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Drug biotransformation studies emerges as an alternative to pharmacological investigations of metabolites, development of new drug candidates with reduced investment and most efficient production. The present study aims to evaluate the capacity of biotransformation of rifampicin by the filamentous fungus Aspergillus niger ATCC 9029. After incubation for 312 h, the drug was metabolized to two molecules: an isomer (m/z 455) and the rifampicin quinone (m/z 821). The monitoring of metabolite formation was performed by high-performance liquid chromatography, followed by their identification through ultra-high-performance liquid chromatography coupled to tandem mass spectrometer. In vitro antimicrobial activity of the proposed metabolites was evaluated against Staphylococus aureus microorganism, resulting in the loss of inhibitory activity when compared with the standards, with minimum inhibitory concentration of 7.5 µg/ml. The significant biotransformation power of the ATCC 9029 strain of A. niger was confirmed in this study, making this strain a candidate for pilot studies in fermentation tanks for the enzymatic metabolization of the antimicrobial rifampicin. The unprecedented result allows us to conclude that the prospect of new biotransforming strains in species of anemophilic fungi is a promising choice.

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Brucellosis is an infection widely distributed around the world, and in some countries it is considered a public health problem. Brucellosis causes insidious symptoms that make it difficult to diagnose. Infection can also trigger chronic pain and neuropsychiatric complications. Antibiotics are not always effective to eradicate infection, contributing to chronicity. We aimed to investigate the effects of antibiotic treatment on proinflammatory cytokines, neurotransmitters, corticosterone, and behavior in a murine model of infecrion of B. abortus strain 2308. Four study groups were created: (a) control; (b) antibiotic control; (c) infected with B. abortus 2308; and (d) infected and treated with rifampicin and doxycycline. We determined B. abortus 2308 colony-forming units (CFUs), the count of dendritic cells, and macrophages in the spleen; serum levels of cytokines and corticosterone; levels of serotonin, dopamine, epinephrine, and norepinephrine in the brain; and equilibrium, physical strength, anxiety, and hopelessness tests. The infected and treated mice group was compared with the control and infected mice to assess whether treatment is sufficient to recover neuroimmunoendocrine parameters. Our results showed that despite the treatment of brucellosis with rifampicin and doxycycline, antibiotic-treated mice showed a persistence of B. abortus 2308 CFUs, an increased count in macrophage number, and higher circulating levels of corticosterone. Furthermore, the levels of IL-12, IL-6, and TNF-α remained higher. We found a decrease in muscular strength and equilibrium concomitant to changes in neurotransmitters in the hippocampus, cerebellum, and frontal cortex. Our data suggest that the remaining bacterial load after antibiotic administration favors inflammatory, neurochemical, and behavioral alterations, partly explaining the widespread and paradoxical symptomatology experienced by patients with chronic brucellosis.

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BACKGROUND: To achieve zero leprosy cases in Santa Cruz, Bolivia, we designed a community-based active detection and provision of single-dose rifampicin post-exposure prophylaxis (SDR-PEP) to household contacts with new leprosy patients. METHODS: From July to August 2021, we assessed the current knowledge, attitude, and practices through structured interviews and focus group discussions with community representatives and health staff. This was followed by sensitization sessions, the training of health staff, and the reinforcement of referral mechanisms. Teams, including health staff and community volunteers, visited all new leprosy patients detected in 2021-2023 and household contacts. RESULTS: Among 115 community representatives, knowledge about leprosy etiology was attributed to non-biological factors (74%); fear accounted for 77%, and access to care was perceived as weak (74%), but the outlook was improved by SDR-PEP (80%). Among the 217 health staff interviewed, the programmatic barriers identified were a lack of referral feedback (67%), limited supplies for diagnosis and prevention, and ineffective training (64%). We visited 70 new patients and 258 household contacts. The median age in household contacts was 25 years old; 49% were women, 98% were eligible for SDR-PEP, and all who were eligible accepted it. Those who were non-eligible included one tuberculosis patient and six newly detected leprosy patients (23‱). CONCLUSIONS: A community-based intervention was successful in Santa Cruz, Bolivia. Misbeliefs and a lack of knowledge were identified as barriers. Programmatic components should be reinforced for SDR-PEP extension.

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Introducción. La tuberculosis es una de las enfermedades infecciosas más antiguas y comunes, causada por una bacteria en forma de bastón, o bacilo, llamada Mycobacterium tuberculosis. Esta enfermedad es tratable con antibióticos, los cuales se prescriben durante meses debido a la lenta tasa de crecimiento de las bacterias. Entre los fármacos utilizados la Rifampicina se utiliza terapéuticamente para combatir esta enfermedad, sin embargo, algunos pacientes pueden presentar o desarrollar resistencia a este antibiótico, por lo que, es importante completar el tratamiento para evitar el desarrollo de bacterias farmacorresistentes y la re ocurrencia de la enfermedad. Objetivo. Caracterizar el Mycobacterium tuberculosis resistente a Rifampicina en la provincia de El Oro. Materiales y métodos. Se realizó un estudio con un enfoque cuantitativo, de tipo descriptivo y no experimental. La muestra se obtuvo de la base de datos del laboratorio clínico del área de micobacterias del Hospital Teófilo Dávila en el período 2019 - 2022, quienes luego de aplicar la prueba molecular rápida GeneXpert MTB/RIF o ULTRA determinaron que 48 pacientes presentaron resistencia a la Rifampicina en el tratamiento de la Mycobacterium tuberculosis. Resultados. El reporte del laboratorio evidenció que en el año 2022 se estableció el mayor número de casos de resistencia a Rifampicina para el tratamiento de Mycobacterium tuberculosis, alcanzando el 33,3%; el grupo etario de mayor afectación fue el adulto joven (20 a 49 años) con un 52,1%, y con una frecuencia elevada de 66,7% el sexo masculino. La comorbilidad con mayor predominio estuvo en los pacientes diagnosticados Diabetes Mellitus tipo 2 con un 27,1% y la condición de ingreso de pacientes con resistencia a Rifampicina, son de nuevos casos con 75%. Conclusiones. En la provincia de El Oro, entre el año 2019 - 2022 se presentaron 48 casos resistentes al antibiótico Rifampicina en el tratamiento de la TB, entre ellos el 75% corresponden a una resistencia inicial, es decir, pacientes que no fueron tratados contra la enfermedad, el otro 25% engloba a aquellos pacientes que recayeron en la enfermedad, fracaso o perdida de seguimiento por parte del laboratorio de vigilancia, área de micobacterias del Hospital Teófilo Dávila.

Introduction. Tuberculosis is one of the oldest and most common infectious diseases, caused by a rod-shaped bacterium, or bacillus, called Mycobacterium tuberculosis. This disease is treatable with antibiotics, which are prescribed for months due to the slow growth rate of the bacteria. Among the drugs used, Rifampicin is used therapeutically to combat this disease, however, some patients may present or develop resistance to this antibiotic, therefore, it is important to complete the treatment to avoid the development of drug-resistant bacteria and the reoccurrence of the disease. Objective. To characterize the Mycobacterium tuberculosis resistant to Rifampicin in the province of El Oro. Materials and methods. A quantitative, descriptive and non-experimental study was carried out. The sample was obtained from the database of the clinical laboratory of the mycobacteria area of the Teófilo Dávila Hospital in the period 2019 - 2022, who after applying the rapid molecular test GeneXpert MTB/RIF or ULTRA determined that 48 patients presented resistance to Rifampicin in the treatment of Mycobacterium tuberculosis. Results. The laboratory report showed that in the year 2022 the highest number of cases of resistance to Rifampicin for the treatment of Mycobacterium tuberculosis was established, reaching 33.3%; the age group most affected was young adults (20 to 49 years) with 52.1%, and with a high frequency of 66.7% in the male sex. The most prevalent comorbidity was in patients diagnosed with Diabetes Mellitus type 2 with 27.1% and the condition of admission of patients with resistance to Rifampicin, are new cases with 75%. Conclusions. In the province of El Oro, between 2019 - 2022 there were 48 cases resistant to the antibiotic Rifampicin in the treatment of TB, among them 75% correspond to an initial resistance, that is, patients who were not treated against the disease, the other 25% encompasses those patients who relapsed in the disease, failure or loss of follow-up by the surveillance laboratory, mycobacteria area of the Teófilo Dávila Hospital.

Introdução. A tuberculose é uma das doenças infecciosas mais antigas e mais comuns, causada por uma bactéria em forma de bastonete, ou bacilo, chamada Mycobacterium tuberculosis. A doença pode ser tratada com antibióticos, que são prescritos por meses devido à lenta taxa de crescimento da bactéria. Entre os medicamentos utilizados, a rifampicina é usada terapeuticamente para combater essa doença; no entanto, alguns pacientes podem desenvolver resistência a esse antibiótico, por isso é importante concluir o tratamento para evitar o desenvolvimento de bactérias resistentes aos medicamentos e a recorrência da doença. Objetivo. Caracterizar o Mycobacterium tuberculosis resistente à rifampicina na província de El Oro. Materiais e métodos. Foi realizado um estudo quantitativo, descritivo e não experimental. A amostra foi obtida do banco de dados do laboratório clínico da área de micobactérias do Hospital Teófilo Dávila no período de 2019 a 2022, que, após aplicar o teste molecular rápido GeneXpert MTB/RIF ou ULTRA, determinou que 48 pacientes apresentavam resistência à rifampicina no tratamento de Mycobacterium tuberculosis. Resultados. O laudo laboratorial demonstrou que o maior número de casos de resistência à Rifampicina para o tratamento do Mycobacterium tuberculosis se estabeleceu em 2022, atingindo 33,3%; a faixa etária mais afetada foi a de adultos jovens (20-49 anos) com 52,1%, e com alta frequência de 66,7% no sexo masculino. A comorbidade mais prevalente foi em pacientes diagnosticados com Diabetes Mellitus tipo 2 com 27,1% e a condição de admissão de pacientes com resistência à Rifampicina, são casos novos com 75%. Conclusões. Na província de El Oro, entre 2019 e 2022, houve 48 casos resistentes ao antibiótico Rifampicina no tratamento da TB, entre eles 75% correspondem a uma resistência inicial, ou seja, pacientes que não foram tratados contra a doença, os outros 25% incluem aqueles pacientes que recaíram na doença, falha ou perda de monitoramento pelo laboratório de vigilância, área de micobactérias do Hospital Teófilo Dávila.

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Background: Recommended standard treatment for leprosy is multidrugtherapy (MDT/WHO), consisting Rifampicin+Dapsone+Clofazimine. Other medications are recommended in cases of resistance, adverse reactions and intolerances, including ROM regimen, Rifampicin+Ofloxacin+Minocycline. Therefore, pharmacovigilance is an important tool in understanding these adverse drug reactions (ADRs), supporting pharmacotherapy management and medication safety. This study seeks to evaluate ADRs comparing two therapeutic regimens, MDT and ROM, used in treatment of patients with leprosy, analyzing prognostic factors regarding risk and safety. Methods:A retrospective cohort study was performed by assessing medical records of 433 patients diagnosed with leprosy from 2010 to 2021 at a National Reference Center in Brazil. They were subject to 24 months or more of treatment with MDT or ROM regimens. ADR assessments were analyzed by two experienced researchers, who included clinical and laboratory variables, correlating them with temporality, severity and the causality criteria of Naranjo and WHO. Results: The findings observed an average of 1.3 reactions/patient. Out of individuals experiencing reactions, 67.0% (69/103) were utilizing MDT/MB, while 33.0% (34/103) were using ROM. The median time for ADR of 79 days for MDT and 179 days for ROM. In first reaction, Dapsone was the most frequently involved medication; the most affected system was hematopoietic. As compared to Clofazimine, results indicated that use of Dapsone was associated with 7% increased risk of ADR occurrence (HR: 1.07; p = 0.866). Additionally, Rifampicin was linked to 31% increased risk of ADRs (HR: 1.31; p = 0.602); and Ofloxacin showed 35% elevated risk (HR: 1.35; p = 0.653). Conversely, results for Minocycline indicated 44% reduction in the risk of ADRs (HR: 0.56; p = 0.527), although statistical significance was not reached. The use of MDT conferred 2.51 times higher risk of developing ADRs in comparison to ROM. Conclusion: The comparison between MDT and ROM revealed that MDT caused more ADRs, and these reactions were more severe, indicating less safety for patients. Dapsone was the most common medication causing ADRs, followed by Rifampicin. The combination with Clofazimine was associated with an additional risk of ADRs, warranting further studies to confirm this hypothesis. Given the high magnitude of ADRs, healthcare teams need to monitor patients undergoing leprosy treatment with focus on pharmacovigilance.

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Background: The scope of the study was to analyze original preclinical studies on the antimicrobial effects of carvacrol and derivatives on the Mycobacterium genus. Materials & methods: According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, four databases (PubMed, Web of Science, SCOPUS and EMBASE) were searched. Results: The search retrieved 392 records, of which 11 papers were selected. Heterogeneity in the techniques and mycobacterial targets was observed. Carvacrol demonstrated synergistic antimycobacterial activity with rifampicin against multidrug-resistant Mycobacterium tuberculosis on membranes and biofilms. In silico approaches showed specific targets in mycobacteria, by inhibition and molecular docking assays, on the enzyme chorismate mutase and the heat shock protein 16.3. Conclusion: Carvacrol has been shown to be a scaffold candidate for future molecules with activity against mycobacteria.

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BACKGROUND: The duration of the protective effect of tuberculosis preventive therapy (TPT) is controversial. Some studies have found that the protective effect of TPT is lost after cessation of therapy among people with human immunodeficiency virus (HIV) in settings with very high tuberculosis incidence, but others have found long-term protection in low-incidence settings. METHODS: We estimated the incidence rate (IR) of new tuberculosis disease for up to 12 years after randomization to 4 months of rifampin or 9 months of isoniazid, among 991 Brazilian participants in a TPT trial in the state of Rio de Janeiro, with an incidence of 68.6/100 000 population in 2022. The adjusted hazard ratios (aHRs) of independent variables for incident tuberculosis were calculated. RESULTS: The overall tuberculosis IR was 1.7 (95% confidence interval [CI], 1.01- 2.7) per 1000 person-years (PY). The tuberculosis IR was higher among those who did not complete TPT than in those who did (2.9 [95% CI, 1.3-5.6] vs 1.1 [.4-2.3] per 1000 PY; IR ratio, 2.7 [1.0-7.2]). The tuberculosis IR was higher within 28 months after randomization (IR, 3.5 [95% CI, 1.6-6.6] vs 1.1 [.5-2.1] per 1000 PY between 28 and 143 months; IR ratio, 3.1 [1.2-8.2]). Treatment noncompletion was the only variable associated with incident tuberculosis (aHR, 3.2 [95% CI, 1.1-9.7]). CONCLUSIONS: In a mostly HIV-noninfected population, a complete course of TPT conferred long-term protection against tuberculosis.

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Rifampicin (RIF) is an antibiotic used to treat tuberculosis and leprosy. Even though RIF is a market-available drug, it has a low aqueous solubility, hindering its bioavailability. Among the strategies for bioavailability improvement of poorly soluble drugs, coamorphous systems have been revealed as an alternative in the increase of the aqueous solubility of drug systems and at the same time also increasing the amorphous state stability and dissolution rate when compared with the neat drug. In this work, a new coamorphous form from RIF and tromethamine (TRIS) was synthesized by slow evaporation. Structural, electronic, and thermodynamic properties and solvation effects, as well as drug-coformer intermolecular interactions, were studied through density functional theory (DFT) calculations. Powder X-ray diffraction (PXRD) data allowed us to verify the formation of a new coamorphous. In addition, the DFT study indicates a possible intermolecular interaction by hydrogen bonds between the available amino and carbonyl groups of RIF and the hydroxyl and amino groups of TRIS. The theoretical spectra obtained are in good agreement with the experimental data, suggesting the main interactions occurring in the formation of the coamorphous system. PXRD was used to study the physical stability of the coamorphous system under accelerated ICH conditions (40 °C and 75% RH), indicating that the material remained in an amorphous state up to 180 days. The thermogravimetry result of this material showed a good thermal stability up to 153 °C, and differential scanning calorimetry showed that the glass temperature (Tg) was at 70.0 °C. Solubility studies demonstrated an increase in the solubility of RIF by 5.5-fold when compared with its crystalline counterpart. Therefore, this new material presents critical parameters that can be considered in the development of new coamorphous formulations.

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First-line tuberculostatic agents, Rifampicin (RIF), Isoniazid (ISH), Ethambutol (ETB), and Pyrazinamide (PZA) are generally administered as a fixed-dose combination (FDC) for improving patient adherence. The major quality challenge of these FDC products is their variable bioavailability, where RIF and its solid state are key factors. In this work, the analysis of the impact of the polymorphism in the performance of RIF in RIF-ISH and PZA-RIF-ISH combined products was carried out by an overall approach that included the development and validation of two methodologies combining near-infrared (NIR) spectroscopy and partial least squares (PLS) to the further evaluation of commercial products. For NIR-PLS methods, training and validation sets were prepared with mixtures of Form I/Form II of RIF, and the appropriate amount of ISH (for double associations) or ISH-PZA (for triple associations). The corresponding matrix of the excipients was added to the mixture of APIs to simulate the environment of each FDC product. Four PLS factors, reduced spectral range, and the combination of standard normal variate and Savitzky-Golay 1st derivative (SNV-D') were selected as optimum data pre-treatment for both methods, yielding satisfactory recoveries during the analysis of validation sets (98.5±2.0%, and 98.7±1.8% for double- and triple-FDC products, respectively). The NIR-PLS model for RIF-ISH successfully estimated the polymorphic purity of Form II in double-FDC capsules (1.02 ± 0.02w/w). On the other hand, the NIR-PLS model for RIF-ISH-PZA detected a low purity of Form II in triple FDC tablets (0.800 ± 0.021w/w), these results were confirmed by X-ray powder diffraction. Nevertheless, the triple-FDC tablets showed good performance in the dissolution test (Q=99-102%), implying a Form II purity about of 80% is not low enough to affect the safety and efficacy of the product.

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Abstract Anti-tuberculosis drugs are reported to cause hepatotoxicity, which varies from asymptomatic rise of the hepatic enzymes. Hepatoprotective plants plays important role to protect liver. This study investigated the hepatoprotective potential of the Solanum lycopersicum in rats intoxicated with Isoniazid and Rifampicin (INH+RIF) to induce hepatotoxicity. Thirty wistar albino rats were divided into five groups of six animals each. Group 1 rats were kept control while groups II, III, IV and V were administered with INH+RIF (75+150 mg/kg) orally, for seven consecutive days. For treatment, rats in group III received silymarin while animals in group IV and V were provided with 40 mg/kg and 80 mg/kg of Solanum lycopersicum extract, respectively. On day 0 and 8th blood samples were collected for the analysis of hepatic biomarkers. The data were subjected to one-way ANOVA and Bonferronis post hoc test for statistical analysis. Hepatotoxicity induced by INH+RIF resulted in significant elevation of serum hepatic enzymes including Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Alkaline phosphatase (ALP), and total bilirubin while decreased the albumin level. The Solanum lycopersicum at dose of 80 mg/kg significantly reduced the hepatic enzymes AST, ALT, ALP and bilirubin while the albumin level was significantly increased. The treatment had non-significant effect on body and liver weight. Drug induced hepatotoxicity can be effectively treated with Solanum lycopersicum at 80 mg/kg dose.

Resumo As drogas antituberculose são relatadas como causadoras de hepatotoxicidade, ocasionando o aumento assintomático das enzimas hepáticas. As plantas hepatoprotetoras desempenham um papel importante na proteção do fígado. Este estudo investigou o potencial hepatoprotetor de Solanum lycopersicum em ratos que foram intoxicados com isoniazida e rifampicina (INH + RIF) para induzir hepatotoxicidade. Trinta ratos wistar albinos foram divididos em cinco grupos de seis animais cada. Os ratos do grupo 1 representaram o grupo controle, enquanto os ratos dos grupos II, III, IV e V receberam INH + RIF (75 + 150 mg/kg) por via oral, por sete dias consecutivos. Para o tratamento, os ratos do grupo III receberam silimarina, enquanto os animais do grupo IV e V receberam 40 mg/kg e 80 mg/kg de extrato de S. lycopersicum, respectivamente. Nos dias 0 e 8, foram coletadas amostras de sangue para análise de biomarcadores hepáticos. Os dados foram submetidos a teste unilateral (ANOVA) e post hoc de Bonferroni para análise estatística. A hepatotoxicidade induzida por INH + RIF resultou em elevação significativa das enzimas hepáticas séricas, incluindo aspartato aminotransferase (AST), alanina aminotransferase (ALT), fosfatase alcalina (ALP) e bilirrubina total, enquanto houve a diminuição do nível de albumina. O S. lycopersicum, na dose de 80 mg / kg, reduziu significativamente as enzimas hepáticas AST, ALT, ALP e bilirrubina, enquanto o nível de albumina aumentou de forma significativa. O tratamento não teve efeito significativo no peso corporal e hepático. A hepatotoxicidade induzida por drogas pode ser tratada de forma eficaz com S. lycopersicum na dose de 80 mg/kg.