n = 471) were mapped to small geographies and linked to area-level aggregated socioeconomic and demographic data. Disease mapping and ecological regression models were used to infer the most likely transmission niches for each MRSA genetic classification and to describe the spatial epidemiology of MRSA in relation to social determinants. Specifically, we aimed to identify demographic and socioeconomic population traits that explain cross-area extra variation in HA- and CA-MRSA relative risks following adjustment for hospital attendance data. We explored the potential for associations with the English Indices of Deprivation 2010 (including the Index of Multiple Deprivation and several deprivation domains and subdomains) and the 2011 England and Wales census demographic and socioeconomic indicators (including numbers of households by deprivation dimension) and indicators of population health. Both CA-and HA-MRSA were associated with household deprivation (CA-MRSA relative risk [RR]: 1.72 [1.03-2.94]; HA-MRSA RR: 1.57 [1.06-2.33]), which was correlated with hospital attendance (Pearson correlation coefficient [PCC] = 0.76). HA-MRSA was also associated with poor health (RR: 1.10 [1.01-1.19]) and residence in communal care homes (RR: 1.24 [1.12-1.37]), whereas CA-MRSA was linked with household overcrowding (RR: 1.58 [1.04-2.41]) and wider barriers, which represent a combined score for household overcrowding, low income, and homelessness (RR: 1.76 [1.16-2.70]). CA-MRSA was also associated with recent immigration to the UK (RR: 1.77 [1.19-2.66]). For the area-level variation in RR for CA-MRSA, 28.67% was attributable to the spatial arrangement of target geographies, compared with only 0.09% for HA-MRSA. An advantage to our study is that it provided a representative sample of usual residents receiving care in the catchment areas. A limitation is that relationships apparent in aggregated data analyses cannot be assumed to operate at the individual level.Conclusions: There was no evidence of community transmission of HA-MRSA strains, implying that HA-MRSA cases identified in the community originate from the hospital reservoir and are maintained by frequent attendance at health care facilities. In contrast, there was a high risk of CA-MRSA in deprived areas linked with overcrowding, homelessness, low income, and recent immigration to the UK, which was not explainable by health care exposure. Furthermore, areas adjacent to these deprived areas were themselves at greater risk of CA-MRSA, indicating community transmission of CA-MRSA. This ongoing community transmission could lead to CA-MRSA becoming the dominant strain types carried by patients admitted to hospital, particularly if successful hospital-based MRSA infection control programmes are maintained. These results suggest that community infection control programmes targeting transmission of CA-MRSA will be required to control MRSA in both the community and hospital. These epidemiological changes will also have implications for effectiveness of risk-factor-based hospital admission MRSA screening programmes. [ABSTRACT FROM AUTHOR]

The article presents information on a study by D. M. Hartley, J. G. Morris Jr. and D. L. Smith on the cholera pathogen Vibrio cholerae. The researchers isolated and characterized V. cholerae from human stools and discovered that passage through the human gastrointestinal tract induces a transient hyperinfectious state in the bacteria.

The article presents author's views on aspects of translational medicine in global health gains. He discusses the advantages of translational medicine which includes medical advances that improves clinical practice and public health, helps to predict prognosis for stage II-III colon cancers and detects grampositive bacteria in blood cultures.

Background Lipoarabinomannan (LAM) is a major antigen of Mycobacterium tuberculosis (MTB). In this report, we evaluated the ability of a novel immunoassay to measure concentrations of LAM in sputum as a biomarker of bacterial load prior to and during treatment in pulmonary tuberculosis (TB) patients. Methods and findings Phage display technology was used to isolate monoclonal antibodies binding to epitopes unique in LAM from MTB and slow-growing nontuberculous mycobacteria (NTM). Using these antibodies, a sandwich enzyme-linked immunosorbent assay (LAM-ELISA) was developed to quantitate LAM concentration. The LAM-ELISA had a lower limit of quantification of 15 pg/mL LAM, corresponding to 121 colony-forming units (CFUs)/mL of MTB strain H37Rv. It detected slow-growing NTMs but without cross-reacting to common oral bacteria. Two clinical studies were performed between the years 2013 and 2016 in Manila, Philippines, in patients without known human immunodeficiency virus (HIV) coinfection. In a case-control cohort diagnostic study, sputum specimens were collected from 308 patients (aged 17-69 years; 62% male) diagnosed as having pulmonary TB diseases or non-TB diseases, but who could expectorate sputum, and were then evaluated by smear microscopy, BACTEC MGIT 960 Mycobacterial Detection System (MGIT) and Lowenstein-Jensen (LJ) culture, and LAM-ELISA. Some sputum specimens were also examined by Xpert MTB/RIF. The LAM-ELISA detected all smear- and MTB-culture-positive samples (n = 70) and 50% (n = 29) of smear-negative but culture-positive samples (n = 58) (versus 79.3%; 46 positive cases by the Xpert MTB/RIF), but none from non-TB patients (n = 56). Among both LAM and MGIT MTB-culture-positive samples, log.sub.10 -transformed LAM concentration and MGIT time to detection (TTD) showed a good inverse relationship (r = -0.803, p < 0.0001). In a prospective longitudinal cohort study, 40 drug-susceptible pulmonary TB patients (aged 18-69 years; 60% male) were enrolled during the first 56 days of the standard 4-drug therapy. Declines in sputum LAM concentrations correlated with increases of MGIT TTD in individual patients. There was a 1.29 log.sub.10 decrease of sputum LAM concentration, corresponding to an increase of 221 hours for MGIT TTD during the first 14 days of treatment, a treatment duration often used in early bactericidal activity (EBA) trials. Major limitations of this study include a relatively small number of patients, treatment duration up to only 56 days, lack of quantitative sputum culture CFU count data, and no examination of the correlation of sputum LAM to clinical cure. Conclusions These results indicate that the LAM-ELISA can determine LAM concentration in sputum, and sputum LAM measured by the assay may be used as a biomarker of bacterial load prior to and during TB treatment. Additional studies are needed to examine the predictive value of this novel biomarker on treatment outcomes., Author(s): Masanori Kawasaki 1, Carmenchu Echiverri 2, Lawrence Raymond 3, Elizabeth Cadena 4, Evelyn Reside 5, Maria Tarcela Gler 6, Tetsuya Oda 1, Ryuta Ito 1, Ryo Higashiyama 1, Kiyonori [...]