Anti-tubercular treatment-induced granulomatous acute interstitial nephritis.

ABSTRACT: This case emphasizes the value of meticulous observation and regular follow-up of patients receiving rifampicin therapy. The prognosis for complete improvement in renal function in such cases was excellent, with prompt recognition and discontinuation of rifampicin. Teaching patients about these possible adverse effects and encouraging immediate reporting of signs and symptoms are likely to be beneficial because acute kidney injury can manifest itself very quickly after rifampicin is started. Even if renal failure can happen with any dose of rifampicin, primary physicians must have awareness about patients on intermittent or irregular therapy and those who have previously used this medication. It is challenging to determine the prevalence of adverse reactions to common antibiotics where a state- or country-wide reporting system is absent. Along with withdrawal of the causative agent patients were treated with corticosteroids (0.5-1 mg/kg/day) for an average period of 4-12 weeks showing significant recovery of renal function.

The performance of Xpert MTB/RIF and MTBDRplus within a Programmatic setting at TB Laboratory in Rio de Janeiro, Brazil.

BACKGROUND: Few studies in routine settings have confirmed the high accuracy of the Xpert MTB/RIF assay for detecting rifampicin resistance (RR) and the first-line probe assay (FL-LPA) for detecting both RR and isoniazid resistance (INHR). METHODS: The performance of Xpert MTB/RIF and MTBDRplus VER 2.0 LPA was evaluated in 180 Mycobacterium tuberculosis samples collected from January 2018 to December 2019 in Rio de Janeiro, Brazil. The results were compared with those from BACTEC MGIT 960 culture and drug susceptibility testing (DST). Whole-genome sequencing was performed on the samples with discordant results. RESULTS: The Xpert MTB/RIF assay showed a sensitivity (Se) of 93.3% and a specificity (Sp) of 97.6%, detecting RR. The performance of FL-LPA to identify RIF and INH resistance was, respectively, (Se) 100% and 83.3% and (Sp) 98.8% and 100%. Among 18 clinical isolates with INHR detected by FL-LPA, mutations in the katG gene were observed in 100% of samples, of which only two (11.1%) had mutations in both katG and inhA genes. Overall, the discordant results were identified in 9 (5%) samples. Among the four Xpert RIF-resistant and DST-sensitive, two harbored mutations in rpoB Leu430Pro. Among the four FL-LPA-sensitive and DST-resistant, one had a mutation in inhA 17G>T. FL-LPA showed high accuracy in detecting RR and INHR. CONCLUSIONS: The MTBDRplus test demonstrated excellent performance in detecting RR, and INHR in clinical isolates under routine conditions at a reference laboratory in Rio de Janeiro, Brazil. Incorporating both tests can improve drug-resistant tuberculosis treatment outcomes and monitor the INHR incidence.

Synergy of Xpert (MTB/RIF) and Line probe assay for detection of rifampicin resistant strains of Mycobacterium tuberculosis.

INTRODUCTION: Early diagnosis and successful treatment of drug-resistant tuberculosis (TB) demands rapid, precise, and consistent diagnostic methods to minimise the development of resistance. Therefore, this comparative study was designed to evaluate the diagnostic performance of Xpert (MTB/RIF) and Line probe assay (LPA) for detecting drug-resistant TB. METHODOLOGY: This study comprised 389 (279 pulmonary and 110 extrapulmonary) samples from patients suspected of having TB. All samples were subjected to Xpert (MTB/RIF), LPA, solid culture, and drug-susceptibility testing. Out of 320 samples, only 180 culture (gold standard) positive were included in the final evaluation. The diagnostic characteristics for methods used were determined by calculating diagnostic sensitivity, specificity, and predictive values. The agreement between all methods was determined by calculating the kappa coefficient. RESULTS: The sensitivity and specificity for Xpert (MTB/RIF) for detecting TB were 88.5% and 96.4%, respectively, against the solid culture. On the other hand, LPA showed sensitivity and specificity at 94.3% and 100%, respectively. Xpert (MTB/RIF) showed moderate agreement (kappa 0.65, p < 0.01) - (73.3% sensitivity; 97.6% specificity) for the detection of rifampicin resistance. However, LPA achieved better diagnostic accuracy (kappa 0.80, p < 0.01) - (84.6% sensitivity; 98.4% specificity) against drug-resistant TB. CONCLUSIONS: Xpert (MTB/RIF) and LPA have outstanding diagnostic sensitivity and specificity against RIF resistance with a shorter turnaround time, which could result in a substantial therapeutic outcome. Our findings showed LPA superiority over Xpert (MTB/RIF) for drug resistance. However, due to operational challenges, the requirement of technical expertise and infrastructure issues, LPA cannot be used as point-of-care testing in resource-limited countries.

Cryo-EM structures of a mycobacterial ABC transporter that mediates rifampicin resistance.

Drug-resistant Tuberculosis (TB) is a global public health problem. Resistance to rifampicin, the most effective drug for TB treatment, is a major growing concern. The etiological agent, Mycobacterium tuberculosis (Mtb), has a cluster of ATP-binding cassette (ABC) transporters which are responsible for drug resistance through active export. Here, we describe studies characterizing Mtb Rv1217c-1218c as an ABC transporter that can mediate mycobacterial resistance to rifampicin and have determined the cryo-electron microscopy structures of Rv1217c-1218c. The structures show Rv1217c-1218c has a type V exporter fold. In the absence of ATP, Rv1217c-1218c forms a periplasmic gate by two juxtaposed-membrane helices from each transmembrane domain (TMD), while the nucleotide-binding domains (NBDs) form a partially closed dimer which is held together by four salt-bridges. Adenylyl-imidodiphosphate (AMPPNP) binding induces a structural change where the NBDs become further closed to each other, which downstream translates to a closed conformation for the TMDs. AMPPNP binding results in the collapse of the outer leaflet cavity and the opening of the periplasmic gate, which was proposed to play a role in substrate export. The rifampicin-bound structure shows a hydrophobic and periplasm-facing cavity is involved in rifampicin binding. Phospholipid molecules are observed in all determined structures and form an integral part of the Rv1217c-1218c transporter system. Our results provide a structural basis for a mycobacterial ABC exporter that mediates rifampicin resistance, which can lead to different insights into combating rifampicin resistance.

Diagnostic Accuracy of FluoroCycler XT MTBDR Assay for Detection of Rifampicin and Isoniazid-resistant Mycobacteria tuberculosis in Clinical Isolates from Kenya.

BACKGROUND: Drug-resistant tuberculosis (DR-TB) poses a major global challenge to public health and therapeutics. It is an emerging global concern associated with increased morbidity and mortality mostly seen in the low- and middle-income countries. Molecular techniques are highly sensitive and offer timely and accurate results for TB drug resistance testing, thereby positively influencing patient management plan. METHODS: The study was carried out at the National Tuberculosis Reference Laboratory (NTRL) in Kenya in the period between January and October 2022. A total of 243 Mycobacterium tuberculosis (M.tb) clinical isolates were included in the study. These isolates comprised of 50 isolates with mutations in rpoB, 51 isolates with katG mutations, 51 isolates with mutations in inhA, and 91 M.tb isolates lacking mutations in these genes based on Genotype MTBDRplus results. DNA from the isolates was extracted using the FluoroLyse extraction kit. Real-time polymerase chain reaction targeting the rpoB, InhA, and katG genes was performed using the FluoroType MTBDR amplification mix. Isolates with discordant results between Genotype MTBDRplus and FluoroCycler® MTBDR assays underwent targeted sequencing for the respective genes, then, sequences were analyzed for mutations using Geneious version 11.0 software. RESULTS: The sensitivity of the Fluorocycler XT MTBDR assay for the detection of mutations that confer drug resistance was 86% (95% confidence interval [CI] 73.0-94.0) for rpoB, 96% (95% CI 87-100) for katG and 92% (95% CI 81-98) for inhA. The assay's specificity was 97% (95% CI 93-99) for rpoB, 98% (95% CI 96-100) for katG, and 97% (95% CI 93-99) for inhA. CONCLUSION: The diagnostic accuracy of FluoroType MTBDR for the detection of mutations conferring resistance to rifampicin and isoniazid was high compared with that of Genotype MTBDRplus and demonstrates its suitability as a replacement assay for Genotype MTBDRplus.

Affecting Factors Unfavorable Treatment Outcomes of Rifampicin-resistant/Multidrug-resistant Tuberculosis Patients Treated with Long-term Regimen.

BACKGROUND: Drug-resistant tuberculosis (DR-TB) poses a significant threat to global TB control and remains a major public health issue. This study aims to evaluate treatment outcomes and identify risk factors for unfavorable outcomes in patients with multi-DR-TB (MDR-TB) treated at a major reference hospital in Istanbul. METHODS: We conducted a retrospective analysis of 413 patients with rifampicin-resistant and MDR-TB who received treatment between January 1, 2013, and December 31, 2023, at the University of Health Sciences Süreyyapasa Chest Diseases Training and Research Hospital. Patients were treated following the World Health Organization and national guidelines, with regimens tailored to individual drug resistance profiles and side effect management. Demographic data, comorbidities, microbiological follow-up, drug resistance patterns, treatment regimens, and radiological findings were analyzed. RESULTS: Treatment success was achieved in 350 patients (84.74%). Thirty-two patients (7.74%) were lost to follow-up, and 32 patients (7.74%) died. Logistic regression analysis identified several factors associated with unfavorable treatment outcomes: comorbidities (odds ratio [OR]: 7.555, P = 0.001), quinolone resistance (OR: 3.695, P = 0.030), and bronchiectasis (OR: 4.126, P = 0.013). Additional significant factors included male gender (P = 0.007), foreign-born status (P = 0.013), age over 35 years (P = 0.002), previous treatment history (P = 0.058), and drug side effects (P = 0.012). CONCLUSION: The long-term regimen for MDR-TB was found to be highly successful, with an 84.74% treatment success rate. Effective treatment regimens, close patient follow-up, early recognition of side effects, and comprehensive management are crucial for achieving successful outcomes. Identifying and addressing risk factors such as comorbidities, drug resistance, and specific patient demographics can further improve treatment success rates. This study underscores the importance of tailored treatment strategies and robust patient management in combating MDR-TB.

Diagnostics Evaluation of Smart Sure™ Mycobacterium tuberculosis Screening Kit and Smart Sure™ Multidrug-resistant Tuberculosis Detection Kit on Nonsputum Specimens at a Tertiary Care Center of North India.

BACKGROUND: Tuberculosis (TB) is caused due to the infection of Mycobacterium tuberculosis (MTB) and it can infect the various parts of the human body. The disease is highly prevalent and is the second most common cause of death worldwide after COVID-19. Apart from sputum specimen, it is exceedingly difficult to diagnose due to its paucibacillary nature. The current study was intended to evaluate the accuracy of Smart Sure™ MTB and multidrug-resistant-TB (MDR-TB) kits (Genetix Biotech Asia Pvt. Ltd., India) with Xpert ultra and Mycobacterium growth indicator tube (MGIT) culture on nonsputum specimens from TB suspects. METHODS: A total of 205 nonsputum specimens were received between October 2023 and May 2024 at Intermediate Reference Laboratory, Department of Medicine, All India Institute of Medical Sciences, New Delhi, India. Xpert ultra and Smart Sure™ MTB and MDR-TB tests were done directly on samples. However, processed specimens were used for MGIT culture and drug-susceptibility testing (DST). Invalid and MGIT contaminated specimens were excluded from the final calculation. RESULTS: Overall, sensitivity and specificity of Smart Sure™ MTB screening kit was 71.59% and 98.28%, respectively, with Xpert ultra and 68.35% and 90.83%, respectively, with MGIT culture. While comparing with both Xpert ultra and MGIT-DST to detect rifampicin (RIF) resistant, Smart Sure™ MDR-TB kits showed sensitivity of 75.0% and 100% of specificity. However, for isoniazid (INH) resistance, Smart Sure™ MDR-TB kits showed 100% of sensitivity and specificity with MGIT-DST. CONCLUSION: For the detection of MTB and its drug-resistance patterns (RIF and INH) in the specimens other than sputum, Smart Sure™ MTB and MDR-TB kits could play a vital role in TB endemic countries. While comparing the set-ups and skilled staffs, it required almost same as compared with previously approved WHO diagnostics used in resource-limited countries.

Unveiling the complexity of rifampicin drug susceptibility testing in Mycobacterium tuberculosis: comparative analysis with next-generation sequencing.

Introduction. The discordance between phenotypic and molecular methods of rifampicin (RIF) drug susceptibility testing (DST) in Mycobacterium tuberculosis poses a significant challenge, potentially resulting in misdiagnosis and inappropriate treatment.Hypothesis/gap statement. A comparison of RIF phenotypic and molecular methods for DST, including whole genome sequencing (WGS), may provide a better understanding of resistance mechanisms.Aim. This study aims to compare RIF DST in M. tuberculosis using two phenotypic and molecular methods including the GeneXpert RIF Assay (GX) and WGS for better understanding.Methodology. The study evaluated two phenotypic liquid medium methods [Lowenstein-Jensen (LJ) and Mycobacterium Growth Indicator Tube (MGIT)], one targeted molecular method (GX), and one WGS method. Moreover, mutational frequency in ponA1 and ponA2 was also screened in the current and previous RIF resistance M. tuberculosis genomic isolates to find their compensatory role.Results. A total of 25 RIF-resistant isolates, including nine from treatment failures and relapse cases with both discordant and concordant DST results on LJ, MGIT and GX, were subjected to WGS. The phenotypic DST results indicated that 11 isolates (44%) were susceptible on LJ and MGIT but resistant on GX. These isolates exhibited multiple mutations in rpoB, including Thr444>Ala, Leu430>Pro, Leu430>Arg, Asp435>Gly, His445>Asn and Asn438>Lys. Conversely, four isolates that were susceptible on GX and MGIT but resistant on LJ were wild type for rpoB in WGS. However, these isolates possessed several novel mutations in the PonA1 gene, including a 10 nt insertion and two nonsynonymous mutations (Ala394>Ser, Pro631>Ser), as well as one nonsynonymous mutation (Pro780>Arg) in PonA2. The discordance rate of RIF DST is higher on MGIT than on LJ and GX when compared to WGS. These discordances in the Delhi/CAS lineages were primarily associated with failure and relapse cases.Conclusion. The WGS of RIF resistance is relatively expensive, but it may be considered for isolates with discordant DST results on MGIT, LJ and GX to ensure accurate diagnosis and appropriate treatment options.

LATENT TUBERCULOSIS IN PATIENTS WITH CROHN'S DISEASE IN A UNIVERSITY HOSPITAL IN NORTHEASTERN BRAZIL: A RETROSPECTIVE STUDY.

BACKGROUND: Among chronic condition problems, tuberculosis still represents a serious public health problem globally. OBJECTIVE: To investigate latent tuberculosis infection in patients with Crohn's disease. Retrospective, descriptive cross-sectional study of quantitative analysis. METHODS: The research was conducted on diagnosed cases of Crohn's disease at the University Hospital located in a city in Northeastern Brazil. All cases of patients with Crohn's disease undergoing isoniazid or rifampicin therapy for latent tuberculosis (LTBI) were included in the study. The data obtained were subsequently subjected to statistical analysis using the Statistical Package for the Social Sciences (SPSS) program. RESULTS: We analyzed 235 medical records, and it was observed that 56% were male, with a mean age of 42.7. Among these, 54% declared themselves as brown, 31% had completed high school, and 47% were residents of the city of Teresina. Regarding the clinical and epidemiological characteristics of the studied patients classified as having ILTB, 34% of the medical records were diagnosed by tuberculin test, 48.51% were investigated by x-ray examination, and the recent location affected the colon with 27%. CONCLUSION: Overall, the health profile of the participants in this study aligns with findings previously established in the literature, particularly studies conducted in other Brazilian states, as well as in other developing countries.

EFFICACY AND SAFETY OF SILVER NANOCOMPOSITES ON RIFAMPICIN-RESISTANT M. TUBERCULOSIS STRAINS.

BACKGROUND: Control of rifampicin-resistant tuberculosis (RR-MTB) requires novel technologies for restoring the anti-TB efficacy of priority drugs. We sought to evaluate the ability of nanotechnology application in the recovery of the anti-tuberculosis efficacy of rifampicin. METHODS: Nanocomposite- standard dose of rifampicin and 20 nm silver nanoparticles (AgNPs) suspension solution of 6 different concentrations: 0.25%; 0.5%; 1%; 2.5%; 5%; and 10%, were supplemented to 70 rifampicin-resistant mycobacterium tuberculosis (RR-MTB) isolates. The control arm consisted of 35 RR-MTB isolates and AgNPs suspension with identical concentrations. The inhibitory effect of nanocomposites was evaluated by MTB growth rate using the BACTECTM MGIT 960TM. The safety assessment of single-use AgNPs was conducted in experimental animals. RESULTS: The suppression process of AgNPs on RR-MTB isolates started with 2,5% nanocomposite solution application and full suppression was achieved in 5% and 10% nanocomposite solutions. A standard dose of rifampicin and a 2.5% solution of AgNPs increased the minimal inhibitory effect on RR-MTB by 10% (total 80%) vs the isolated use of a 2.5% solution of AgNPs (70%). An experiment on animals revealed the complete safety of a single injection of ultra-high doses of AgNPs. CONCLUSION: The study showed the potentiating effect of AgNPs in overcoming the resistance of MTB to rifampicin providing a scientific basis for further research.

Pharmacokinetics of olverembatinib (HQP1351) in the presence of a strong CYP3A4 inhibitor (itraconazole) or inducer (rifampin) in healthy volunteers.

Olverembatinib (HQP1351) is a BCR-ABL1 tyrosine kinase inhibitor with promising clinical activity. It is approved in China for the treatment of patients with chronic myeloid leukemia harboring drug-resistant mutations, such as T315I. In vitro studies suggested that metabolism of olverembatinib is primarily mediated by cytochrome P450 (CYP3A4). The effects of CYP3A4 inhibition and induction on the pharmacokinetics of olverembatinib were evaluated in an open-label, 2-part, fixed-sequence study in healthy volunteers. In Part 1 of this study, 16 participants received a single oral dose of olverembatinib (20 mg) and the oral CYP3A4 inhibitor itraconazole (200 mg). In Part 2, 16 participants received a single oral dose of olverembatinib (40 mg) and the oral CYP3A4 inducer rifampin (600 mg). To measure pharmacokinetic parameters, serial blood samples were collected after administration of olverembatinib alone and combined with itraconazole or rifampin. Coadministration of olverembatinib with itraconazole increased the peak plasma concentration of olverembatinib, its area under the time-concentration curve (AUC)0-last, and AUC0-inf by 75.63%, 147.06%, and 158.66%, respectively. Coadministration with rifampin decreased these same variables by 61.27%, 74.21%, and 75.19%, respectively. These results confirm that olverembatinib is primarily metabolized by CYP3A4 in humans, suggesting that caution should be exercised with concurrent use of olverembatinib and strong CYP3A4 inhibitors or inducers.

[Skin disease caused by Mycobacterium marinum:a case report].

Mycobacterium marinum infection often affects the extremities, causing single or multiple skin lesions. With the improvement of molecular detection technology and the clinical application of NGS pathogen detection, the diagnosis rate of Mycobacterium marinum skin disease is gradually increasing. This article reported the case of a 54-year-old man who was stung by a marine fish and gradually developed swelling and nodules on his right hand and right upper limb. He was diagnosed with Mycobacterium marinum infection by detection of the tuberculosis resistance gene dissolution curve of the pus and the identification of the bacteria. Oral rifampicin combined with clarithromycin and minocycline was given for anti-infection treatment. During follow-up, the abscesses and nodules gradually shrank and eventually disappeared. By presenting the diagnosis and treatment of this case, the understanding of this disease among clinicians can be improved to avoid misdiagnosis and missed diagnosis.

A machine-learning based model for automated recommendation of individualized treatment of rifampicin-resistant tuberculosis.

BACKGROUND: Rifampicin resistant tuberculosis remains a global health problem with almost half a million new cases annually. In high-income countries patients empirically start a standardized treatment regimen, followed by an individualized regimen guided by drug susceptibility test (DST) results. In most settings, DST information is not available or is limited to isoniazid and fluoroquinolones. Whole genome sequencing could more accurately guide individualized treatment as the full drug resistance profile is obtained with a single test. Whole genome sequencing has not reached its full potential for patient care, in part due to the complexity of translating a resistance profile into the most effective individualized regimen. METHODS: We developed a treatment recommender clinical decision support system (CDSS) and an accompanying web application for user-friendly recommendation of the optimal individualized treatment regimen to a clinician. RESULTS: Following expert stakeholder meetings and literature review, nine drug features and 14 treatment regimen features were identified and quantified. Using machine learning, a model was developed to predict the optimal treatment regimen based on a training set of 3895 treatment regimen-expert feedback pairs. The acceptability of the treatment recommender CDSS was assessed as part of a clinical trial and in a routine care setting. Within the clinical trial setting, all patients received the CDSS recommended treatment. In 8 of 20 cases, the initial recommendation was recomputed because of stock out, clinical contra-indication or toxicity. In routine care setting, physicians rejected the treatment recommendation in 7 out of 15 cases because it deviated from the national TB treatment guidelines. A survey indicated that the treatment recommender CDSS is easy to use and useful in clinical practice but requires digital infrastructure support and training. CONCLUSIONS: Our findings suggest that global implementation of the novel treatment recommender CDSS holds the potential to improve treatment outcomes of patients with RR-TB, especially those with 'difficult-to-treat' forms of RR-TB.

Treatment for multidrug-resistant tuberculosis: A comparative analysis of programmatic outcome indicators between Buenaventura and other municipalities of Valle del Cauca, Colombia / Tratamiento para tuberculosis resistente a rifampicina o multirresistente: análisis comparativo de indicadores programáticos entre Buenaventura y otros municipios del Valle del Cauca, Colombia

Introduction. Proper management of multidrug-resistant tuberculosis is a prioritized strategy for tuberculosis control worldwide. Objective. To evaluate differences concerning demographic and clinical characteristics and programmatic indicators of Buenaventura patient cohort with confirmed diagnosis of multidrug-resistant tuberculosis, compared to those of the other municipalities from Valle del Cauca, Colombia, 2013-2016. Materials and methods. We conducted an analytical cohort study to compare records of patients older than 15 years with multidrug-resistant tuberculosis included in the Programa de Tuberculosis de Buenaventura (with para-aminosalicylic acid) versus the other municipalities of Valle del Cauca (without para-aminosalicylic). Results. Ninety-nine cases were recorded with a median age of 40 years (IQR = 26 - 53); in Buenaventura, 56% of the patients were women, while in the other municipalities, men predominated with 67%; 95% had health insurance. The most common comorbidity was diabetes (14%). Adverse reactions to antituberculosis medications in Buenaventura were 1.3 times more frequent than in the other municipalities (OR = 2.3; 95% CI = 0.993 - 5.568; p = 0.04). In Buenaventura, the mortality rate was 5% compared to the 15% reported in the other municipalities. Treatment failures were not reported in Buenaventura, but 35% did not continue with the follow-up. Treatment success was higher in Buenaventura (56 %). Conclusion. A strengthened program in Buenaventura presented better programmatic results than those from the other municipalities of Valle del Cauca. Access to molecular tests, availability of shortened treatments, and continuous monitoring to identify adverse reactions to antituberculosis medications are routes for all other control programs.

Introducción. El manejo adecuado de la tuberculosis multirresistente es una estrategia priorizada para el control de la tuberculosis en el mundo. Objetivo. Evaluar las diferencias entre las características demográficas y clínicas, y los indicadores programáticos de los pacientes con diagnóstico confirmado de tuberculosis pulmonar resistente a rifampicina o multirresistente en Buenaventura, frente a la cohorte de los demás municipios del Valle del Cauca entre 2013 y 2016. Materiales y métodos. Se desarrolló un estudio analítico de cohortes para comparar los registros de pacientes mayores de 15 años con tuberculosis multirresistente, del Programa de Tuberculosis de Buenaventura (con ácido paraaminosalicílico), frente a los demás municipios del Valle del Cauca (sin ácido paraaminosalicílico). Resultados. Se registraron 99 casos con una mediana de edad de 40 años (RIC = 26- 53); en Buenaventura, el 56 % eran mujeres; en los demás municipios, predominaron los hombres (67 %); el 95 % de los evaluados tenía aseguramiento en salud. La comorbilidad más frecuente fue diabetes (14 %). Las reacciones adversas a medicamentos antituberculosos en Buenaventura fueron 1,3 veces más frecuentes que en los demás municipios (OR = 2,3; IC95 %: 0,993 - 5,568; p = 0,04). En Buenaventura falleció el 5 % de los casos frente al 15 % reportado en los demás municipios. No hubo fracasos con el tratamiento en Buenaventura, pero se reportó un 35 % de pérdida del seguimiento. El éxito del tratamiento fue mayor en Buenaventura en el 56 %. Conclusión. El programa fortalecido de Buenaventura presentó mejores resultados programáticos que los demás municipios del Valle del Cauca. El acceso a pruebas moleculares, la disponibilidad de tratamientos acortados y el seguimiento continuo para identificar reacciones adversas a medicamentos antituberculosos son un derrotero para todos los programas de control.

Rifampicin tolerance and growth fitness among isoniazid-resistant clinical Mycobacterium tuberculosis isolates from a longitudinal study.

Antibiotic tolerance in Mycobacterium tuberculosis reduces bacterial killing, worsens treatment outcomes, and contributes to resistance. We studied rifampicin tolerance in isolates with or without isoniazid resistance (IR). Using a minimum duration of killing assay, we measured rifampicin survival in isoniazid-susceptible (IS, n=119) and resistant (IR, n=84) isolates, correlating tolerance with bacterial growth, rifampicin minimum inhibitory concentrations (MICs), and isoniazid-resistant mutations. Longitudinal IR isolates were analyzed for changes in rifampicin tolerance and genetic variant emergence. The median time for rifampicin to reduce the bacterial population by 90% (MDK90) increased from 1.23 days (IS) and 1.31 days (IR) to 2.55 days (IS) and 1.98 days (IR) over 15-60 days of incubation, indicating fast and slow-growing tolerant sub-populations. A 6 log10-fold survival fraction classified tolerance as low, medium, or high, showing that IR is linked to increased tolerance and faster growth (OR = 2.68 for low vs. medium, OR = 4.42 for low vs. high, p-trend = 0.0003). High tolerance in IR isolates was associated with rifampicin treatment in patients and genetic microvariants. These findings suggest that IR tuberculosis should be assessed for high rifampicin tolerance to optimize treatment and prevent the development of multi-drug-resistant tuberculosis.

Clinical characterization of brucellosis in children from non-pastoral areas: a report of five cases.

BACKGROUND: Brucellosis is a global public health concern and occurs mainly in young adults and the elderly, with children having a lower incidence, thus often leading to delayed treatment. This study aimed to describe the epidemiologic features and clinical characteristics of brucellosis in children. METHODS: In this retrospective study, the clinical data of five children diagnosed with brucellosis in Anhui Provincial Children's Hospital between January 1, 2021 and December 30, 2022 were analyzed. RESULTS: All five cases were from non-pastoral areas, among which three have a history of livestock exposure and originated from the countryside. All patients had medium-high grade fever, mostly accompanied by night sweats and malaise, and three had joint pains. Laboratory tests showed that their white blood cell count was normal or mildly raised, with lymphocytes as the predominant cell population. Four patients had anemia, four had aspartate aminotransferase and alanine aminotransferase abnormality, and two had elevated ferritin levels. All blood samples were positive for Brucella culture, one of which had positive bone marrow culture, and all had positive serology test results. All patients were treated with rifampicin, in combination with sulfamethoxazole or doxycycline for 6 weeks following diagnosis. Four children had a good prognosis, but one child had recurrent joint pain. CONCLUSIONS: The epidemiologic history of children from non-pastoral areas with brucellosis is often unclear; clinical manifestations and laboratory tests lack specificity; and they are easily delayed diagnosis. Clinicians should remain vigilant regarding the possibility of this disease in children with fever of unknown origin. The epidemiological history should be investigated in detail to improve the diagnostic ability of brucellosis. We recommend emphasizing serological testing. Children with brucellosis who receive timely diagnosis and standardized treatment can expect a favorable prognosis.

Combination Therapy of Oral LDN and Topical Pentoxifylline, Rifampin, Clindamycin for Hidradenitis Suppurativa.

Hidradenitis Suppurativa (HS) is a chronic inflammatory skin disease that may have profound effects on the patient's quality of life. A personalized HS combination therapy treatment was prescribed to a 54-year-old female suffering from multiple painful sores, as follows: naltrexone capsules titrated from 0.5 mg up to 4.5 mg; pentoxifylline 5%, rifampin 2%, clindamycin 1%, and glycolic acid topical cream. Clinical improvements were observed using two disease-specific outcome measures: Hurley Staging System and HS Score. The patient's HS improved from Stage II (moderate) to Stage I (mild), and the HS score decreased from 103 points with five anatomical regions reported, to 19 points with only three regions affected. Furthermore, the before and after treatment photographs showed a visible reduction in the number of boils/skin abscesses and an overall recovery. Improvements were also observed across all domains of the patient's self-reported quality of life (Hidradenitis Suppurativa Quality of Life Assessment). The patient did not experience any undesirable effects. Compounded medications may be customized to meet the patient's special needs and may be adjusted throughout the course of treatment to match the patient's individual progress. Although further studies are necessary, this personalized, combination therapy may be a key treatment option in HS.

Investigating aqueous micellar systems enhancement tools for a sensitive spectrofluorimetric determination of anti-TB: Rifampicin.

Rifampicin is a frontline antibiotic in the management of tuberculosis. Since no spectrofluorimetric methods are reported for this drug, this approach was challenged to craft a sensitive, reliable, valid, fast, and green methodology. In recent years, fluorescence spectroscopy has received a lot of interest. Its benefits include ecological greenness and analytical performance. The pharmaceutical industries greatly like this approach because of its low energy and decreased solvent usage, which make it both economical and environmentally friendly. This methodology was based on utilizing the enhanced native fluorescence of the rifampicin at 341 nm after excitation at 241 nm in a beta-cyclodextrin micellar system. Modern developments in analytical chemistry have been applied to reduce risks to the workplace and environment by using distilled water as a dilution solvent for method application and optimization. The method was found excellent green with 97 eco-scale and 0.86 AGREE scores besides an 89.6 overall whiteness score. The range of linearity for rifampicin raw material was 0.2-1.5 µg·mL-1, and the average recoveries for raw material and spiked plasma were 100.15% and 99.64%, respectively. The suggested technique worked well for the commercial oral syrup of Rimactane® and did not conflict with any common additives.

Effectiveness of bedaquiline containing all oral longer regimens in treating multidrug/rifampicin resistant tuberculosis in Pakistan.

BACKGROUND: Despite the introduction of bedaquiline (Bdq) containing all-oral regimens for treating patients with rifampicin resistant/multidrug resistant tuberculosis (MDR/RR-TB) in 2019, data on its effectiveness in Pakistan, which has the fifth highest MDR-TB burden, is lacking. This study evaluates treatment outcomes and identifies factors associated with unsuccessful outcomes among MDR/RR-TB patients treated with an all-oral longer treatment regimen (LTR). METHODS: This retrospective record review included all microbiologically confirmed pulmonary MDR/RR-TB patients treated with an all-oral LTR between August 2019 and February 2021 across nine PMDT centres in Pakistan. Sociodemographic and clinical data were retrieved from the Electronic Nominal Recording and Reporting System. Treatment outcomes, defined by WHO criteria, were analysed using SPSS and multivariate binary logistic regression to identify factors associated with unsuccessful outcomes. A p-value < 0.05 was considered statistically significant. RESULTS: The final analysis included 644 MDR/RR-TB patients (mean age 37.9 ± 17.6 years), mostly male (53.0 %), underweight (68.0 %), with TB treatment history (66.1 %), MDR-TB (84.9 %), lung cavitation (71.0 %), and no comorbidities (86.4 %). Fluoroquinolone resistance was found in 41.9 %, 16 % had used second-line drugs, and 9.8 % had previous MDR-TB treatment. A total of 400 (62.1 %) patients were declared cured, 53 (8.2 %) treatment completed, 117 (18.2 %) died, 37 (5.7 %) lost to follow-up (LTFU), and 37 (5.7 %) treatment failures. Overall treatment success rate was 70.3 % (n = 453). In multivariate analysis, history of TB treatment (OR:1.63, 95 %CI:1.09-2.64, p = 0.023), previous SLD use (OR:2.09, 95 %CI: 1.20-3.37, p = 0.012), resistance to Z (OR:0.43, 95 %CI: 0.20-0.81, p = 0.023), and resistance to > 5 drugs (OR:3.12, 95 %CI:1.36-11.64, p = 0.013) were significantly associated with death and treatment failure. Whereas, lung cavitation had statistically significant association with LTFU (OR:2.66, 95 %CI:1.10-7.32, p = 0.045). CONCLUSION: Treatment success rate (70.3 %) in this study fell below the WHO recommended target success rate (>90 %). Enhanced clinical management, coupled with special attention to patients exhibiting identified risk factors could improve treatment outcomes.

Targeted next-generation sequencing of Mycobacterium tuberculosis from patient samples: lessons learned from high drug-resistant burden clinical settings in Bangladesh.

Lack of appropriate early diagnostic tools for drug-resistant tuberculosis (DR-TB) and their incomplete drug susceptibility testing (DST) profiling is concerning for TB disease control. Existing methods, such as phenotypic DST (pDST), are time-consuming, while Xpert MTB/RIF (Xpert) and line probe assay (LPA) are limited to detecting resistance to few drugs. Targeted next-generation sequencing (tNGS) has been recently approved by WHO as an alternative approach for rapid and comprehensive DST. We aimed to investigate the performance and feasibility of tNGS for detecting DR-TB directly from clinical samples in Bangladesh. pDST, LPA and tNGS were performed among 264 sputum samples, either rifampicin-resistant (RR) or rifampicin-sensitive (RS) TB cases confirmed by Xpert assay. Resistotypes of tNGS were compared with pDST, LPA and composite reference standard (CRS, resistant if either pDST or LPA showed a resistant result). tNGS results revealed higher sensitivities for rifampicin (RIF) (99.3%), isoniazid (INH) (96.3%), fluoroquinolones (FQs) (94.4%), and aminoglycosides (AMGs) (100%) but comparatively lower for ethambutol (76.6%), streptomycin (68.7%), ethionamide (56.0%) and pyrazinamide (50.7%) when compared with pDST. The sensitivities of tNGS for INH, RIF, FQs and AMGs were 93.0%, 96.6%, 90.9%, and 100%, respectively and the specificities ranged from 91.3 to 100% when compared with CRS. This proof of concept study, conducted in a high-burden setting demonstrated that tNGS is a valuable tool for identifying DR-TB directly from the clinical specimens. Its feasibility in our laboratory suggests potential implementation and moving tNGS from research settings into clinical settings.