-
Clinical Laboratory Jun 2024Non-tuberculous mycobacterial pulmonary infections (NTM-PD) are becoming increasingly common in clinical practice, and early detection and accurate determination of the...
BACKGROUND
Non-tuberculous mycobacterial pulmonary infections (NTM-PD) are becoming increasingly common in clinical practice, and early detection and accurate determination of the infecting pathogen is crucial for subsequent treatment. We report a case of NTM-PD in a healthy middle-aged female with Mycobacterium tuberculosis complex group (MAC) infection confirmed by mNGS examination.
METHODS
Appropriate laboratory tests, chest CT scan, bronchoscopic alveolar lavage fluid (BALF) examination, and macrogenomic next-generation sequencing (mNGS) were performed to establish the diagnosis.
RESULTS
Chest CT showed multiple inflammatory lesions in the right middle lobe, and BALF sent for mNGS finally confirmed the diagnosis of MAC infection. After symptomatic treatment with azithromycin combined with ethambutol and rifampicin, the patient improved and was discharged from the hospital.
CONCLUSIONS
In patients with pulmonary infections, pathogens should be clarified early to determine the diagnosis. mNGS of BALF samples have high specificity in detecting pathogens of infectious diseases, especially complex mixed infectious disease pathogens.
Topics: Humans; Female; Mycobacterium avium-intracellulare Infection; Mycobacterium avium Complex; Bronchoalveolar Lavage Fluid; Middle Aged; Tomography, X-Ray Computed; High-Throughput Nucleotide Sequencing; Pneumonia; Azithromycin; Rifampin
PubMed: 38868891
DOI: 10.7754/Clin.Lab.2024.240108 -
Scientific Reports Jun 2024Hyperglycemia is prevalent and closely associated with pulmonary tuberculosis (PTB). This study aimed to investigate the effects of hyperglycemia on the outcomes of PTB...
Hyperglycemia is prevalent and closely associated with pulmonary tuberculosis (PTB). This study aimed to investigate the effects of hyperglycemia on the outcomes of PTB treatment. This study comprised 791 patients with PTB in total. Patients with fasting plasma glucose levels of ≥ 6.1 mmol/L were diagnosed with hyperglycemia. Anthropometric and baseline demographic data were also collected. The treatment response was assessed based on clinical symptoms (sputum production, cough, chest pain, fever, hemoptysis, night sweats, loss of appetite, and fatigue), sputum smear, chest computed tomography (CT), and adverse gastrointestinal responses (vomiting, nausea, abdominal distension, diarrhea, and constipation). A generalized estimating equation (GEE) was used to evaluate these relationships. Hyperglycemia affected 266 (33.6%) of the 791 patients with PTB. In GEE analyses, patients with hyperglycemia exhibited a greater incidence of elevated tuberculosis (TB) scores (odds ratio (OR) 1.569; 95% CI 1.040-2.369), cough (OR 1.332; 95% CI 1.050-1.690), and night sweats (OR 1.694; 95% CI 1.288-2.335). Hyperglycemia was linked with a higher risk of positive sputum smears (OR 1.941; 95% CI 1.382-2.727). During therapy, hyperglycemia was also associated with an increased incidence of vomiting (OR 2.738; 95% CI 1.041-7.198), abdominal distension (OR 2.230; 95% CI 1.193-4.171), and constipation (OR 2.372; 95% CI 1.442-3.902). However, the CT results indicated that hyperglycemia did not affect pulmonary lesions in patients with TB. Patients with TB and hyperglycemia are at a higher risk of severe clinical manifestations, positive sputum smears, and adverse gastrointestinal effects and, therefore, the special situation of hyperglycemic patients should be considered in the prevention and treatment of TB.
Topics: Humans; Female; Male; Hyperglycemia; Middle Aged; Tuberculosis, Pulmonary; Treatment Outcome; Adult; Cohort Studies; Antitubercular Agents; Aged; Blood Glucose; Sputum
PubMed: 38866898
DOI: 10.1038/s41598-024-64525-3 -
The New England Journal of Medicine Jun 2024
Topics: Humans; Male; Antitubercular Agents; Mycobacterium tuberculosis; Skin; Tuberculosis, Cutaneous; Middle Aged; Biopsy; Isoniazid; Rifampin; Ethambutol; Hand Dermatoses; Veterinarians; Occupational Exposure
PubMed: 38865663
DOI: 10.1056/NEJMicm2313828 -
Microbiology Spectrum Jul 2024Since 1999, doxycycline and hydroxychloroquine have been the recommended treatment for chronic Q fever, a life-threatening disease caused by the bacterial pathogen, ....
UNLABELLED
Since 1999, doxycycline and hydroxychloroquine have been the recommended treatment for chronic Q fever, a life-threatening disease caused by the bacterial pathogen, . Despite the duration of its use, the treatment is not ideal due to the lengthy treatment time, high mortality rate, resistant strains, and the potential for contraindicated usage. A literature search was conducted to identify studies that screened large panels of drugs against to identify novel targets with potential efficacy against . Twelve candidate antimicrobials approved for use in humans by the US Food and Drug Administration were selected and minimum inhibitory concentrations (MICs) were determined against the low virulence strain Nine Mile phase II. Rifabutin and rifaximin were the best performing antibiotics tested with MICs of ≤0.01 µg mL. Further screening of these top candidates was conducted alongside two drugs from the same class, rifampin, well-characterized and rifapentine, not previously reported against . These were screened against virulent strains of representing three clinically relevant genotypes. Rifapentine was the most effective in the human monocytic leukemia cell line, THP-1, with a MIC ≤0.01 µg mL. In the human kidney epithelial cell line, A-498, efficacy of rifapentine, rifampin, and rifabutin varied across strains with MICs between ≤0.001 and 0.01 µg mL. Rifampin, rifabutin, and rifapentine were all bactericidal against ; however, rifabutin and rifapentine demonstrated impressive bactericidal activity as low as 0.1 µg mL and should be further explored as alternative Q fever treatments given their efficacy .
IMPORTANCE
This work will help inform investigators and physicians about potential alternative antimicrobial therapies targeting the causative agent of Q fever, . Chronic Q fever is difficult to treat, and alternative antimicrobials are needed. This manuscript explores the efficacy of rifamycin antibiotics against virulent strains of representing three clinically relevant genotypes . Importantly, this study determines the susceptibility of to rifapentine, which has not been previously reported. Evaluation of the bactericidal activity of the rifamycins reveals that rifabutin and rifapentine are bactericidal at low concentrations, which is unusual for antibiotics against .
Topics: Humans; Rifampin; Microbial Sensitivity Tests; Anti-Bacterial Agents; Coxiella burnetii; Rifamycins; Q Fever; Rifabutin; Cell Line
PubMed: 38864598
DOI: 10.1128/spectrum.01034-24 -
The Cochrane Database of Systematic... Jun 2024IgA nephropathy (IgAN) is the most common cause of primary glomerulonephritis. It is a heterogeneous disease with different presentations and high morbidity. Thirty per... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
IgA nephropathy (IgAN) is the most common cause of primary glomerulonephritis. It is a heterogeneous disease with different presentations and high morbidity. Thirty per cent of adults and 20% of children (followed into adulthood) will have a 50% decline in kidney function or develop kidney failure after 10 years.
OBJECTIVES
To determine the benefits and harms of immunosuppressive therapy for the treatment of IgAN in children.
SEARCH METHODS
We contacted the Information Specialist and searched the Cochrane Kidney and Transplant Register of Studies up to 03 October 2023 using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) and non-randomised studies of interventions (NRSIs) investigating the treatment of IgAN in children with immunosuppressive therapies compared to placebo, no treatment, supportive care, standard therapy (Japanese protocol), other immunosuppressive therapies or non-immunosuppressive therapies.
DATA COLLECTION AND ANALYSIS
Two authors independently extracted data and assessed the risk of bias. Random effects meta-analyses were used to summarise estimates of treatment effects. Treatment effects were expressed as risk ratios (RR) and 95% confidence intervals (CI) for dichotomous outcomes, and the mean difference (MD) and 95% CI for continuous outcomes. The risk of bias was assessed using the Cochrane risk of bias tool for RCTs and the ROBIN-I tool for NRSIs. The certainty of the evidence was assessed using Grading of Recommendations, Assessment, Development, and Evaluations (GRADE).
MAIN RESULTS
This review included 13 studies with 686 participants. Ten RCTs included 334 children and 191 adults, and three NRSIs included 151 participants, all children. Most participants had mild kidney disease. The risk of bias was unclear for most of the domains relating to allocation concealment, blinding of participants, personnel, and outcome assessment. In children with IgAN, it is uncertain if corticosteroid (steroid) therapy, compared to placebo reduces proteinuria (1 study, 64 children and young adults: RR 0.47, 95% CI 0.13 to 1.72; low certainty evidence) or the decline in estimated glomerular filtration rate (eGFR) (1 study, 64 children and young adults: RR 0.47, 95% CI 0.09 to 2.39; low certainty evidence). It is uncertain if steroids reduce proteinuria compared to supportive care (2 studies, 61 children: RR 0.04, 95% CI -0.83 to 0.72; low certainty evidence). Adverse events associated with steroid therapy were not assessed due to heterogeneity in steroid protocols, including dose and duration, and lack of systematic assessment for adverse events in the included studies. Azathioprine, mycophenolate mofetil, mizoribine, or cyclophosphamide alone or in combination with steroid therapy had uncertain effects on improving proteinuria or preventing eGFR decline in children with IgAN. Fish oil, vitamin E and tonsillectomy had uncertain effects on improving proteinuria or preventing eGFR decline. Effects of other immunosuppressive therapies, secondary outcomes and adverse events were not assessed due to insufficient data.
AUTHORS' CONCLUSIONS
There is a lack of high-quality evidence to guide the management of IgAN in children. There is no evidence to indicate that steroids, other immunosuppressive therapies, or tonsillectomy, when added to optimal supportive care, prevent a decline in eGFR or proteinuria in children with IgAN. Available studies were few, with small numbers, low-quality evidence, high or uncertain risk of bias, did not systematically assess harms associated with treatment, or report net benefits or harms. Severe cases and atypical presentations of IgAN were not included in the reviewed studies, and our findings cannot be generalised to these situations.
Topics: Adolescent; Child; Humans; Bias; Disease Progression; Glomerular Filtration Rate; Glomerulonephritis, IGA; Immunosuppressive Agents; Mycophenolic Acid; Placebos; Proteinuria; Randomized Controlled Trials as Topic; Young Adult
PubMed: 38864363
DOI: 10.1002/14651858.CD015060.pub2 -
BMC Infectious Diseases Jun 2024Tuberculosis (TB) remains a global public health event of great concern, however epidemic data on TB covering entire areas during the special period of the COVID-19...
BACKGROUND
Tuberculosis (TB) remains a global public health event of great concern, however epidemic data on TB covering entire areas during the special period of the COVID-19 epidemic have rarely been reported. We compared the dissemination and multidrug-resistance patterns of Mycobacterium tuberculosis complex (MTBC) in the main urban area of Luoyang City, China (including six municipal jurisdictions) and nine county and township areas under its jurisdiction, aimed to establish the epidemiology of TB in this region and to provide reference for precision anti-TB in places with similar settings.
METHODS
From 2020 to 2022, sputum samples were collected from 18,504 patients with confirmed, suspected and unexcluded TB in 10 designated TB medical institutions. Insertion sequence 6110 was amplified by PCR (rpoB gene detection if necessary) to confirm the presence of MTBC. PCR-positive specimens were analyzed by multicolor melting curve analysis to detect multidrug resistance.
RESULTS
Among the 18,504 specimens, 2675 (14.5%) were MTBC positive. The positive rate was higher in the main urban area than in the county and township areas (29.8% vs. 10.9%, p < 0.001). Male, re-treated and smear-positive groups were high-burden carriers of MTBC. Individuals aged > 60 years were the largest group infected with MTBC in the main urban area, compared with individuals aged < 61 years in the county and township areas. The detection of multidrug-resistant TB (MDR-TB) was higher in the main urban area than in the county and township areas (13.9% vs. 7.8%, p < 0.001). In all areas, MDR-TB groups were dominated by males, patients with a history of TB treatment, and patients aged < 61 years. Stratified analysis of MDR-TB epidemiology showed that MDR4 (INH þ RIF þ EMB þ SM) was predominant in the main urban area, while MDR3 (INH þ RIF þ SM) was predominant in the county and township areas. MDR-TB detection rate and epidemiology differed among the county and township areas.
CONCLUSIONS
For local TB control, it is necessary to plan more appropriate and accurate prevention and control strategies according to the regional distribution of MTBC infection.
Topics: Humans; Male; Middle Aged; Female; Mycobacterium tuberculosis; China; Adult; Tuberculosis, Multidrug-Resistant; COVID-19; Aged; Adolescent; Young Adult; Drug Resistance, Multiple, Bacterial; Antitubercular Agents; Child; Sputum; SARS-CoV-2; Child, Preschool; Aged, 80 and over; Infant; Epidemics
PubMed: 38862881
DOI: 10.1186/s12879-024-09395-w -
BMC Infectious Diseases Jun 2024Globally, multidrug-resistant tuberculosis (MDR-TB) is a major public health problem. The tuberculosis rate in Sierra Leone is 298 per 100,000 people, and Sierra Leone...
BACKGROUND
Globally, multidrug-resistant tuberculosis (MDR-TB) is a major public health problem. The tuberculosis rate in Sierra Leone is 298 per 100,000 people, and Sierra Leone is considered a country with a high burden of tuberculosis. In Sierra Leone, there are few studies on the outcomes of MDR-TB treatment, especially those exacerbated by COVID-19. We identified factors associated with unfavorable treatment outcomes among people with MDR-TB in Sierra Leone.
METHODS
We conducted a cross-sectional study to analyze hospital-based MDR-TB data from 2017 to 2021. Demographic, clinical, and treatment outcome data were extracted from the main MDR-TB referral hospital database. We defined unfavorable outcomes as patients who died, were lost to follow-up, or defaulted. We calculated adjusted odds ratios (aORs) and 95% confidence intervals (CIs) to identify predictors of the outcomes of MDR-TB treatment.
RESULTS
Between 2017 and 2021, 628 people with MDR-TB were reported at Lakka Hospital; 441 (71%) were male, with a median age of 25 years (interquartile ranges: 17-34). Clinically, 21% of the 628 MDR-TB patients were HIV positive, and 413 were underweight (66%). 70% (440) of MDR-TB patients received tuberculosis treatment. The majority of patients, 457 (73%), were treated with a short treatment regimen, and 126 (20%) experienced unfavorable outcomes. Age 45 years or younger (aOR = 5.08; CI:1.87-13.82), 21-45 years (aOR = 2.22; CI:140-3.54), tuberculosis retreatment (aOR = 3.23; CI:1.82-5.73), age group, HIV status (aOR = 2.16; CI:1.33-3.53), and malnourishment status (aOR = 1.79; CI:1.12-2.86) were significantly associated with unfavorable treatment outcomes for DR-TB patients.
CONCLUSION
This analysis revealed a high proportion of unfavorable treatment outcomes among MDR-TB patients in Sierra Leone. Malnourishment, TB retreatment, HIV coinfection, and age 45 years or younger were associated with unfavorable outcomes of MDR-TB treatment. Increasing patients' awareness, mainly among young people, heightens treatment adherence and HIV monitoring by measuring the amount of HIV in patient blood, which can reduce adverse treatment outcomes in Sierra Leone and other sub-Saharan African countries.
Topics: Humans; Sierra Leone; Tuberculosis, Multidrug-Resistant; Cross-Sectional Studies; Male; Female; Adult; Adolescent; Young Adult; Antitubercular Agents; Treatment Outcome; Middle Aged; COVID-19; Risk Factors; HIV Infections; SARS-CoV-2; Secondary Data Analysis
PubMed: 38862873
DOI: 10.1186/s12879-024-09370-5 -
Proceedings of the National Academy of... Jun 2024Tuberculosis (TB) is the world's deadliest infectious disease, with over 1.5 million deaths and 10 million new cases reported anually. The causative organism (Mtb) can...
Tuberculosis (TB) is the world's deadliest infectious disease, with over 1.5 million deaths and 10 million new cases reported anually. The causative organism (Mtb) can take nearly 40 d to culture, a required step to determine the pathogen's antibiotic susceptibility. Both rapid identification and rapid antibiotic susceptibility testing of Mtb are essential for effective patient treatment and combating antimicrobial resistance. Here, we demonstrate a rapid, culture-free, and antibiotic incubation-free drug susceptibility test for TB using Raman spectroscopy and machine learning. We collect few-to-single-cell Raman spectra from over 25,000 cells of the Mtb complex strain Bacillus Calmette-Guérin (BCG) resistant to one of the four mainstay anti-TB drugs, isoniazid, rifampicin, moxifloxacin, and amikacin, as well as a pan-susceptible wildtype strain. By training a neural network on this data, we classify the antibiotic resistance profile of each strain, both on dried samples and on patient sputum samples. On dried samples, we achieve >98% resistant versus susceptible classification accuracy across all five BCG strains. In patient sputum samples, we achieve ~79% average classification accuracy. We develop a feature recognition algorithm in order to verify that our machine learning model is using biologically relevant spectral features to assess the resistance profiles of our mycobacterial strains. Finally, we demonstrate how this approach can be deployed in resource-limited settings by developing a low-cost, portable Raman microscope that costs <$5,000. We show how this instrument and our machine learning model enable combined microscopy and spectroscopy for accurate few-to-single-cell drug susceptibility testing of BCG.
Topics: Spectrum Analysis, Raman; Machine Learning; Mycobacterium tuberculosis; Humans; Microbial Sensitivity Tests; Antitubercular Agents; Drug Resistance, Bacterial; Tuberculosis, Multidrug-Resistant; Tuberculosis; Isoniazid
PubMed: 38861604
DOI: 10.1073/pnas.2315670121 -
PloS One 2024Whole Genome Sequencing (WGS) is a promising tool in the global fight against tuberculosis (TB). The aim of this study was to evaluate the use of WGS in routine...
Whole Genome Sequencing (WGS) is a promising tool in the global fight against tuberculosis (TB). The aim of this study was to evaluate the use of WGS in routine conditions for detection of drug resistance markers and transmission clusters in a multidrug-resistant TB hot-spot area in Peru. For this, 140 drug-resistant Mycobacterium tuberculosis strains from Lima and Callao were prospectively selected and processed through routine (GenoType MTBDRsl and BACTEC MGIT) and WGS workflows, simultaneously. Resistance was determined in accordance with the World Health Organization mutation catalogue. Agreements between WGS and BACTEC results were calculated for rifampicin, isoniazid, pyrazinamide, moxifloxacin, levofloxacin, amikacin and capreomycin. Transmission clusters were determined using different cut-off values of Single Nucleotide Polymorphism differences. 100% (140/140) of strains had valid WGS results for 13 anti-TB drugs. However, the availability of final, definitive phenotypic BACTEC MGIT results varied by drug with 10-17% of invalid results for the seven compared drugs. The median time to obtain results of WGS for the complete set of drugs was 11.5 days, compared to 28.6-52.6 days for the routine workflow. Overall categorical agreement by WGS and BACTEC MGIT for the compared drugs was 96.5%. Kappa index was good (0.65≤k≤1.00), except for moxifloxacin, but the sensitivity and specificity values were high for all cases. 97.9% (137/140) of strains were characterized with only one sublineage (134 belonging to "lineage 4" and 3 to "lineage 2"), and 2.1% (3/140) were mixed strains presenting two different sublineages. Clustering rates of 3.6% (5/140), 17.9% (25/140) and 22.1% (31/140) were obtained for 5, 10 and 12 SNP cut-off values, respectively. In conclusion, routine WGS has a high diagnostic accuracy to detect resistance against key current anti-TB drugs, allowing results to be obtained through a single analysis and helping to cut quickly the chain of transmission of drug-resistant TB in Peru.
Topics: Mycobacterium tuberculosis; Peru; Tuberculosis, Multidrug-Resistant; Whole Genome Sequencing; Humans; Antitubercular Agents; Polymorphism, Single Nucleotide; Drug Resistance, Multiple, Bacterial; Microbial Sensitivity Tests; Genome, Bacterial; Male; Female
PubMed: 38861531
DOI: 10.1371/journal.pone.0304130 -
Current Drug Targets Jun 2024The increasing demand for novel antitubercular agents has been the main 'force' of many TB research efforts due to the uncontrolled growing number of drug-resistant...
The increasing demand for novel antitubercular agents has been the main 'force' of many TB research efforts due to the uncontrolled growing number of drug-resistant strains of M. tuberculosis in the clinical setting. Many strategies have been employed to address the drug-resistant issue, including a trend that is gaining attention, which is the design and discovery of Mtb inhibitors that are either dual- or multitargeting. The multiple-target design concept is not new in medicinal chemistry. With a growing number of newly discovered Mtb proteins, numerous targets are now available for developing new biochemical/cell-based assays and computer-aided drug design (CADD) protocols. To describe the achievements and overarching picture of this field in anti- infective drug discovery, we provide in this review small molecules that exhibit profound inhibitory activity against the tubercle bacilli and are identified to trace two or more Mtb targets. This review also presents emerging design methodologies for developing new anti-TB agents, particularly tailored to structure-based CADD. Dedicated on the special occasion of the 70th birthday of Prof. Dr. Ma. Alicia Aguinaldo, whose scientific efforts elevated antituberculosis drug discovery in the Philippines.
PubMed: 38859782
DOI: 10.2174/0113894501306302240526160804