Culture-positive TB Research Articles

Impact of isoniazid monoresistance on overall and vulnerable patient populations in Taiwan

ABSTRACT Isoniazid is an early bactericidal anti-tuberculosis (TB) agent and isoniazid mono-resistance TB is the most prevalent drug-resistant TB worldwide. Concerns exist regarding whether resistance to isoniazid would lead to delayed culture conversion and worst outcomes. From January 2008 to November 2017, adult culture-positive pulmonary TB patients receiving isoniazid, rifampicin, pyrazinamide, and ethambutol were identified through Taiwan Center for Disease Control database and were followed until the end of 2017. Primary outcomes included time to sputum culture conversion (SCC) within two months. Secondary outcomes included death and unfavourable outcomes at the end of 2nd month. A total of 37,193 drug-susceptible and 2,832 isoniazid monoresistant pulmonary TB patients were identified. Compared with no resistance, isoniazid monoresistance was not associated with a delayed SCC (HR: 0.99, 95% CI: 0.94─1.05, p = 0.8145), a higher risk of 2-month mortality (HR: 1.19, 95% CI: 0.92─1.53, p = 0.1884), and unfavourable outcomes at 2nd month (OR: 1.05, 95% CI: 0.97─1.14, p = 0.2427). Isoniazid monoresistance was associated with delayed SCC (HR: 0.90, 95% CI: 0.83─0.98, p = 0.0099) and a higher risk of unfavourable outcomes (OR:1.18, 95% CI: 1.05─1.32, p = 0.0053) in patients aged between 20 and 65, and delayed SCC in patients without underlying comorbidities (HR: 0.90, 95% CI: 0.81─0.98, p = 0.0237). Isoniazid mono-resistant TB had a comparable outcome with drug-susceptible TB at the end of the intensive phase. Healthy, and non-elderly patients were more likely to had culture persistence, raising concerns about disease transmission in these subgroups and warranting early molecular testing for isoniazid resistance.

Comparison of microscopic and xpert MTB diagnoses of presumptive mycobacteria tuberculosis infection: retrospective analysis of routine diagnosis at Cape Coast Teaching Hospital

IntroductionTuberculosis is a global health problem that causes 1. 4 million deaths every year. It has been estimated that sputum smear-negative diagnosis but culture-positive pulmonary TB diagnosis contribute to 12.6% of pulmonary TB transmission. TB diagnosis by smear microscopy smear has a minimum detection limit (LOD) of 5,000 to 10,000 bacilli per milliliter (CFU/ml) of sputum result in missed cases and false positives. However, GeneXpert technology, with a LOD of 131–250 CFU/ml in sputum samples and its implementation is believe to facilitate early detection TB and drug-resistant TB case. Since 2013, Ghana health Service (GHS) introduce GeneXpert MTB/RIF diagnostic in all regional hospitals in Ghana, however no assessment of performance between microscopy and GeneXpert TB diagnosis cross the health facilities has been reported. The study compared the results of routine diagnoses of TB by microscopy and Xpert MTB from 2016 to 2020 at the Cape Coast Teaching Hospital (CCTH).MethodsThe study compared routine microscopic and GeneXpert TB diagnosis results at the Cape Coast Teaching Hospital (CCTH) from 2016 to 2020 retrospectively. Briefly, sputum specimens were collected into 20 mL sterile screw-capped containers for each case of suspected TB infection and processed within 24 h. The samples were decontaminated using the NALC-NaOH method with the final NaOH concentration of 1%. The supernatants were discarded after the centrifuge and the remaining pellets dissolved in 1–1.5 ml of phosphate buffer saline (PBS) and used for diagnosis. A fixed smears were Ziehl-Neelsen acid-fast stain and observed under microscope and the remainings were used for GeneXpert MTB/RIF diagnosis. The data were analyze using GraphPad Prism.Results50.11% (48.48–51.38%) were females with an odd ratio (95% CI) of 1.004 (0.944–1.069) more likely to report to the TB clinic for suspected TB diagnosis. The smear-positive cases for the first sputum were 6.6% (5.98–7.25%), and the second sputum was 6.07% (5.45–6.73%). The Xpert MTB-RIF diagnosis detected 2.93% (10/341) (1.42–5.33%) in the first and 5.44% (16/294) (3.14–8.69%) in the second smear-negative TB samples. The prevalence of Xpert MTB-RIF across smear positive showed that males had 56.87% (178/313) and 56.15% (137/244) and females had 43.13% (135/313) and 43.85% (107/244) for the first and second sputum. Also, false negative smears were 0.18% (10/5607) for smear 1 and 0.31% (16/5126) for smear 2.ConclusionIn conclusion, the study highlights the higher sensitivity of the GeneXpert assay compared to traditional smear microscopy for detecting MTB. The GeneXpert assay identified 10 and 16 positive MTB from smear 1 and smear 2 samples which were microscopic negative.

Drug-Resistant Profiles and Genetic Diversity of Mycobacterium Tuberculosis Revealed by Whole-Genome Sequencing in Hinggan League of Inner Mongolia, China.

Tuberculosis remains a major public health concern in China, with varying prevalence and drug resistance profiles across regions. This study explores the genetic diversity and drug-resistant profiles of MTB strains in Hinggan League, a high TB burden in Inner Mongolia, China. This population-based retrospective study, encompassing all culture-positive TB cases from Jun. 2021 to Jun. 2023 in Hinggan League. Drug resistant profiles and genetic diversity of MTB strains were assessed using phenotypic drug susceptibility testing and whole-genome sequencing. Risk factors associated with drug resistance were analyzed using univariate and multivariate logistic regression models. A total of 211 MTB strains were recovered successfully and included into final analysis. Lineage 2.2.1 (88.6%, 187/211) was the dominant sub-lineage, followed by lineage 4.5 (7.1%, 15/211) and lineage 4.4 (4.3%, 9/211). MTB strains exhibited the highest resistance rates to isoniazid (16.1%, 34/211), followed by rifampicin (10.0, 21/211). In addition, the MTB strains also showed relatively high rates of resistance against new and repurposed anti-TB drugs, with resistant rates of 2.4% (5/211) to delamanid and 1.9% (4/211) to bedaquiline. Overall, 25.6% (54/211) of MTB strains were DR-TB, and 14 MTB strains met the definition of MDR-TB, including 7 strains of simple-MDR-TB, 5 of pre-XDR-TB, and 2 of XDR-TB. Genetic analysis revealed that the dominant mutations of isoniazid-, rifampin-, ethambutol-, levofloxacin-/moxifloxacin-, and ethionamide- resistance were katG_Ser315Thr(46.4%), rpoB_Ser450Leu (47.4%), embB_Met306Val (25.0%), gyrA_Asp94Ala (40.0%), and fabG1_c15t (42.9%), respectively. Previously treated patients (AOR = 2.015, 95% CI: 1.052-4.210) and male patients (AOR = 3.858, 95% CI: 1.416-10.511) were identified as independent risk factors associated with DR-TB. Our study offers crucial insights into the genetic diversity and drug-resistant profiles of TB strains circulating in Hinggan League. These findings are valuable for DR-TB surveillance and for guiding treatment regimens and public health interventions in the region.

The effect of statins on the risk of anti-tuberculosis drug-induced liver injury among patients with active tuberculosis: A cohort study

BackgroundTuberculosis (TB) remains prevalent worldwide, and anti-TB drugs are associated with drug-induced liver injury (DILI). Statins have pleiotropic effects which may decrease inflammation and achieve immunomodulation. However, few studies have investigated the pleiotropic effects of statins on the risk of DILI. The purpose of this study was to investigate whether statins prevent anti-tuberculosis DILI among active TB patients on standard anti-TB drug therapy. MethodsWe conducted a hospital-based retrospective cohort study using claims data from the Integrated Medical Database of National Taiwan University Hospital (NTUH-iMD). Patients with a positive TB culture were included. The use of statins was defined as a daily equivalent dose >0.5 mg of pitavastatin. Deterioration in liver function was evaluated according to elevated liver enzyme levels. The primary and secondary endpoints were the DILI and the severe DILI. The prognostic value of statins was evaluated by Kaplan–Meier analysis, and Cox proportional hazards models. ResultsA total of 1312 patients with a diagnosis of TB and receiving anti-TB treatment were included. During the study period, 193 patients had the DILI and 140 patients had the severe DILI. Kaplan–Meier analysis showed a significant difference between the usual statin users and controls in the DILI. In multivariable Cox proportional hazards analysis, statins showed a protective effect against the primary and secondary endpoints. In addition, the protective effect of statins showed a dose–response relationship against the DILI. ConclusionStatin treatment had a protective effect against the risk of anti-TB DILI with a positive dose–response relationship.

Spiritual Holy Water Sites in Ethiopia: Unrecognized High-Risk Settings for Transmission of Pulmonary Tuberculosis.

Ethiopia is a high-tuberculosis (TB) burden country with 157 new cases per 100,000 people, with 23,800 TB-related deaths in 2020. In Ethiopia, TB patients have different healthcare-seeking behaviors. They frequently visit spiritual places, such as holy water sites (HWSs), to seek treatment for their illness spiritually. This study examined the prevalence of pulmonary TB (PTB) and drug susceptibility profiles of Mycobacterium tuberculosis (MTB) isolates among spiritual HWS attendees in Northwest Ethiopia. A cross-sectional study was conducted from June 2019 to March 2020. Sputum samples were collected, processed, and cultured using Löwenstein-Jensen (LJ) culture medium. Second-generation line probe assays (LPAs), GenoType®MTBDRplus VER2.0 and GenoType®MTBDRsl VER2.0, were used to detect anti-TB drug-resistant isolates. STATA 17 was utilized to perform descriptive statistics, bivariate, and multivariate regression analyses. Of 560 PTB-symptomatic participants, 21.8% ((95% confidence interval (95 CI): 18.4-25.2%)) were culture-positive, resulting in a point prevalence of 1,183/100,000 attendees. Amongst HWS attendees, culture-positive TB occurred most commonly in persons 18-33 years of age (28.5% (95 CI 23.4-34.3%)). Other participant characteristics significantly associated with culture-positive PTB were as follows: rural residents (adjusted odds ratio (aOR) 2.65; 95 CI 1.38-5.10), married participants (aOR 2.43; 95 CI 1.28-4.63), family members >5 per household (aOR 1.84; 95 CI 1.04-3.24), and sharing living space (aOR 10.57; 95 CI 3.60-31.13). Also, among 438 participants followed for 12 months after showing negative TB culture results while at the HWS, 6.8% (95 CI 4.4-9.4%) developed or contracted culture-positive TB post-residency at the HWSs. Of the 122 tested isolates, 20 (16.4%) were isoniazid (INH) and/or rifampicin (RIF) resistant. Multidrug-resistant (MDR) TB was detected in 15 cases (12.3%), five of which were fluoroquinolones (FLQs) resistant. The findings from this study should raise a concern about HWSs as potential high-risk settings for TB transmission. It is recommended that appropriate control measures be instituted that include compulsory TB testing and tightened infection control at HWSs, where an increased risk exists for transmission of TB.

Insidious transmission of Mycobacterium tuberculosis in Ordos, China: a molecular epidemiology study.

In this study, we conducted this population-based study to evaluate the genetic diversity and clustering rate of Mycobacterium tuberculosis (MTB) strains using the whole-genome sequencing (WGS), to better understand its transmission in Ordos. All patients with culture-positive TB notified in Ordos from January 2021 to December 2022 were recruited. WGS was performed to analyze single-nucleotide polymorphism (SNP) and to identify genotypic drug susceptibilities of MTB isolates. Overall, a total of 186 patients were included in the present study, of whom 35 (18.8%) had no symptoms suggestive of active TB. Lineage 2 was the predominant MTB sublineage, accounting for 186 of isolates tested. When the pairwise SNP difference ≤ 12 was used as the cutoff for WGS-based clusters, we identified 17 genotypic clusters, and 38 isolates belonged to these 17 clusters, resulting in a clustering rate of 20.4%. The Beijing genotype was an independent factor associating with genomic-clustering (adjusted OR 4.219, 95% CI 0.962-18.502). The overall sensitivity on WGS-based resistance prediction was 85.7% for rifampicin, 73.1% for isoniazid, 60.0% for Ethambutol, 72.7% for streptomycin, and 72.7% for fluoroquinolones. To conclude, the present study demonstrates the extensive recent transmission of Beijing genotype strains in the community of Ordos. The failure to provide a comprehensive pattern of transmission indicated the missed diagnosis of active TB within the community. A substantial proportion of subclinical TB cases are recognized in the bacteria-positive cases, emphasizing that we must interrupt transmission by finding people with active TB before they infect others.

Implications for TB control among migrants in large cities in China: A prospective population-based genomic epidemiology study in Shenzhen

Internal migrants are a challenge for TB control in large Chinese cities and understanding this epidemiology is crucial for designing effective control and prevention strategies. We conducted a prospective genomic epidemiological study of culture-positive TB patients diagnosed between June 1, 2018 and May 31, 2021 in the Longhua District of Shenzhen. Treatment status was obtained from local and national TB registries and all isolates were sequenced. Genomic clusters were defined as strains differing by ≤12 SNPs. Risk factors for clustering were identified with multivariable analysis and then Bayesian models and TransPhylo were used to infer the timing of transmission within clusters. Of the 2277 culture-positive patients, 70.1% (1596/2277) were migrants: 72.1% (1043/1446) of the migrants patients developed TB within two years of arriving in Longhua; 38.8% within 6 months of arriving; and 12.3% (104/843) had TB symptoms when they arrived. Only 15.4% of Longhua strains were in genomic clusters. More than one third (33.6%) of patients were not treated in Shenzhen but were involved in nearly one third of the recent transmission events. Clustering was associated with migrants not treated in Shenzhen, males, and teachers/trainers. TB in Longhua is prinicipally due to reactivation of infections in migrants, but a proportion may have had clinical or incipient TB upon arrival in the district. Patients diagnosed but not treated in Longhua were involved in recent local TB transmission. Controlling TB in Shenzhen will require strategies to comprehensively diagnose and treat active TB in the internal migrant population.

Household drug-resistant TB contact tracing in Tajikistan.

BACKGROUND: Tajikistan has a high burden of rifampicin-resistant TB (RR-TB), with 2,700 new cases estimated for 2021 (28/100,000 population). TB is spread among household members through close interaction and children exposed through household contact progress to disease rapidly and frequently.METHODS: We retrospectively analysed programmatic data from household contact tracing in Dushanbe over 50 months. We calculated person-years of follow-up, contact tracing yield, number needed to screen (NNS) and number needed to test (NNT) to find one new case, and time to diagnosis.RESULTS: We screened 6,654 household contacts of 830 RR-TB index cases; 47 new RR-TB cases were detected, 43 in Year 1 and 4 in Years 2 or 3. Ten were aged <5 years; 46/47 had TB symptoms, 34/45 had chest radiographs consistent with TB, 11/35 were Xpert Ultra-positive, 29/32 were tuberculin skin test-positive and 28/47 had positive TB culture and phenotypic drug susceptibility results. The NNS to find one RR-TB case was 141.57 and the NNT was 34.49. The yields for different types of contacts were as follows: 0.7% for screened contacts, 2.9% for tested contacts, 17.0% for symptomatic contacts and 12.1% for symptomatic contacts aged below 5 years.CONCLUSION: RR-TB household contact tracing was feasible and productive in Tajikistan, a low middle-income country with an inefficient healthcare delivery system.

Discrepancy in the transmissibility of multidrug-resistant mycobacterium tuberculosis in urban and rural areas in China

ABSTRACT The fitness of multidrug-resistant tuberculosis (MDR-TB) is thought to be an important determinant of a strain’s ability to be transmitted. Studies in the laboratory have demonstrated that MDR-TB strains have reduced fitness but the relative transmissibility of MDR-TB versus drug-susceptible (DS) TB strains in human populations remains unresolved. We used data on genomic clustering from our previous molecular epidemiological study in Songjiang (2011-2020) and Wusheng (2009-2020), China, to compare the relative transmissibility of MDR-TB versus DS-TB. Genomic clusters were defined with a threshold distance of 12-single-nucleotide-polymorphisms and the risk for MDR-TB clustering was analyzed by logistic regression. In total, 2212 culture-positive pulmonary TB patients were enrolled in Songjiang and 1289 in Wusheng. The clustering rates of MDR-TB and DS-TB strains were 19.4% (20/103) and 26.3% (509/1936), respectively in Songjiang, and 43.9% (29/66) and 26.0% (293/1128) in Wusheng. The risk of MDR-TB clustering was 2.34 (95% CI 1.38-3.94) times higher than DS-TB clustering in Wusheng and 0.64 (95% CI 0.38-1.06) times lower in Songjiang. Neither lineage 2, compensatory mutations nor rpoB S450L were significantly associated with MDR-TB transmission, and katG S315 T increased MDR-TB transmission only in Wusheng (OR 5.28, 95% CI 1.42-19.21). MDR-TB was not more transmissible than DS-TB in either Songjiang or Wusheng. It appears that the different transmissibility of MDR-TB in Songjiang and Wusheng is likely due to differences in the quality of the local TB control programmes. Suggesting that the most effective way to control MDR-TB is by improving local TB control programmes.

Epidemiology of Culture-Negative Pulmonary Tuberculosis-Alameda County, 2010-2019.

Patients with culture-negative pulmonary TB (PTB) can face delays in diagnosis that worsen outcomes and lead to ongoing transmission. An understanding of current trends and characteristics of culture-negative PTB can support earlier detection and access to care. Describe epidemiology of culture-negative PTB. We utilized Alameda County TB surveillance data from 2010 to 2019. Culture-negative PTB cases met clinical but not laboratory criteria for PTB per US National Tuberculosis Surveillance System definitions. We calculated trends in annual incidence and proportion of culture-negative PTB using Poisson and weighted linear regression, respectively. We further compared demographic and clinical characteristics among culture-negative versus culture-positive PTB cases. During 2010-2019, there were 870 cases of PTB, of which 152 (17%) were culture-negative. The incidence of culture-negative PTB declined by 76%, from 1.9/100 000 to 0.46/100 000 ( P for trend <.01), while the incidence of culture-positive PTB reduced by 37% (6.5/100 000 to 4.1/100 000, P for trend =.1). Culture-negative PTB case-patients were more likely than culture-positive PTB case-patients to be younger (7.9% were children <15 years old vs 1.1%; P < .01), recent immigrants within 5 years of arrival (38.2% vs 25.5%; P < .01), and have a TB contact (11.2% vs 2.9%; P < .01). Culture-negative PTB case-patients were less likely than culture-positive PTB case-patients to be evaluated because of TB symptoms (57.2% vs 74.7%; P < .01) or have cavitation on chest imaging (13.1% vs 38.8%; P < .01). At the same time culture-negative PTB case-patients were less likely to die during TB treatment (2.0% vs 9.6%; P < .01). The incidence of culture-negative PTB disproportionately declined compared with culture-positive TB and raises concern for gaps in detection. Expansion of screening programs for recent immigrants and TB contacts and greater recognition of risk factors may increase detection of culture-negative PTB.

Endogenous relapse and exogenous reinfection in recurrent pulmonary tuberculosis: A retrospective study revealed by whole genome sequencing.

Tuberculosis may reoccur due to reinfection or relapse after initially successful treatment. Distinguishing the cause of TB recurrence is crucial to guide TB control and treatment. This study aimed to investigate the source of TB recurrence and risk factors related to relapse in Hunan province, a high TB burden region in southern China. A population-based retrospective study was conducted on all culture-positive TB cases in Hunan province, China from 2013 to 2020. Phenotypic drug susceptibility testing and whole-genome sequencing were used to detect drug resistance and distinguish between relapse and reinfection. Pearson chi-square test and Fisher exact test were applied to compare differences in categorical variables between relapse and reinfection. The Kaplan-Meier curve was generated in R studio (4.0.4) to describe and compare the time to recurrence between different groups. p < 0.05 was considered statistically significant. Of 36 recurrent events, 27 (75.0%, 27/36) paired isolates were caused by relapse, and reinfection accounted for 25.0% (9/36) of recurrent cases. No significant difference in characteristics was observed between relapse and reinfection (all p > 0.05). In addition, TB relapse occurs earlier in patients of Tu ethnicity compared to patients of Han ethnicity (p < 0.0001), whereas no significant differences in the time interval to relapse were noted in other groups. Moreover, 83.3% (30/36) of TB recurrence occurred within 3 years. Overall, these recurrent TB isolates were predominantly pan-susceptible strains (71.0%, 49/69), followed by DR-TB (17.4%, 12/69) and MDR-TB (11.6%, 8/69), with mutations mainly in codon 450 of the rpoB gene and codon 315 of the katG gene. 11.1% (3/27) of relapse cases had acquired new resistance during treatment, with fluoroquinolone resistance occurring most frequently (7.4%, 2/27), both with mutations in codon 94 of gyrA. Endogenous relapse is the main mechanism leading to TB recurrences in Hunan province. Given that TB recurrences can occur more than 4 years after treatment completion, it is necessary to extend the post-treatment follow-up period to achieve better management of TB patients. Moreover, the relatively high frequency of fluoroquinolone resistance in the second episode of relapse suggests that fluoroquinolones should be used with caution when treating TB cases with relapse, preferably guided by DST results.

Pre-sensitization with tuberculosis and non-tuberculosis mycobacteria and its impact on TB incidence in different age groups: Chengalpattu BCG trial revisited

Individuals pre-sensitized with Mycobacterium tuberculosis (MTB), non-tuberculosis mycobacteria, and its impact on TB incidence are relatively unexplored in a high TB burden setting. We conducted secondary data analysis of a double-blind, randomized Chengalpattu BCG trial, India. Induration to Purified Protein Derivative (PPD)-S and PPD-B were proxies for exposures to MTB and M. intracellulare respectively. Optimum cut-off for PPD-S and B were determined using Receiver-Operating Characteristic curves and induration ≥12 mm for PPD-S and ≥10 mm for PPD-B were considered strong reaction. Incidence rates of culture positive pulmonary TB per 100,000 person-years (PY) were calculated. Of 270,043 individuals with skin test results, children <14 years (n = 109,383, 64% showed strong-reaction to PPD-B and 17% to PPD-S) and adults between 25 and 34 years (n = 40,292, 98% were strong reactors to PPD-B and 73% to PPD-S). Overall incidence rate was lower in individuals with PPD-S < PPD-B (136, 95% CI: 130–141/100,000 PY) compared to individuals with PPD-S > PPD-B (447, 95% CI: 427–468/100,000 PY). Incidence rates of culture positive pulmonary TB was affected by early age of exposure to cross-reactive mycobacterial antigens represented by PPD-B and exposure to MTB represented by PPD-S during adolescence and early adulthood.

267. Delayed Pulmonary Tuberculosis (PTB) Diagnosis During the COVID-19 Pandemic: A Case Series

Abstract Background The COVID-19 pandemic has been associated with underreporting of pulmonary tuberculosis (PTB). Overlapping risk factors, clinical features, and chronicity of post COVID-19 sequelae can lead to attribution of respiratory disease solely to COVID-19 and result in delayed recognition of PTB. Methods Identification of inpatients with both sputum (spu) culture (clt) positive TB and SARS-CoV-2 + PCR was achieved using data extraction tool Slicer Dicer Epic system during 3/2020-1/2022 followed by a retrospective review of electronic medical records. We defined COVID-PTB as a patient (pt) who had positive spu clt for TB ≤ 12 months (mos) following a COVID-19 diagnosis. Results 8 pts had both PTB and COVID-19. Two had PTB &amp;gt; 5 mos prior to, and one had PTB &amp;gt; 12 mos after COVID-19. 3/8 were promptly suspected to have PTB [1 with right upper lobe (RUL) infiltrate; 1 RUL cavitary infiltrate; 1 with miliary nodules and cavities]; in these 3, spu was tested for MTB ≤ 48 hours (h) (hrs) of presentation. 5/8 had COVID-PTB. All 5 had fever and/or respiratory symptoms and ≥ 1 risk factors for TB identified at the time of presentation with COVID-19. Spu was tested for MTB in 48 hs in 1 with RUL cavitary infiltrate, and 5 days after chest CT findings of apical densities and scattered nodules in another. In the remaining 3, spu testing was delayed a median of 36 days (range, 8-133) after initial TB consistent CT findings (LUL opacity and nodular densities in 1; RLL cavitary infiltrate in 1; and clustered RML nodules in 1) and despite immigration from high burden TB countries in all 3; known LTBI in 2; diabetes in 1, and immunosuppressive therapies in 2. Conclusion We observed a delay in sputum collection after COVID-19 diagnosis in the presence of epidemiological risk factors for TB disease and clinical features consistent with PTB. Lack of familiarity with the range radiological TB features, a diagnostic bias towards more typical radiographic (e.g., cavities, miliary patterns) and COVID-19 anchoring bias may have contributed to delayed PTB diagnosis. PTB should be considered, when clinically appropriate, in the setting of COVID-19 or apparent post COVID-19 sequelae. Disclosures All Authors: No reported disclosures.

Low-Dose Linezolid for Treatment of Patients With Multidrug-Resistant Tuberculosis.

Linezolid has been prioritized for treating multidrug-resistant tuberculosis (MDR TB), but toxicity limits its use. We report treatment outcomes for MDR TB patients in California who received standard-dose linezolid vs those who switched to low-dose. We include culture-positive MDR TB cases treated with linezolid and receiving California MDR TB Service consultation during 2009-2016. Demographic, clinical, and laboratory data are analyzed using univariate analysis to compare patients who received linezolid of different dosing strategies. Analysis end points are linezolid treatment duration (measure of tolerability), treatment success (completion or cure), and adverse events (AEs). Sixty-nine of 194 (36%) MDR TB patients met inclusion criteria. While all patients began linezolid treatment at 600 mg daily, 39 (57%) continued at this dosage (standard-dose), and 30 (43%) switched to 300 mg daily (29%) or intermittent dosing (14%) (low dose). Patients on standard-dose linezolid were treated for 240 days, compared with 535 for those on low-dose (P < .0001). Sixty-three patients (91%) achieved treatment success, 2 (2.9%) died, 1 (1.5%) failed treatment, 1 (1.5%) stopped treatment due to side effects, and 2 (2.9%) were lost or moved. Treatment success was higher (P = .03) in the low-dose group. Sixty-two patients experienced ≥1 hematologic (71%) or neurologic (65%) AE. Those on low-dose linezolid experienced significantly (P = .03) fewer AEs per linezolid-month after switching (0.32 vs 0.10). Patients who switched to low dose tolerated linezolid longer with better treatment outcomes and fewer recurring AEs.

Whole-genome sequencing for surveillance of fluoroquinolone resistance in rifampicin-susceptible tuberculosis in a rural district of Shanghai: A 10-year retrospective study.

BackgroundFluoroquinolones (FQs) are the most important second-line anti-tuberculosis (anti-TB) drugs, primarily used for the treatment of multidrug- or rifampicin-resistant TB (MDR/RR-TB). However, FQs are also commonly used to treat other bacterial infections. There are few published data on the rates of FQ resistance among rifampicin-susceptible TB.MethodsWe used whole-genome sequencing (WGS) to determine the prevalence of FQ resistance among rifampicin-susceptible TB in a rural district of Shanghai. This was a population-based retrospective study of all culture-positive pulmonary TB patients diagnosed in the Chongming district of Shanghai, China during 2009–2018.ResultsThe rate of FQ resistance was 8.4% (29/345) among TB, 6.2% (20/324) among rifampicin-susceptible TB, and 42.9% (9/21) among MDR/RR-TB. Transmission of FQ-resistant strains was defined as strains differing within 12 single-nucleotide polymorphisms (SNPs) based on WGS. Among the rifampicin-susceptible TB, 20% (4/20) of FQ resistance was caused by the transmission of FQ-resistant strains and 45% (9/20) of FQ resistance was identified as hetero-resistance.ConclusionsThe prevalence of FQ resistance in rifampicin-susceptible TB was higher than expected in Shanghai. Both the transmission and the selection of drug-resistant strains drive the emergence of FQ resistance in rifampicin-susceptible TB isolates. Therefore, the WGS-based surveillance system for TB should be urgently established and the clinical awareness of the rational use of FQs for respiratory infections should be enhanced to prevent the premature occurrence of FQ resistance.

Characteristics and Trend of Drug-Resistant Tuberculosis at a Major Specialized Hospital in Chongqing, China: 2016 Versus 2019.

The epidemic of drug-resistant tuberculosis (DR-TB) has become a major concern in global TB control. This study aimed to investigate the patterns and trend of DR-TB epidemic between different time periods in Chongqing. A total of 985 and 835 culture positive TB patients with drug susceptibility testing (DST) results admitted to the hospital in 2016 and 2019, respectively, were included. Chi-square testing was used to compare the prevalence and trends of DR-TB in 2016 and 2019. The proportion of previously treated TB cases with culture positivity was 45.7% in 2019, significantly higher than that in 2016 (39.1%, P = 0.004). The overall rate of drug resistance in 2019 was 43.1%, higher than that in 2016 (40.2%). The rates of multi-drug resistant TB (MDR-TB) and pre-extensively drug resistant TB (pre-XDR-TB) increased significantly from 2016 to 2019 among all TB cases (MDR: 25% vs 33.4%, P < 0.001 and pre-XDR: 7.1% vs 12.8%, P < 0.001, respectively) and previously treated TB cases (MDR: 46.5% vs 56%, P = 0.008 and pre-XDR: 13.2% vs 21.5%, P = 0.003, respectively). Our findings indicated that the prevalence of DR-TB remains high in Chongqing. The trend of resistance to anti-TB drugs beccame worse between 2016 and 2019. Moreover, acquired MDR may play a major role in MDR-TB epidemic in Chongqing. Therefore, rapid diagnosis and effective treatment of TB patients will be important to reduce the burden of DR-TB in Chongqing.

How much do smear-negative patients really contribute to tuberculosis transmissions? Re-examining an old question with new tools.

SummaryBackgroundSputum smear microscopy is a common surrogate for tuberculosis infectiousness. Previous estimates that smear-negative patients contribute 13–20% of transmissions and are, on average, 20 to 25% as infectious as smear-positive cases are understood to be high. Herein, we use an ideal real-world setting, a comprehensive dataset, and new high-resolution techniques to more accurately estimate the true transmission risk of smear-negative cases.MethodsWe treated all adult culture-positive pulmonary TB patients diagnosed in the province of Alberta, Canada from 2003 to 2016 as potential transmitters. The primary data sources were the Alberta TB Registry and the Provincial Laboratory for Public Health. We measured, as primary outcomes, the proportion of transmissions attributable to smear-negative sources and the relative transmission rate. First, we replicated previous studies by using molecular (DNA) fingerprint clustering. Then, using a prospectively collected registry of TB contacts, we defined transmission events as active TB amongst identified contacts who either had a 100% DNA fingerprint match to the source case or a clinical diagnosis. We supplemented our analysis with genome sequencing on temporally and geographically linked DNA fingerprint clusters of cases not identified as contacts.FindingsThere were 1176 cases, 563 smear-negative and 613 smear-positive, and 23,131 contacts. Replicating previous studies, the proportion of transmissions attributable to smear-negative source cases was 16% (95% CI, 12–19%) and the relative transmission rate was 0.19 (95% CI, 0.14–0.26). With our combined approach, the proportion of transmission was 8% (95% CI, 3–14%) and the relative transmission rate became 0.10 (95% CI, 0.05–0.19).InterpretationWhen we examined the same outcomes as in previous studies but refined transmission ascertainment with the addition of conventional epidemiology and genomics, we found that smear-negative cases were ∼50% less infectious than previously thought.FundingAlberta Innovates Health Solutions

Multi Drug Resistant Tuberculosis Detection by Phenotypic Method inTreatment Naïve Pulmonary Tuberculosis Patients

Background and Aims The emergence of multi drug-resistant tuberculosis MDR-TB in treatment naiumlve Pulmonary Tuberculosis PTB is an epidemiological indicator indicating transmission of drug-resistant strains in the community. This study aimed to assess the patterns of drug resistance to any first-line anti-TB drugs and MDR-TB in culture-positive TB isolates obtained from treatment naiumlve PTB in a tertiary care hospital.Methods A total of 240 culture-positive TB isolates obtained from newly diagnosed pulmonary TB patients during the study period September 2018- June 2021 were enrolled in this study. All culture-positive isolates were subjected to phenotypic drug susceptibility testing DST by the conventional 1 proportion method against all the five first-line anti-tubercular antibiotics.Results Of the 240 isolates 127 52.9 were susceptible to all the first-line anti-tubercular drugs. Mono resistance to Rifampicin Isoniazid Streptomycin and Pyrazinamide was observed in 11 4.6 8 3.3 15 6.3 and 14 5.8 of the isolates respectively. Resistance to Ethambutol was not exhibited by any of the isolates. The proportion of MDR-TB in the study was 12.5.Conclusions The study has identified a high rate of MDR-TB in the study area indicating the need to strengthen and expand the National level TB eradication programmes for early identification and proper treatment to interrupt the chain of transmission of MDR-TB in the community

Childhood Intra-Thoracic Tuberculosis Clinical Presentation Determines Yield of Laboratory Diagnostic Assays.

Diagnosis of intra-thoracic tuberculosis (ITTB) in children is difficult due to the paucibacillary nature of the disease, the challenge in collecting appropriate specimens, and the low sensitivity of smear microscopy and culture. Culture and Xpert MTB/RIF provide higher diagnostic yield in presumptive TB in adults than in children. Current study was designed to understand poor yield of diagnostic assays in children. Children with presumptive ITTB were subjected to gastric aspirates and induced sputum twice. Samples were tested by Ziehl-Neelsen stain, Xpert MTB/RIF-assay, and MGIT-960 culture. Subjects were grouped as Confirmed, Unconfirmed, and Unlikely TB, and classified as progressive primary disease (PPD, lung parenchymal lesion), and primary pulmonary complex (PPC, hilar lymphadenopathy) on chest X-ray. Of children with culture-positive TB 51/394 (12.9%), culture-negative TB 305 (77.4%), and unlikely TB 38 (9.6%), 9 (2.3%) were smear positive, while 95 (24.1%) were Xpert-MTB/RIF positive. Xpert-MTB/RIF detected 40/51 culture confirmed cases (sensitivity 78.4% and NPV 96.3%). Culture was positive in more children presenting as PPD (p < 0.04). In culture-negative TB group, Xpert positivity was seen in 31% of those with PPD and 11.9% in those with PPC (p < 0.001).Conclusion: Xpert-MTB/RIF improved diagnosis by 2-fold and increased detection of MDR-TB. Both liquid culture and Xpert-MTB/RIF gave higher yield in children with lung parenchymal lesions. Children with hilar lymphadenopathy without active lung parenchymal lesions had poor diagnostic yield even with sensitive nucleic acid amplification tests, due to paucibacillary/localized disease, suggesting possible utility of invasively collected samples in early diagnosis and treatment.

The utility of point-of-care urinary lipoarabinomannan testing for the diagnosis of tuberculosis in critically ill patients: a prospective observational study

BackgroundTuberculosis is a major global public health concern. Patients with tuberculosis who require critical care have a high mortality and delay in initiating antituberculous therapy is associated with increased mortality. Lipoarabinomannan (LAM) is a lipopolysaccharide found in the cell wall of Mycobacterium tuberculosis. Urinary LAM may be used as a bedside diagnostic test for tuberculosis.MethodsThe study was a single centre, prospective observational study that compared the utility of urinary LAM with conventional tuberculosis diagnostic modalities in patients with suspected tuberculosis who required intensive care admission. Urinary LAM testing was performed using the Alere Determine TB LAM Ag lateral flow assay test strips. A patient was classified as having confirmed tuberculosis if they met the following criteria: a clinical presentation compatible with tuberculosis, with either a positive TB culture, a positive GeneXpert, or a histological diagnosis of tuberculosis.ResultsFifty patients were included in the study, with 12 having confirmed tuberculosis. All patients received mechanical ventilation, and the ICU mortality was 60%. Urinary LAM had a sensitivity of 50.0% (95% CI, 21.1 to 78.9%) and a specificity of 84.2% (95% CI, 68.8 to 94.0%) for confirmed tuberculosis.ConclusionUrinary LAM allows for rapid bedside diagnosis of tuberculosis in critically ill patients. A positive urinary LAM should prompt consideration to initiate antituberculous treatment while the results of further diagnostic testing are awaited.