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1.
Braz J Microbiol ; 53(2): 633-639, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1872828

ABSTRACT

Tuberculosis (TB) and COVID-19 affect the lungs and are transmitted mainly by aerosols or particles of saliva from infected persons. Clinical similarities between diseases can affect correct diagnosis. Individuals belonging to the population deprived of liberty (PDL) are at increased risk of contagion due to precarious sanitary conditions and overcrowded environments. A variety of specimens may be suitable for the diagnosis of COVID-19, using molecular diagnostic techniques; however, there is little data on the analysis of sputum samples with the Xpert Xpress SARS-CoV-2® for the diagnosis of COVID-19, especially in this population group. The present study reports a case of TB and COVID-19 co-infection detected in sputum from an individual belonging to the PDL. For the detection, it used the GeneXpert platform (Cepheid, USA). Mycobacterium tuberculosis complex (MTC) was detected using the Xpert MTB/RIF Ultra® cartridge and SARS-CoV-2 was detected using the Xpert Xpress SARS-CoV-2® cartridge. The genes IS6110 and IS1081 were detected within 80 min indicating the presence of MTC, with no mutations related to resistance to rifampicin. The SARS-CoV-2 E and N2 genes were detected within 45 min. The result was confirmed by RT-qPCR with detection of E, N, and RdRP/S genes in the sputum and nasopharyngeal (NP) specimens. Rapid diagnoses that allow the identification and differentiation of such diseases are important for adequate epidemiological surveillance, isolation of infected individuals, and interruption of the transmission chain. Using the GeneXpert platform, specimens can be tested as soon as they are received, without the need for prior preparation. The US Food and Drug Administration has issued emergency authorization for the use of the Cepheid Xpert Xpress SARS-CoV-2 for the rapid detection of SARS-CoV-2 using specimens from a NP or nasal wash/aspirate. The case presented here gains an innovation with the use of the sputum to COVID-19 diagnosis.


Subject(s)
COVID-19 , Coinfection , Mycobacterium tuberculosis , Tuberculosis , COVID-19/diagnosis , COVID-19 Testing , Coinfection/diagnosis , Humans , Molecular Diagnostic Techniques/methods , Mycobacterium tuberculosis/genetics , Rifampin , SARS-CoV-2/genetics , Sensitivity and Specificity , Sputum/microbiology , Tuberculosis/diagnosis , Tuberculosis/microbiology
2.
J Med Chem ; 65(11): 7489-7531, 2022 Jun 09.
Article in English | MEDLINE | ID: covidwho-1864721

ABSTRACT

Over the past 2000 years, tuberculosis (TB) has claimed more lives than any other infectious disease. In 2020 alone, TB was responsible for 1.5 million deaths worldwide, comparable to the 1.8 million deaths caused by COVID-19. The World Health Organization has stated that new TB drugs must be developed to end this pandemic. After decades of neglect in this field, a renaissance era of TB drug discovery has arrived, in which many novel candidates have entered clinical trials. However, while hundreds of molecules are reported annually as promising anti-TB agents, very few successfully progress to clinical development. In this Perspective, we critically review those anti-TB compounds published in the last 6 years that demonstrate good in vivo efficacy against Mycobacterium tuberculosis. Additionally, we highlight the main challenges and strategies for developing new TB drugs and the current global pipeline of drug candidates in clinical studies to foment fresh research perspectives.


Subject(s)
COVID-19 , Mycobacterium tuberculosis , Tuberculosis , Antitubercular Agents/pharmacology , Antitubercular Agents/therapeutic use , COVID-19/drug therapy , Drug Discovery , Humans , Tuberculosis/drug therapy
3.
Lancet Infect Dis ; 22(4): 496-506, 2022 04.
Article in English | MEDLINE | ID: covidwho-1839428

ABSTRACT

BACKGROUND: Bedaquiline improves outcomes of patients with rifampicin-resistant and multidrug-resistant (MDR) tuberculosis; however, emerging resistance threatens this success. We did a cross-sectional and longitudinal analysis evaluating the epidemiology, genetic basis, and treatment outcomes associated with bedaquiline resistance, using data from South Africa (2015-19). METHODS: Patients with drug-resistant tuberculosis starting bedaquiline-based treatment had surveillance samples submitted at baseline, month 2, and month 6, along with demographic information. Culture-positive baseline and post-baseline isolates had phenotypic resistance determined. Eligible patients were aged 12 years or older with a positive culture sample at baseline or, if the sample was invalid or negative, a sample within 30 days of the baseline sample submitted for bedaquiline drug susceptibility testing. For the longitudinal study, the first surveillance sample had to be phenotypically susceptible to bedaquiline for inclusion. Whole-genome sequencing was done on bedaquiline-resistant isolates and a subset of bedaquiline-susceptible isolates. The National Institute for Communicable Diseases tuberculosis reference laboratory, and national tuberculosis surveillance databases were matched to the Electronic Drug-Resistant Tuberculosis Register. We assessed baseline resistance prevalence, mutations, transmission, cumulative resistance incidence, and odds ratios (ORs) associating risk factors for resistance with patient outcomes. FINDINGS: Between Jan 1, 2015, and July 31, 2019, 8041 patients had surveillance samples submitted, of whom 2023 were included in the cross-sectional analysis and 695 in the longitudinal analysis. Baseline bedaquiline resistance prevalence was 3·8% (76 of 2023 patients; 95% CI 2·9-4·6), and it was associated with previous exposure to bedaquiline or clofazimine (OR 7·1, 95% CI 2·3-21·9) and with rifampicin-resistant or MDR tuberculosis with additional resistance to either fluoroquinolones or injectable drugs (pre-extensively-drug resistant [XDR] tuberculosis: 4·2, 1·7-10·5) or to both (XDR tuberculosis: 4·8, 2·0-11·7). Rv0678 mutations were the sole genetic basis of phenotypic resistance. Baseline resistance could be attributed to previous bedaquiline or clofazimine exposure in four (5·3%) of 76 patients and to primary transmission in six (7·9%). Odds of successful treatment outcomes were lower in patients with baseline bedaquiline resistance (0·5, 0·3-1). Resistance during treatment developed in 16 (2·3%) of 695 patients, at a median of 90 days (IQR 62-195), with 12 of these 16 having pre-XDR or XDR. INTERPRETATION: Bedaquiline resistance was associated with poorer treatment outcomes. Rapid assessment of bedaquiline resistance, especially when patients were previously exposed to bedaquiline or clofazimine, should be prioritised at baseline or if patients remain culture-positive after 2 months of treatment. Preventing resistance by use of novel combination therapies, current treatment optimisation, and patient support is essential. FUNDING: National Institute for Communicable Diseases of South Africa.


Subject(s)
Mycobacterium tuberculosis , Tuberculosis, Multidrug-Resistant , Antitubercular Agents/pharmacology , Antitubercular Agents/therapeutic use , Clofazimine/therapeutic use , Cross-Sectional Studies , Diarylquinolines/therapeutic use , Humans , Longitudinal Studies , Microbial Sensitivity Tests , Mycobacterium tuberculosis/genetics , Rifampin/pharmacology , Rifampin/therapeutic use , Tuberculosis, Multidrug-Resistant/drug therapy , Tuberculosis, Multidrug-Resistant/epidemiology
4.
Lancet Infect Dis ; 22(4): 507-518, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1839425

ABSTRACT

BACKGROUND: The WHO-recommended tuberculosis screening and diagnostic algorithm in ambulatory people living with HIV is a four-symptom screen (known as the WHO-recommended four symptom screen [W4SS]) followed by a WHO-recommended molecular rapid diagnostic test (eg Xpert MTB/RIF [hereafter referred to as Xpert]) if W4SS is positive. To inform updated WHO guidelines, we aimed to assess the diagnostic accuracy of alternative screening tests and strategies for tuberculosis in this population. METHODS: In this systematic review and individual participant data meta-analysis, we updated a search of PubMed (MEDLINE), Embase, the Cochrane Library, and conference abstracts for publications from Jan 1, 2011, to March 12, 2018, done in a previous systematic review to include the period up to Aug 2, 2019. We screened the reference lists of identified pieces and contacted experts in the field. We included prospective cross-sectional, observational studies and randomised trials among adult and adolescent (age ≥10 years) ambulatory people living with HIV, irrespective of signs and symptoms of tuberculosis. We extracted study-level data using a standardised data extraction form, and we requested individual participant data from study authors. We aimed to compare the W4SS with alternative screening tests and strategies and the WHO-recommended algorithm (ie, W4SS followed by Xpert) with Xpert for all in terms of diagnostic accuracy (sensitivity and specificity), overall and in key subgroups (eg, by antiretroviral therapy [ART] status). The reference standard was culture. This study is registered with PROSPERO, CRD42020155895. FINDINGS: We identified 25 studies, and obtained data from 22 studies (including 15 666 participants; 4347 [27·7%] of 15 663 participants with data were on ART). W4SS sensitivity was 82% (95% CI 72-89) and specificity was 42% (29-57). C-reactive protein (≥10 mg/L) had similar sensitivity to (77% [61-88]), but higher specificity (74% [61-83]; n=3571) than, W4SS. Cough (lasting ≥2 weeks), haemoglobin (<10 g/dL), body-mass index (<18·5 kg/m2), and lymphadenopathy had high specificities (80-90%) but low sensitivities (29-43%). The WHO-recommended algorithm had a sensitivity of 58% (50-66) and a specificity of 99% (98-100); Xpert for all had a sensitivity of 68% (57-76) and a specificity of 99% (98-99). In the one study that assessed both, the sensitivity of sputum Xpert Ultra was higher than sputum Xpert (73% [62-81] vs 57% [47-67]) and specificities were similar (98% [96-98] vs 99% [98-100]). Among outpatients on ART (4309 [99·1%] of 4347 people on ART), W4SS sensitivity was 53% (35-71) and specificity was 71% (51-85). In this population, a parallel strategy (two tests done at the same time) of W4SS with any chest x-ray abnormality had higher sensitivity (89% [70-97]) and lower specificity (33% [17-54]; n=2670) than W4SS alone; at a tuberculosis prevalence of 5%, this strategy would require 379 more rapid diagnostic tests per 1000 people living with HIV than W4SS but detect 18 more tuberculosis cases. Among outpatients not on ART (11 160 [71·8%] of 15 541 outpatients), W4SS sensitivity was 85% (76-91) and specificity was 37% (25-51). C-reactive protein (≥10 mg/L) alone had a similar sensitivity to (83% [79-86]), but higher specificity (67% [60-73]; n=3187) than, W4SS and a sequential strategy (both test positive) of W4SS then C-reactive protein (≥5 mg/L) had a similar sensitivity to (84% [75-90]), but higher specificity than (64% [57-71]; n=3187), W4SS alone; at 10% tuberculosis prevalence, these strategies would require 272 and 244 fewer rapid diagnostic tests per 1000 people living with HIV than W4SS but miss two and one more tuberculosis cases, respectively. INTERPRETATION: C-reactive protein reduces the need for further rapid diagnostic tests without compromising sensitivity and has been included in the updated WHO tuberculosis screening guidelines. However, C-reactive protein data were scarce for outpatients on ART, necessitating future research regarding the utility of C-reactive protein in this group. Chest x-ray can be useful in outpatients on ART when combined with W4SS. The WHO-recommended algorithm has suboptimal sensitivity; Xpert for all offers slight sensitivity gains and would have major resource implications. FUNDING: World Health Organization.


Subject(s)
Antibiotics, Antitubercular , HIV Infections , Mycobacterium tuberculosis , Tuberculosis, Pulmonary , Tuberculosis , Adolescent , Adult , Antibiotics, Antitubercular/therapeutic use , Child , Cross-Sectional Studies , HIV Infections/complications , HIV Infections/drug therapy , Humans , Prospective Studies , Rifampin , Sensitivity and Specificity , Tuberculosis/diagnosis , Tuberculosis, Pulmonary/diagnosis , Tuberculosis, Pulmonary/drug therapy
5.
Int J Infect Dis ; 118: 264-269, 2022 May.
Article in English | MEDLINE | ID: covidwho-1838867

ABSTRACT

OBJECTIVES: The study aimed to explore the efficacy and safety of linezolid-based chemotherapeutic regimens for patients with postoperative multidrug-resistant spinal tuberculosis. METHODS: The randomized controlled study included 50 Mycobacterium tuberculosis culture or pathological-confirmed multidrug resistant tuberculosis patients who received spinal surgery from January 2018 to February 2020. Twenty-five patients were assigned to the control group and the study group, respectively. Random number method was used for patient allocation and they were treated with levofloxacin, pyrazinamide, thioisonicotinamide enteric-coated tablet, amikacin sulfate injection, and sodium p-amino salicylate injection, accompanied by linezolid or not. RESULTS: The overall effective rate of the study group was higher than that of the control group (88.00% vs 64.00%, P<0.05). The severity of pain at 3 and 6 months postoperatively was lower in the study group than that in the control group (P<0.05). Postoperatively, the study group had higher bone graft fusion rate, shorter mean bone graft fusion time, and higher paraspinal cyst absorption rate than the control group (P<0.05). Postoperatively, the study group had lower levels of PCT, ESR, and CRP than the control group (P <0.05). All patients had normal hepatic and renal function, and no statistical difference of adverse effects between 2 groups were found. CONCLUSIONS: Linezolid-based chemotherapeutic regimens can effectively treat patients with postoperative multidrug-resistant spinal tuberculosis but have higher rates of adverse reactions.


Subject(s)
Linezolid , Tuberculosis, Multidrug-Resistant , Tuberculosis, Spinal , Humans , Linezolid/adverse effects , Mycobacterium tuberculosis/drug effects , Treatment Outcome , Tuberculosis, Multidrug-Resistant/drug therapy , Tuberculosis, Multidrug-Resistant/surgery , Tuberculosis, Spinal/drug therapy , Tuberculosis, Spinal/surgery
6.
mSphere ; 7(2): e0048221, 2022 04 27.
Article in English | MEDLINE | ID: covidwho-1832361

ABSTRACT

Mycobacterium tuberculosis is the etiological agent of tuberculosis (TB), one of the deadliest infectious diseases. The alarming health context coupled with the emergence of resistant M. tuberculosis strains highlights the urgent need to expand the range of anti-TB antibiotics. A subset of anti-TB drugs in use are prodrugs that require bioactivation by a class of M. tuberculosis enzymes called Baeyer-Villiger monooxygenases (BVMOs), which remain understudied. To examine the prevalence and the molecular function of BVMOs in mycobacteria, we applied a comprehensive bioinformatic analysis that identified six BVMOs in M. tuberculosis, including Rv3083 (MymA), Rv3854c (EthA), Rv0565c, and Rv0892, which were selected for further characterization. Homology modeling and substrate docking analysis, performed on this subset, suggested that Rv0892 is closer to the cyclohexanone BVMO, while Rv0565c and EthA are structurally and functionally similar to MymA, which is by far the most prominent type I BVMO enzyme. Thanks to an unprecedented purification and assay optimization, biochemical studies confirmed that all four BVMOs display BV-oxygenation activity. We also showed that MymA displays a distinctive substrate preference that we further investigated by kinetic parameter determination and that correlates with in silico modeling. We provide insights into distribution of BVMOs and the structural basis of their substrate profiling, and we discuss their possible redundancy in M. tuberculosis, raising questions about their versatility in prodrug activation and their role in physiology and infection. IMPORTANCE Tuberculosis (TB), caused by Mycobacterium tuberculosis, is one of the leading causes of death worldwide. The rise in drug resistance highlights the urgent need for innovation in anti-TB drug development. Many anti-TB drugs require bioactivation by Baeyer-Villiger monooxygenases (BVMOs). Despite their emerging importance, BVMO structural and functional features remain enigmatic. We applied a comprehensive bioinformatic analysis and confirmed the presence of six BVMOs in M. tuberculosis, including MymA, EthA, and Rv0565c-activators of the second-line prodrug ethionamide-and the novel BVMO Rv0892. Combining in silico characterization with in vitro validation, we outlined their structural framework and substrate preference. Markedly, MymA displayed an enhanced capacity and a distinct selectivity profile toward ligands, in agreement with its catalytic site topology. These features ground the molecular basis for structure-function comprehension of the specificity in these enzymes and expand the repertoire of BVMOs with selective and/or overlapping activity for application in the context of improving anti-TB therapy.


Subject(s)
Mycobacterium tuberculosis , Prodrugs , Antitubercular Agents/pharmacology , Computational Biology , Mixed Function Oxygenases/chemistry , Mixed Function Oxygenases/genetics , Mycobacterium tuberculosis/genetics
7.
Immunobiology ; 227(3): 152224, 2022 05.
Article in English | MEDLINE | ID: covidwho-1819510

ABSTRACT

The COVID-19 pandemic has set back progress made on antimicrobial resistance (AMR). Without urgent re-focus, we risk slowing down drug discovery and providing treatment for drug resistant Mycobacterium tuberculosis. Unique in its immune evasion, dormancy and resuscitation, the causal pathogens of tuberculosis (TB) have demonstrated resistance to antibiotics with efflux pumps and the ability to form biofilms. Repurposing drugs is a prospective avenue for finding new anti-TB drugs. There are many advantages to discovering novel targets of an existing drug, as the pharmacokinetic and pharmacodynamic properties have already been established, they are cost-efficient and can be commercially accelerated for the new development. One such group of drugs are non-steroidal anti-inflammatory drugs (NSAIDs) that are originally known for their ability to supress the host proinflammatory responses. In addition to their anti-inflammatory properties, some NSAIDs have been discovered to have antimicrobial modes of action. Of particular interest is Carprofen, identified to inhibit the efflux mechanism and disrupt biofilm formation in mycobacteria. Due to the complexities of host-pathogens interactions in the lung microbiome, inflammatory responses must carefully be controlled alongside the in vivo actions of the prospective anti-infectives. This critical review explores the potential dual role of a selection of NSAIDs, as an anti-inflammatory and anti-tubercular adjunct to reverse the tide of antimicrobial resistance in existing treatments.


Subject(s)
Anti-Infective Agents , COVID-19 , Mycobacterium tuberculosis , Tuberculosis , Anti-Infective Agents/therapeutic use , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Antitubercular Agents/pharmacology , Antitubercular Agents/therapeutic use , COVID-19/drug therapy , Humans , Pandemics , Tuberculosis/drug therapy
8.
Molecules ; 27(8)2022 Apr 15.
Article in English | MEDLINE | ID: covidwho-1810041

ABSTRACT

Tuberculosis remains a global health problem that affects millions of people around the world. Despite recent efforts in drug development, new alternatives are required. Herein, a series of 27 N-(4-(benzyloxy)benzyl)-4-aminoquinolines were synthesized and evaluated for their ability to inhibit the M. tuberculosis H37Rv strain. Two of these compounds exhibited minimal inhibitory concentrations (MICs) similar to the first-line drug isoniazid. In addition, these hit compounds were selective for the bacillus with no significant change in viability of Vero and HepG2 cells. Finally, chemical stability, permeability and metabolic stability were also evaluated. The obtained data show that the molecular hits can be optimized aiming at the development of drug candidates for tuberculosis treatment.


Subject(s)
Mycobacterium tuberculosis , Tuberculosis , Aminoquinolines/pharmacology , Antitubercular Agents/chemistry , Humans , Isoniazid/pharmacology , Microbial Sensitivity Tests , Tuberculosis/drug therapy
9.
EBioMedicine ; 79: 103993, 2022 May.
Article in English | MEDLINE | ID: covidwho-1783294

ABSTRACT

The Mycobacterium bovis BCG vaccine was first used in 1921, but has not controlled the global spread of tuberculosis (TB). There are still no new licensed tuberculosis vaccines, although there much active research and a vaccine development pipeline, with vaccines designed to prevent infection, prevent disease, or accelerate TB treatment. These vaccines are of different types, and designed to replace BCG, or to boost immunity following BCG vaccination. This viewpoint discusses why, when it has been possible to develop new vaccines for SARS-CoV-2 so quickly, it is taking so long to develop new tuberculosis vaccines.


Subject(s)
COVID-19 , Mycobacterium bovis , Mycobacterium tuberculosis , Tuberculosis Vaccines , BCG Vaccine/therapeutic use , COVID-19/prevention & control , COVID-19 Vaccines , Humans , SARS-CoV-2 , Tuberculosis Vaccines/therapeutic use , Vaccination
10.
Int J Mol Sci ; 23(7)2022 Mar 23.
Article in English | MEDLINE | ID: covidwho-1785727

ABSTRACT

The field of immunometabolism seeks to decipher the complex interplay between the immune system and the associated metabolic pathways. The role of small molecules that can target specific metabolic pathways and subsequently alter the immune landscape provides a desirable platform for new therapeutic interventions. Immunotherapeutic targeting of suppressive cell populations, such as myeloid-derived suppressor cells (MDSC), by small molecules has shown promise in pathologies such as cancer and support testing of similar host-directed therapeutic approaches in MDSC-inducing conditions such as tuberculosis (TB). MDSC exhibit a remarkable ability to suppress T-cell responses in those with TB disease. In tumors, MDSC exhibit considerable plasticity and can undergo metabolic reprogramming from glycolysis to fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS) to facilitate their immunosuppressive functions. In this review we look at the role of MDSC during M. tb infection and how their metabolic reprogramming aids in the exacerbation of active disease and highlight the possible MDSC-targeted metabolic pathways utilized during M. tb infection, suggesting ways to manipulate these cells in search of novel insights for anti-TB therapies.


Subject(s)
Mycobacterium tuberculosis , Myeloid-Derived Suppressor Cells , Neoplasms , Tuberculosis , Biology , Humans , Neoplasms/metabolism , Tuberculosis/microbiology
11.
Tuberculosis (Edinb) ; 134: 102186, 2022 05.
Article in English | MEDLINE | ID: covidwho-1783793

ABSTRACT

COVID-19 has affected the progress made in the prevention and treatment of tuberculosis (TB); hence, the mortality of tuberculosis has risen. Different strategies-based novel TB vaccine candidates have been developed. This study identifies strategies to overcome the limitations of Bacille Calmette-Guérin (BCG) in preventing latent infection and reactivation of TB. The latency antigen Rv0572c was selected based on the mechanism of interaction between Mycobacterium tuberculosis and its host. The rRv0572c protein was used to stimulate whole blood samples derived from patients with clinically diagnosed active TB (ATBs) or latent TB infections (LTBIs) and healthy control (HCs) donors, confirming that this protein can be recognized by T cells in patients with TB, especially LTBIs. C57BL/6 mice were used to investigate the immunogenicity of the rRv0572c protein emulsified in the liposome adjuvant dimethyldioctadecylammonium [DDA], monophosphoryl lipid A [MPLA], trehalose-6, 6'-dibehenate [TDB] (DMT). The results demonstrated that rRv0572c/DMT could boost BCG-primed mice to induce antigen-specific CD4+ T cell production and generate functional T cells dominated by antigen-specific CD8+ T cells. The rRv0572c/DMT vaccine could also trigger limited Th2 humoral immune responses. These findings suggest that rRv0572c/DMT is a potential subunit vaccine candidate that can be used as a booster vaccine for BCG.


Subject(s)
COVID-19 , Latent Tuberculosis , Mycobacterium tuberculosis , Tuberculosis Vaccines , Tuberculosis , Adjuvants, Immunologic , Animals , Antigens, Bacterial , BCG Vaccine , CD8-Positive T-Lymphocytes , Humans , Liposomes , Mice , Mice, Inbred C57BL , Tuberculosis/prevention & control , Vaccines, Subunit
12.
BMC Infect Dis ; 22(1): 204, 2022 Mar 02.
Article in English | MEDLINE | ID: covidwho-1779608

ABSTRACT

BACKGROUND: There was a lack of information about prognostic accuracy of time to sputum culture conversion (SCC) in forecasting cure among extensively drug-resistant tuberculosis (XDR-TB) patients. Therefore, this study evaluated the prognostic accuracy of SCC at various time points in forecasting cure among XDR-TB patients. METHODS: This retrospective observational study included 355 eligible pulmonary XDR-TB patients treated at 27 centers in Pakistan between 01-05-2010 and 30-06-2017. The baseline and follow-up information of patients from treatment initiation until the end of treatment were retrieved from electronic nominal recording and reporting system. Time to SCC was analyzed by Kaplan-Meier method, and differences between groups were compared through log-rank test. Predictors of time to SCC and cure were respectively evaluated by multivariate Cox proportional hazards and binary logistic regression analyses. A p-value < 0.05 was considered statistically significant. RESULTS: A total of 226 (63.6%) and 146 (41.1%) patients respectively achieved SCC and cure. Median time to SCC was significantly shorter in patients who achieved cure, 3 months (95% confidence interval [CI]: 2.47-3.53), than those who did not (median: 10 months, 95% CI: 5.24-14.76) (p-value < 0.001, Log-rank test). Patient's age > 40 years (hazards ratio [HR] = 0.632, p-value = 0.004), baseline sputum grading of scanty, + 1 (HR = 0.511, p-value = 0.002), + 2, + 3 (HR = 0.523, p-value = 0.001) and use of high dose isoniazid (HR = 0.463, p-value = 0.004) were significantly associated with early SCC. Only SCC at 6 month of treatment had statistically significant association with cure (odds ratio = 15.603, p-value < 0.001). In predicting cure, the sensitivities of SCC at 2, 4 and 6 months were respectively 41.8% (95%CI: 33.7-50.2), 69.9% (95%CI: 61.7-77.2) and 84.9% (95%CI: 78.1-90.3), specificities were respectively, 82.8% (95%CI: 76.9-87.6), 74.6% (95%CI: 68.2-80.4) and 69.4% (95%CI: 62.6-75.5) and prognostic accuracies were respectively 65.9% (95%CI: 60.7-70.8), 72.7% (95%CI: 67.7-77.2) and 75.8% (95%CI: 71.0-80.1). CONCLUSION: In forecasting cure, SCC at month 6 of treatment performed better than SCC at 2 and 4 months. However, it would be too long for clinicians to wait for 6 months to decide about the regimen efficacy. Therefore, with somewhat comparable prognostic accuracy to that SCC at 6 month, using SCC at 4 month of treatment as a prognostic marker in predicting cure among XDR-TB patients can decrease the clinicians waiting time to decide about the regimen efficacy.


Subject(s)
Extensively Drug-Resistant Tuberculosis , Mycobacterium tuberculosis , Tuberculosis, Multidrug-Resistant , Tuberculosis, Pulmonary , Adult , Antitubercular Agents/therapeutic use , Extensively Drug-Resistant Tuberculosis/diagnosis , Extensively Drug-Resistant Tuberculosis/drug therapy , Humans , Prognosis , Retrospective Studies , Sputum , Treatment Outcome , Tuberculosis, Multidrug-Resistant/drug therapy , Tuberculosis, Pulmonary/diagnosis , Tuberculosis, Pulmonary/drug therapy
13.
Int J Environ Res Public Health ; 19(7)2022 04 05.
Article in English | MEDLINE | ID: covidwho-1776235

ABSTRACT

A significant drop in tuberculosis (TB) case-finding has been widely reported during the period of the COVID-19 pandemic. To address a decrease in TB notification, Belarus introduced laboratory TB testing in patients with the laboratory-confirmed coronavirus disease 2019 (COVID-19). We conducted a secondary analysis of health records among 844 patients with laboratory-confirmed COVID-19 diagnosis who were admitted to repurposed departments at TB hospitals and who were tested by Xpert MTB/RIF (Cepheid Inc., Sunnyvale, CA, USA) in five Belarus regions between April and October 2021. Quantitative analysis followed by 13 individual interviews with health managers, physicians, and nurses participating in the intervention. Most patients were male (64%) and mean age was 43.5 ± 16 years. One in twenty (n = 47, 5.6%) patients were co-infected with active pulmonary TB, and over one-third of them (n = 18) had rifampicin resistance. In-hospital mortality was comparable in patients with and without TB co-infection (2.1% and 2.3% respectively, p > 0.99). Laboratory TB testing among patients with COVID-19 at repurposed departments of TB hospitals is feasible in Belarus and may improve TB case-finding.


Subject(s)
Antibiotics, Antitubercular , COVID-19 , Coinfection , Latent Tuberculosis , Mycobacterium tuberculosis , Tuberculosis , Adult , Antibiotics, Antitubercular/therapeutic use , COVID-19/epidemiology , COVID-19 Testing , Coinfection/drug therapy , Coinfection/epidemiology , Hospitalization , Humans , Latent Tuberculosis/drug therapy , Male , Middle Aged , Pandemics , Republic of Belarus/epidemiology , Rifampin , Sensitivity and Specificity , Tuberculosis/diagnosis , Tuberculosis/drug therapy , Tuberculosis/epidemiology
14.
Front Public Health ; 10: 808626, 2022.
Article in English | MEDLINE | ID: covidwho-1776005

ABSTRACT

Background: Tuberculosis (TB) is a leading cause of morbidity and mortality in Ethiopia. Investigation of the Mycobacterium tuberculosis complex (MTBC) species circulating in the Ethiopian population would contribute to the efforts made to control TB in the country. Therefore, this study was conducted to investigate the MTBC species and spoligo patterns in the Oromia region (central) of Ethiopia. Methods: A cross-sectional study design was used to recruit 450 smear positive pulmonary TB (PTB) cases from the Oromia region between September 2017 and August 2018. Mycobacteria were isolated from sputum samples on the Lowenstein Jensen (LJ) medium. Molecular identification of the isolates was performed by spoligotyping. The results of spoligotyping were transferred into a query box in the SITVIT2 database and Run TB-Lineage in the TB Insight website for the identification of spoligo international type (SIT) number and linages of the isolates, respectively. Statistical Product and Service Solutions (SPSS) 20 was applied for statistical analysis. Results: Three hundred and fifteen isolates were grouped under 181 different spoligotype patterns. The most dominantly isolated spoligotype pattern was SIT149 and it consisted of 23 isolates. The majority of the isolates were grouped under Euro-American (EA), East-African-Indian (EAI), and Indo-Oceanic (IO) lineages. These lineages consisted of 79.4, 9.8, and 9.8% of the isolates, respectively. One hundred and sixty-five of the isolates were classified under 31 clustered spoligotypes whereas the remaining 150 were singleton types. Furthermore, 91.1% of the total isolates were classified as orphan types. Clustering of spoligotypes was associated (p < 0.001) with EAI lineage. Conclusion: SIT149 and EA lineage were predominantly isolated from the Oromia region substantiating the findings of the similar studies conducted in other regions of Ethiopia. The observation of significant number of singleton and orphan spoligotypes warrants for additional genetic typing of the isolates using method(s) with a better discriminatory power than spoligotyping.


Subject(s)
Mycobacterium tuberculosis , Tuberculosis, Pulmonary , Bacterial Typing Techniques , Cross-Sectional Studies , Ethiopia/epidemiology , Humans , Mycobacterium tuberculosis/classification , Tuberculosis, Pulmonary/epidemiology , Tuberculosis, Pulmonary/microbiology
15.
EBioMedicine ; 78: 103939, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1763702

ABSTRACT

Rapid, accurate, sputum-free tests for tuberculosis (TB) triage and confirmation are urgently needed to close the widening diagnostic gap. We summarise key technologies and review programmatic, systems, and resource issues that could affect the impact of diagnostics. Mid-to-early-stage technologies like artificial intelligence-based automated digital chest X-radiography and capillary blood point-of-care assays are particularly promising. Pitfalls in the diagnostic pipeline, included a lack of community-based tools. We outline how these technologies may complement one another within the context of the TB care cascade, help overturn current paradigms (eg, reducing syndromic triage reliance, permitting subclinical TB to be diagnosed), and expand options for extra-pulmonary TB. We review challenges such as the difficulty of detecting paucibacillary TB and the limitations of current reference standards, and discuss how researchers and developers can better design and evaluate assays to optimise programmatic uptake. Finally, we outline how leveraging the urgency and innovation applied to COVID-19 is critical to improving TB patients' diagnostic quality-of-care.


Subject(s)
COVID-19 , Mycobacterium tuberculosis , Tuberculosis , Antigens, Bacterial , Artificial Intelligence , COVID-19/diagnosis , Humans , Sputum , Tuberculosis/diagnosis
16.
Jpn J Infect Dis ; 75(2): 202-204, 2022 Mar 24.
Article in English | MEDLINE | ID: covidwho-1761197

ABSTRACT

Many studies have been conducted on ventilator-associated complications (VACs) in patients with coronavirus 2019 (COVID-19). However, in these studies, the causative organisms were similar, and there were no reports on VAC corresponding with Corynebacteria. Coryneforms are frequently cultured in cases of polymicrobial infections and are usually considered contaminants in respiratory specimens. However, Corynebacterium pseudodiphtheriticum or C. striatum is known to be a pathogen in lower respiratory tract infections. We report three cases of VAC, probably due to C. pseudodiphtheriticum, in patients with COVID-19. If purulent lower respiratory tract specimens showed coryneform predominantly upon Gram staining, empirical therapy should be started. Furthermore, species identification and drug susceptibility testing should be performed.


Subject(s)
COVID-19 , Coinfection , Corynebacterium Infections , Mycobacterium tuberculosis , Coinfection/complications , Corynebacterium , Corynebacterium Infections/complications , Corynebacterium Infections/diagnosis , Humans , Microbial Sensitivity Tests , Respiration, Artificial/adverse effects
17.
Int J Mol Sci ; 23(4)2022 Feb 17.
Article in English | MEDLINE | ID: covidwho-1760640

ABSTRACT

Tuberculosis is still an important medical and social problem. In recent years, great strides have been made in the fight against M. tuberculosis, especially in the Russian Federation. However, the emergence of a new coronavirus infection (COVID-19) has led to the long-term isolation of the population on the one hand and to the relevance of using personal protective equipment on the other. Our knowledge regarding SARS-CoV-2-induced inflammation and tissue destruction is rapidly expanding, while our understanding of the pathology of human pulmonary tuberculosis gained through more the 100 years of research is still limited. This paper reviews the main molecular and cellular differences and similarities caused by M. tuberculosis and SARS-CoV-2 infections, as well as their critical immunological and pathomorphological features. Immune suppression caused by the SARS-CoV-2 virus may result in certain difficulties in the diagnosis and treatment of tuberculosis. Furthermore, long-term lymphopenia, hyperinflammation, lung tissue injury and imbalance in CD4+ T cell subsets associated with COVID-19 could propagate M. tuberculosis infection and disease progression.


Subject(s)
COVID-19/etiology , Tuberculosis/diagnosis , Tuberculosis/etiology , COVID-19/immunology , Coinfection , Host-Pathogen Interactions , Humans , Inflammation/microbiology , Inflammation/pathology , Inflammation/virology , Lymphopenia/microbiology , Lymphopenia/virology , Mycobacterium tuberculosis/pathogenicity , SARS-CoV-2/pathogenicity
18.
Genes (Basel) ; 13(3)2022 03 08.
Article in English | MEDLINE | ID: covidwho-1760488

ABSTRACT

Kenya is a country with a high tuberculosis (TB) burden. However, knowledge on the genetic diversity of Mycobacterium tuberculosis complex (MTBC) strains and their transmission dynamics is sparsely available. Hence, we used whole-genome sequencing (WGS) to depict the genetic diversity, molecular markers of drug resistance, and possible transmission clusters among MTBC strains in urban and slum settings of Nairobi. We analyzed 385 clinical MTBC isolates collected between 2010 and 2015 in combination with patients' demographics. We showed that the MTBC population mainly comprises strains of four lineages (L1-L4). The two dominating lineages were L4 with 55.8% (n = 215) and L3 with 25.7% (n = 99) of all strains, respectively. Genome-based cluster analysis showed that 30.4% (117/385) of the strains were clustered using a ≤5 single-nucleotide polymorphism (SNP) threshold as a surrogate marker for direct patient-to-patient MTBC transmission. Moreover, 5.2% (20/385) of the strains were multidrug-resistant (MDR), and 50.0% (n = 10) were part of a genome-based cluster (i.e., direct MDR MTBC transmission). Notably, 30.0% (6/20) of the MDR strains were resistant to all first-line drugs and are part of one molecular cluster. Moreover, TB patients in urban living setting had 3.8 times the odds of being infected with a drug-resistant strain as compared to patients from slums (p-value = 0.002). Our results show that L4 strains are the main causative agent of TB in Nairobi and MDR strain transmission is an emerging concern in urban settings. This emphasizes the need for more focused infection control measures and contact tracing of patients with MDR TB to break the transmission chains.


Subject(s)
Mycobacterium tuberculosis , Tuberculosis , Antitubercular Agents/pharmacology , Antitubercular Agents/therapeutic use , Drug Resistance, Multiple, Bacterial/genetics , Humans , Kenya/epidemiology , Molecular Epidemiology , Mycobacterium tuberculosis/genetics , Poverty Areas , Tuberculosis/epidemiology , Tuberculosis/genetics
19.
PLoS Pathog ; 18(3): e1010093, 2022 03.
Article in English | MEDLINE | ID: covidwho-1759969

ABSTRACT

Mycobacterium tuberculosis (Mtb) and SARS-CoV-2 (CoV2) are the leading causes of death due to infectious disease. Although Mtb and CoV2 both cause serious and sometimes fatal respiratory infections, the effect of Mtb infection and its associated immune response on secondary infection with CoV2 is unknown. To address this question we applied two mouse models of COVID19, using mice which were chronically infected with Mtb. In both model systems, Mtb-infected mice were resistant to the pathological consequences of secondary CoV2 infection, and CoV2 infection did not affect Mtb burdens. Single cell RNA sequencing of coinfected and monoinfected lungs demonstrated the resistance of Mtb-infected mice is associated with expansion of T and B cell subsets upon viral challenge. Collectively, these data demonstrate that Mtb infection conditions the lung environment in a manner that is not conducive to CoV2 survival.


Subject(s)
COVID-19 , Coinfection , Mycobacterium tuberculosis , Acute Disease , Animals , Mice , Mice, Inbred C57BL , SARS-CoV-2
20.
ACS Infect Dis ; 8(3): 557-573, 2022 03 11.
Article in English | MEDLINE | ID: covidwho-1758137

ABSTRACT

Rising antimicrobial resistance challenges our ability to combat bacterial infections. The problem is acute for tuberculosis (TB), the leading cause of death from infection before COVID-19. Here, we developed a framework for multiple pharmaceutical companies to share proprietary information and compounds with multiple laboratories in the academic and government sectors for a broad examination of the ability of ß-lactams to kill Mycobacterium tuberculosis (Mtb). In the TB Drug Accelerator (TBDA), a consortium organized by the Bill & Melinda Gates Foundation, individual pharmaceutical companies collaborate with academic screening laboratories. We developed a higher order consortium within the TBDA in which four pharmaceutical companies (GlaxoSmithKline, Sanofi, MSD, and Lilly) collectively collaborated with screeners at Weill Cornell Medicine, the Infectious Disease Research Institute (IDRI), and the National Institute of Allergy and Infectious Diseases (NIAID), pharmacologists at Rutgers University, and medicinal chemists at the University of North Carolina to screen ∼8900 ß-lactams, predominantly cephalosporins, and characterize active compounds. In a striking contrast to historical expectation, 18% of ß-lactams screened were active against Mtb, many without a ß-lactamase inhibitor. One potent cephaloporin was active in Mtb-infected mice. The steps outlined here can serve as a blueprint for multiparty, intra- and intersector collaboration in the development of anti-infective agents.


Subject(s)
COVID-19 , Mycobacterium tuberculosis , Animals , Drug Industry , Mice , SARS-CoV-2 , Universities , beta-Lactams/pharmacology
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