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The Lancet. Global Health Jun 2024Post-exposure prophylaxis (PEP) using single-dose rifampicin reduces progression from infection with Mycobacterium leprae to leprosy disease. We compared effectiveness... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Post-exposure prophylaxis (PEP) using single-dose rifampicin reduces progression from infection with Mycobacterium leprae to leprosy disease. We compared effectiveness of different administration modalities, using a higher (20 mg/kg) dose of rifampicin-single double-dose rifampicin (SDDR)-PEP.
METHODS
We did a cluster randomised study in 16 villages in Madagascar and 48 villages in Comoros. Villages were randomly assigned to four study arms and inhabitants were screened once a year for leprosy, for 4 consecutive years. All permanent residents (no age restriction) were eligible to participate and all identified patients with leprosy were treated with multidrug therapy (SDDR-PEP was provided to asymptomatic contacts aged ≥2 years). Arm 1 was the comparator arm, in which no PEP was provided. In arm 2, SDDR-PEP was provided to household contacts of patients with leprosy, whereas arm 3 extended SDDR-PEP to anyone living within 100 m. In arm 4, SDDR-PEP was offered to household contacts and to anyone living within 100 m and testing positive to anti-phenolic glycolipid-I. The main outcome was the incidence rate ratio (IRR) of leprosy between the comparator arm and each of the intervention arms. We also assessed the individual protective effect of SDDR-PEP and explored spatial associations. This trial is registered with ClinicalTrials.gov, NCT03662022, and is completed.
FINDINGS
Between Jan 11, 2019, and Jan 16, 2023, we enrolled 109 436 individuals, of whom 95 762 had evaluable follow-up data. Our primary analysis showed a non-significant reduction in leprosy incidence in arm 2 (IRR 0·95), arm 3 (IRR 0·80), and arm 4 (IRR 0·58). After controlling for baseline prevalence, the reduction in arm 3 became stronger and significant (IRR 0·56, p=0·0030). At an individual level SDDR-PEP was also protective with an IRR of 0·55 (p=0·0050). Risk of leprosy was two to four times higher for those living within 75 m of an index patient at baseline.
INTERPRETATION
SDDR-PEP appears to protect against leprosy but less than anticipated. Strong spatial associations were observed within 75 m of index patients. Targeted door-to-door screening around index patients complemented by a blanket SDDR-PEP approach will probably have a substantial effect on transmission.
FUNDING
European and Developing Countries Clinical Trials Partnership.
TRANSLATION
For the French translation of the abstract see Supplementary Materials section.
Topics: Humans; Leprosy; Male; Female; Adult; Rifampin; Leprostatic Agents; Post-Exposure Prophylaxis; Middle Aged; Adolescent; Young Adult; Madagascar; Child; Cluster Analysis; Incidence; Mycobacterium leprae
PubMed: 38762282
DOI: 10.1016/S2214-109X(24)00062-7 -
Mirvetuximab soravtansine: A breakthrough in targeted therapy for platinum-resistant ovarian cancer.Medicine May 2024Ovarian cancer, ranked as the second leading cause of gynecologic malignancy-related deaths globally, poses a formidable challenge despite advances in early detection... (Review)
Review
Ovarian cancer, ranked as the second leading cause of gynecologic malignancy-related deaths globally, poses a formidable challenge despite advances in early detection and treatment modalities. This paper explores the efficacy and safety of mirvetuximab soravtansine, the first folate receptor alpha (FRα)-targeting antibody-drug conjugate, in platinum-resistant ovarian cancer expressing FRα. A review of 4 key studies involving 453 participants consistently demonstrates mirvetuximab soravtansine's clinically meaningful antitumor activity and favorable safety profile. Clinical implications emphasize mirvetuximab soravtansine's pivotal role in targeted therapy, especially for high FRα-expressing tumors, potentially reshaping platinum-resistant ovarian cancer management. The combination therapy approach introduces a novel dimension, suggesting enhanced therapeutic outcomes. Even in heavily pretreated patients, mirvetuximab soravtansine's favorable tolerability positions it as a viable option. The reliability of archival tissue for FRα assessment simplifies patient selection, streamlining accessibility to targeted therapies. However, identified gaps, including limited diversity in patient populations, sparse quality of life data, and the need for long-term safety information, indicate areas for future research. Exploration of additional biomarkers predicting mirvetuximab soravtansine responsiveness is essential for personalized treatment.
Topics: Humans; Female; Ovarian Neoplasms; Maytansine; Antibodies, Monoclonal, Humanized; Drug Resistance, Neoplasm; Immunoconjugates; Folate Receptor 1; Antineoplastic Agents
PubMed: 38758856
DOI: 10.1097/MD.0000000000038132 -
PloS One 2024The emergence of drug-resistant tuberculosis (DR-TB) has been a major obstacle to global tuberculosis control programs, especially in developing countries, including...
Genotypic and phenotypic drug resistance patterns of Mycobacterium tuberculosis isolated from presumptive pulmonary tuberculosis patients in Ethiopia: A multicenter study.
BACKGROUND
The emergence of drug-resistant tuberculosis (DR-TB) has been a major obstacle to global tuberculosis control programs, especially in developing countries, including Ethiopia. This study investigated drug resistance patterns and associated mutations of Mycobacterium tuberculosis Complex (MTBC) isolates from the Amhara, Gambella, and Benishangul-Gumuz regions of Ethiopia.
METHODS
A cross-sectional study was conducted using 128 MTBC isolates obtained from patients with presumptive tuberculosis (TB). Phenotypic (BACTEC MGIT 960) and genotypic (MTBDRplus and MTBDRsl assays) methods were used for drug susceptibility testing. Data were entered into Epi-info and analyzed using SPSS version 25. Frequencies and proportions were determined to describe drug resistance levels and associated mutations.
RESULTS
Of the 127 isolates recovered, 100 (78.7%) were susceptible to four first-line anti-TB drugs. Any drug resistance, polydrug resistance, and multi-drug resistance (MDR) were detected in 21.3% (27), 15.7% (20), and 15% (19) of the isolates, respectively, by phenotypic and/or genotypic methods. Mono-resistance was observed for Isoniazid (INH) (2, 1.6%) and Streptomycin (STR) (2, 1.6%). There were two genotypically discordant RIF-resistant cases and one INH-resistant case. One case of pre-extensively drug-resistant TB (pre-XDR-TB) and one case of extensively drug-resistant TB (XDR-TB) were identified. The most frequent gene mutations associated with INH and rifampicin (RIF) resistance were observed in the katG MUT1 (S315T1) (20, 76.9%) and rpoB (S531L) (10, 52.6%) genes, respectively. Two MDR-TB isolates were resistant to second-line drugs; one had a mutation in the gyrA MUT1 gene, and the other had missing gyrA WT1, gyrA WT3, and rrs WT1 genes without any mutation.
CONCLUSIONS
The detection of a significant proportion of DR-TB cases in this study suggests that DR-TB is a major public health problem in Ethiopia. Thus, we recommend the early detection and treatment of DR-TB and universal full first-line drug-susceptibility testing in routine system.
Topics: Humans; Ethiopia; Mycobacterium tuberculosis; Tuberculosis, Pulmonary; Antitubercular Agents; Male; Female; Adult; Genotype; Cross-Sectional Studies; Tuberculosis, Multidrug-Resistant; Microbial Sensitivity Tests; Middle Aged; Phenotype; Mutation; Young Adult; Adolescent; Drug Resistance, Multiple, Bacterial; Isoniazid; Rifampin; Bacterial Proteins
PubMed: 38753615
DOI: 10.1371/journal.pone.0303460 -
International Journal of Antimicrobial... Jul 2024Pharmacokinetic data of rifampin, when used for tuberculosis preventive treatment (TPT) are not available. We aimed to describe the pharmacokinetics of rifampin used for... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Pharmacokinetic data of rifampin, when used for tuberculosis preventive treatment (TPT) are not available. We aimed to describe the pharmacokinetics of rifampin used for TPT, at standard and higher doses, and to assess predictors of rifampin exposure.
METHODS
A pharmacokinetic sub-study was performed in Bandung, Indonesia among participants in the 2R randomized trial, which compared TPT regimens of 2 months of high-dose rifampin at 20 mg/kg/day (2R) and 30 mg/kg/day (2R), with 4 months of standard-dose rifampin at 10 mg/kg/day (4R) in adolescents and adults. Intensive pharmacokinetic sampling was performed after 2-8 weeks of treatment. Pharmacokinetic parameters were assessed non-compartmentally. Total exposure (AUC) and peak concentration (C) between arms were compared using one-way ANOVA and Tukey's post-hoc tests. Multivariable linear regression analyses were used to assess predictors of AUC and C.
RESULTS
We enrolled 51 participants in this study. In the 4R, 2R and 2R arms, the geometric mean AUC was 68.0, 186.8, and 289.9 h⋅mg/L, and C was 18.4, 36.7, and 54.4 mg/L, respectively; high interindividual variabilities were observed. Compared with the 4R arm, AUC and C were significantly higher in the 2R and 2R arms (P < 0.001). Drug doses, body weight, and female sex were predictors of higher rifampin AUC and C (P < 0.05). AUC and C values were much higher than those previously reported in persons with TB disease.
CONCLUSIONS
Doubling and tripling the rifampin dose led to three- and four-fold higher exposure compared to standard dose. Pharmacokinetic/pharmacodynamic modelling and simulations are warranted to support trials of shortening the duration of TPT regimens with high-dose rifampin.
Topics: Humans; Rifampin; Female; Male; Adult; Adolescent; Young Adult; Tuberculosis; Indonesia; Antitubercular Agents; Middle Aged; Area Under Curve; Chemoprevention
PubMed: 38750674
DOI: 10.1016/j.ijantimicag.2024.107197 -
Life Science Alliance Jul 2024Developing effective tuberculosis drugs is hindered by mycobacteria's intrinsic antibiotic resistance because of their impermeable cell envelope. Using benzothiazole...
Developing effective tuberculosis drugs is hindered by mycobacteria's intrinsic antibiotic resistance because of their impermeable cell envelope. Using benzothiazole compounds, we aimed to increase mycobacterial cell envelope permeability and weaken the defenses of , serving as a model for Initial hit, BT-08, significantly boosted ethidium bromide uptake, indicating enhanced membrane permeability. It also demonstrated efficacy in the -zebrafish embryo infection model and -infected macrophages. Notably, BT-08 synergized with established antibiotics, including vancomycin and rifampicin. Subsequent medicinal chemistry optimization led to BT-37, a non-toxic and more potent derivative, also enhancing ethidium bromide uptake and maintaining synergy with rifampicin in infected zebrafish embryos. Mutants of resistant to BT-37 revealed that MMAR_0407 (Rv0164) is the molecular target and that this target plays a role in the observed synergy and permeability. This study introduces novel compounds targeting a new mycobacterial vulnerability and highlights their cooperative and synergistic interactions with existing antibiotics.
Topics: Animals; Zebrafish; Benzothiazoles; Drug Synergism; Mycobacterium marinum; Antitubercular Agents; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Humans; Anti-Bacterial Agents; Cell Membrane Permeability; Macrophages; Mycobacterium Infections, Nontuberculous; Cell Membrane; Rifampin
PubMed: 38744470
DOI: 10.26508/lsa.202302509 -
International Journal of Infectious... Aug 2024Monitoring tools that could provide quick predictions of tuberculosis (TB) treatment outcomes are urgently needed. Here, we assessed whether the evolution of selected...
OBJECTIVES
Monitoring tools that could provide quick predictions of tuberculosis (TB) treatment outcomes are urgently needed. Here, we assessed whether the evolution of selected biomarkers of innate immunity may help monitoring TB treatment response within 2 weeks of treatment initiation.
METHODS
ANRS12394-LILAC-TB was a proof-of-concept prospective study: adults with a rifampicin-susceptible TB who are HIV-negative and HIV-infected documented by a positive Xpert MTB/RIF test were enrolled in Cambodia and Côte d'Ivoire. Plasma concentrations of interleukin-1 receptor antagonist (IL-1Ra), interferon-γ-induced protein-10 and clusters of differentiation (CD) (scavenging CD163) were measured by commercial enzyme-linked immunosorbent assay kits. A Wilcoxon test for paired data was used for longitudinal comparisons.
RESULTS
A total of 55 patients were enrolled (women: 31%, median age: 37 years; median CD4 count in the 10 of 13 participants with HIV: 53 cells/mm). Overall, 83% were considered in TB treatment success. Compared with baseline, the IL-1Ra plasma levels significantly decreased as soon as week (W) 1, independent of HIV status (-71% in HIV-positive vs -33% in HIV-negative; P <0.001). The IP-10 plasma levels significantly decreased at W1 and W2 compared with baseline (P <0.0001); however, that decrease was less marked in participants with HIV.
CONCLUSIONS
Our findings suggest that measuring IL-1Ra plasma levels with a standard enzyme-linked immunosorbent assay technique at baseline and then 1 week after TB treatment onset could help clinicians to quickly assess TB treatment response.
Topics: Humans; Female; Adult; Male; Interleukin 1 Receptor Antagonist Protein; Chemokine CXCL10; Tuberculosis; HIV Infections; Prospective Studies; Biomarkers; Middle Aged; Antitubercular Agents; Treatment Outcome; Rifampin; Cote d'Ivoire; Immunity, Innate
PubMed: 38740279
DOI: 10.1016/j.ijid.2024.107096 -
Microbiology Spectrum Jun 2024This study aimed to assess the possible causes of discordant results between Xpert MTB/RIF (Xpert) and Bactec MGIT 960 Culture System (MGIT960) regarding rifampicin...
This study aimed to assess the possible causes of discordant results between Xpert MTB/RIF (Xpert) and Bactec MGIT 960 Culture System (MGIT960) regarding rifampicin (RIF) susceptibility in . Patients with previous RIF-resistant tuberculosis who were admitted to Wenzhou Central Hospital from January 2020 to December 2022 were enrolled. The isolates obtained from these patients were subjected to RIF susceptibility tests using Xpert and MGIT960, and the minimum inhibitory concentration (MIC) of RIF was determined by the MYCOTB MIC plate test. Additionally, molecular docking and molecular dynamics (MD) simulations were performed to evaluate the binding efficacy of rpoB and RIF based on rpoB mutations detected in the isolates with discordant RIF susceptibility results. A total of 28 isolates with discordant RIF susceptibility test results were detected, 15 of them were RIF susceptible with MICs ≤ 0.5 µg/mL. Twelve out of 15 isolates contained borderline RIF resistance-associated mutations [L430P ( = 6), H445N ( = 6)], 1 isolate had D435Y and Q429H double mutation, and the remaining 2 isolates had a silent (Q432Q) mutation. Compared with the affinity of RIF toward the wild type (WT) (-45.83 kcal/mol) by MD, its affinity toward L452P (-55.52 kcal/mol), D435Y (-47.39 kcal/mol), L430P (approximately -69.72 kcal/mol), H445N (-49.53 kcal/mol), and Q429H (-55.67 kcal/mol) increased. Borderline RIF resistance-associated mutations were the main cause for the discordant RIF susceptibility results between Xpert and MGIT960, and the mechanisms of the resistance need further investigated.IMPORTANCEThis study is aimed at assessing discordant results between Xpert MTB/RIF (Xpert) assay and Bactec MGIT 960 Culture System (MGIT960) regarding the detection of rifampicin (RIF)-resistant isolates in Wenzhou, China. The discordant results of RIF between these two assays were mainly caused by borderline RIF resistance-associated mutations, subsequently by silent mutations of rpoB. Borderline RIF resistance- associated mutations detected in our study were demonstrated to not be affected by the affinity of rpoB and RIF by molecular dynamics, and the mechanism of resistance was needed to be clarified. For the discordant results of RIF by Xpert and MGIT960 that occurred, DNA sequencing was recommended to investigate its association with resistance to RIF.
Topics: Mycobacterium tuberculosis; Rifampin; Microbial Sensitivity Tests; Humans; China; Bacterial Proteins; Mutation; Tuberculosis, Multidrug-Resistant; Antitubercular Agents; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Molecular Docking Simulation
PubMed: 38738892
DOI: 10.1128/spectrum.03859-23 -
Clinical Breast Cancer Jul 2024Trastuzumab emtansine (T-DM1), sacituzumab govitecan (SG), and trastuzumab deruxtecan (T-DXd) are three ADCs approved for the treatment of metastatic breast cancer... (Review)
Review
Trastuzumab emtansine (T-DM1), sacituzumab govitecan (SG), and trastuzumab deruxtecan (T-DXd) are three ADCs approved for the treatment of metastatic breast cancer (MBC). Since gastrointestinal toxicities have been commonly observed with these drugs in clinical trials, a pooled analysis evaluating gastrointestinal adverse events (AEs) in patients with MBC treated with ADCs in clinical trials was performed. PubMed, Embase, and the Cochrane Library were searched from inception until May 2023 for phase II and III clinical trials reporting frequency and severity of gastrointestinal AEs during treatment with ADCs. Data were retrieved for nausea, vomiting, diarrhea, constipation, and abdominal pain: overall and grade 3-4 toxicity rates according to NCI-CTCAE were collected and expressed as proportions. A pre-specified subgroup analysis according to the agent was also carried out. Fourteen studies, comprising 5608 patients, were included in the analysis. Gastrointestinal AEs were frequently registered with SG and T-DXd. A significantly higher frequency of nausea (65.6% with SG, 75% with T-DXd), vomiting (43.7% with SG, 45% with T-DXd), and diarrhea (59.7% with SG, 29% with T-DXd) was noticed with these ADCs compared to TDM-1. Furthermore, diarrhea was more frequently associated with SG (grade 3 in 7.5% of patients), while constipation and abdominal pain were less common. Gastrointestinal AEs, notably nausea and diarrhea, were frequently reported by MBC patients treated with SG and T-DXd in clinical trials. Since these ADCs are administered continuously until disease progression or occurrence of unbearable AEs, gastrointestinal toxicity may have a negative impact on patient quality of life. Therefore, appropriate management of gastrointestinal AEs is mandatory to ensure treatment efficacy and adherence.
Topics: Humans; Female; Breast Neoplasms; Immunoconjugates; Gastrointestinal Diseases; Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Trastuzumab; Camptothecin; Nausea; Neoplasm Metastasis; Antineoplastic Agents, Immunological
PubMed: 38734491
DOI: 10.1016/j.clbc.2024.04.003 -
Journal of Infection in Developing... Apr 2024Mycobacterium marinum infection rarely occurs and has atypical symptoms. It is challenging to distinguish disseminated M. marinum infection from multifocal dermatosis...
INTRODUCTION
Mycobacterium marinum infection rarely occurs and has atypical symptoms. It is challenging to distinguish disseminated M. marinum infection from multifocal dermatosis caused by other factors clinically.
CASE PRESENTATION
Herein, we reported a 68-year-old male patient with Human Immunodeficiency Virus (HIV) who presented redness and swelling in his left hand after being stabbed by marine fish for over 2 months. Mycobacterium tuberculosis infection was considered according to biochemical and pathological examinations, while empirical anti-infection treatment was ineffective.
RESULTS
The metagenomic next-generation sequencing (mNGS) detected a large amount of M. marinum sequences, and the patient was finally diagnosed with M. marinum infection. After one month of combination therapy with ethambutol, rifabutin, moxifloxacin, and linezolid, the swelling disappeared significantly. In this case, the successful application of mNGS in diagnosing and treating M. marinum infection has improved the understanding of the microbe both in the laboratory and clinically, especially in patients with HIV.
CONCLUSIONS
For diseases with atypical symptoms or difficulty in determining the pathogens, mNGS is suggested in clinical procedures for rapid and accurate diagnosis and treatment.
Topics: Humans; Male; Mycobacterium Infections, Nontuberculous; Aged; Mycobacterium marinum; HIV Infections; High-Throughput Nucleotide Sequencing; Metagenomics; Ethambutol; Anti-Bacterial Agents
PubMed: 38728638
DOI: 10.3855/jidc.18114 -
Hepatology Communications Jun 2024The aim was to examine rifaximin plus lactulose efficacy in patients with cirrhosis at a risk of developing overt HE who were stratified by important baseline... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The aim was to examine rifaximin plus lactulose efficacy in patients with cirrhosis at a risk of developing overt HE who were stratified by important baseline characteristics such as comorbid ascites or diabetes.
METHODS
Pooled post hoc subgroup analysis of adults receiving rifaximin 550 mg twice daily plus lactulose or lactulose alone for 6 months in a phase 3 randomized, double-blind trial and a phase 4 open-label trial was conducted.
RESULTS AND CONCLUSION
Rifaximin plus lactulose was more efficacious than lactulose alone for reducing the risk of overt HE recurrence and HE-related hospitalization in adults grouped by select baseline disease characteristics.
Topics: Humans; Rifaximin; Lactulose; Male; Middle Aged; Double-Blind Method; Female; Gastrointestinal Agents; Drug Therapy, Combination; Recurrence; Hepatic Encephalopathy; Liver Cirrhosis; Adult; Secondary Prevention; Aged; Treatment Outcome
PubMed: 38727685
DOI: 10.1097/HC9.0000000000000436