Infection by a multidrug-resistant Corynebacterium diphtheriae strain: prediction of virulence factors, CRISPR-Cas system analysis, and structural implications of mutations conferring rifampin resistance.

Cases of diphtheria, even in immunized individuals, are still reported in several parts of the world, including in Brazil. New outbreaks occur in Europe and other continents. In this context, studies on Corynebacterium diphtheriae infections are highly relevant, both for a better understanding of the pathogenesis of the disease and for controlling the circulation of clones and antimicrobial resistance genes. Here we present a case of cutaneous infection by multidrug-resistant Corynebacterium diphtheriae and provide its whole-genome sequencing. Genomic analysis revealed resistance genes, including tet(W), sul1, cmx, rpoB2, rbpA and mutation in rpoB. We performed phylogenetic analyzes and used the BRIG to compare the predicted resistance genes with those found in genomes from other significant isolates, including those associated with some outbreaks. Virulence factors such as spaD, srtBC, spaH, srtDE, surface-anchored pilus proteins (sapD), nonfimbrial adhesins (DIP0733, DIP1281, and DIP1621), embC and mptC (putatively involved in CdiLAM), sigA, dtxR and MdbA (putatively involved) in post-translational modification, were detected. We identified the CRISPR-Cas system in our isolate, which was classified as Type II-U based on the database and contains 15 spacers. This system functions as an adaptive immune mechanism. The strain was attributed to a new sequence type ST-928, and phylogenetic analysis confirmed that it was related to ST-634 of C. diphtheriae strains isolated in French Guiana and Brazil. In addition, since infections are not always reported, studies with the sequence data might be a way to complement and inform C. diphtheriae surveillance.

Efeitos do adalimumabe, clindamicina e/ou rifampicina no tratamento da hidradenite supurativa: um protocolo de revisão sistemática / Effects of adalimumab, clindamycin, and/or rifampicin in the treatment of hidradenitis suppurativa: a systematic review protocol

OBJETIVO: Avaliar a efetividade, segurança, níveis de dor e qualidade de vida associados ao uso de adalimumabe, clindamicina e/ou rifampicina no tratamento da hidradenite supurativa. MÉTODO: Serão incluídos estudos do tipo coorte prospectiva e retrospectiva, ensaios clínicos randomizados e de equivalência, bem como análises econômicas realizadas com adultos diagnosticados com hidradenite supurativa, que tenham utilizado pelo menos uma das seguintes alternativas terapêuticas: adalimumabe, clindamicina ou rifampicina. Os estudos devem abordar um ou mais desfechos, tais como contagem de abscessos e/ou nódulos, presença de nódulos inflamatórios, níveis de dor, qualidade de vida, segurança e custos. As bases de dados consultadas serão: Medical Literature Analysis and Retrieval System Online (MEDLINE, Interface OVID), Excerpta Medica DataBASE (EMBASE), Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS), Cumulative Index to Nursing and Allied Health Literature (CINAHL, interface EBSCO), Psychological Abstracts (PsycINFO, interface EBSCO), Web of Science (WoS) e Source-Neutral Abstract and Citation Database (Scopus). Os processos de triagem, seleção e extração serão conduzidos por pesquisadores independentes e previamente treinados. O risco de viés será avaliado por meio dos instrumentos Risk of Bias 2.0 e ROBINS-I. Os resultados serão combinados em uma síntese qualitativa e quantitativa, com a realização de análises de especificidade e subgrupos.

OBJECTIVE: To evaluate the efficacy, safety, pain, and quality of life associated with the use of adalimumab, clindamycin, and/or rifampicin in the treatment of hidradenitis suppurativa. METHOD: Prospective and retrospective cohort studies randomized clinical trials and equivalence studies, and economic analyses, conducted in adults diagnosed with hidradenitis suppurativa who have used at least one of the following therapeutic alternatives: adalimumab, clindamycin, or rifampicin, will be included. Studies should address one or more outcomes such as abscess and/or nodule counts, presence of inflammatory nodules, pain levels, quality of life, safety, and cost. Databases consulted will include Medical Literature Analysis and Retrieval System Online (MEDLINE, OVID interface), Excerpta Medica DataBASE (EMBASE), Latin American and Caribbean Literature in Health Sciences (LILACS), Cumulative Index to Nursing and Allied Health Literature (CINAHL, EBSCO interface), Psychological Abstracts (PsycINFO, EBSCO interface), Web of Science (WoS), and Source-Neutral Abstract and Citation Database (Scopus). Screening, selection, and extraction processes will be conducted by independent and previously trained researchers. The risk of bias will be assessed using the Risk of Bias 2.0 and ROBINS-I tools. Results will be summarized in a qualitative and quantitative synthesis, including specificity and subgroup analyses.

Human gelatin thrombin matrix with rifampin for the treatment of prosthetic vascular graft infections.

We aim to describe and report on a novel graft preservation technique using a human gelatin thrombin matrix with rifampin for the treatment of vascular graft infections. Eight patients with vascular graft infections were included, one with bilateral infections, for a total of nine cases from January 2016 through June 2021. All the patients underwent wound exploration and placement of human gelatin thrombin matrix with rifampin. No deaths or allergic reactions had been reported at the 30-day follow-up, with only one major amputation. The graft and limb salvage rates were 77.8% at the 1-year follow-up. The mean time to a major amputation was 122 days, and the mean time to graft excision was 30 days.

Partial recovery of tuberculosis preventive treatment in Brazil after pandemic drawback / Recuperação parcial do tratamento preventivo da tuberculose no Brasil após o recuo pandêmico / Recuperación parcial del tratamiento preventivo de la tuberculosis en Brasil tras el retroceso pandémico

Abstract: Brazil was heavily affected by COVID-19 both with death toll and economically, with absence of a centralized Federal Government response. Tuberculosis (TB) notifications decreased in 2020 but partial recovery was observed in 2021. We have previously shown a sharp (93%) reduction in TB preventive treatment notifications among five Brazilian cities with more than 1,000 notifications in 2021. We hypothesized TB preventive treatment would also recover. We updated the previous analysis by adding other cities that hold more than a 1,000 notifications until 2022. Data aggregated by 2-week periods were extracted from the Information System for Notifying People Undergoing Treatment for LTBI (IL-TB). Biweekly percentage change (BPC) of notifications until October 2022 and outcomes until July 2022 (in the two weeks of TB preventive treatment initiation) were analyzed using Joinpoint software. A total of 39,701 notifications in 11 cities were included, 66% from São Paulo and Rio de Janeiro, Brazil. We found a significant increase of TB preventive treatment notifications in the beginning of 2021 (BPC range 1.4-49.6), with sustained progression in seven out of the 11 cities. Overall, median completion rates were 65%. In most cities, a gradual and steady decrease of treatment completion rates was found, except for Rio de Janeiro and Manaus (Amazonas State, Brazil), where a BPC of 1.5 and 1.2, respectively, was followed by a sustained increase. Notifications and completion proportions of TB preventive treatment were heterogeneous, which partly reflects the heterogeneity in local response to the pandemic. We found that notifications were recovered, and that the sharp 2021 decrease was no longer observed, which suggests delays in notification. In conclusion, the sharp reductions in TB preventive treatment completion rates in most cities might have been caused by delays in reporting; however, the sustained and progressive decrease are a concern.

Resumo: O Brasil foi fortemente atingido pela COVID-19 tanto com número de mortes quanto economicamente, com ausência de uma resposta centralizada do Governo Federal. As notificações de tuberculose (TB) diminuíram em 2020, mas se recuperaram parcialmente em 2021. Já mostramos uma redução acentuada (93%) nas notificações de tratamento preventivo de TB nas cinco cidades brasileiras com mais de 1.000 notificações em 2021. Hipotetizamos que o tratamento preventivo de TB também recuperar-se-ia. Atualizamos a análise anterior acrescentando outras cidades que apresentaram mais de 1.000 notificações até 2022. Os dados agregados por períodos de duas semanas foram extraídos do Sistema de Informação para Notificação das Pessoas em Tratamento de ILTB (IL-TB). As notificações quinzenais de variação percentual até outubro de 2022 e os desfechos até julho de 2022 (nas duas semanas de início do tratamento precoce de TB) foram analisados usando o software Joinpoint. Foram incluídas 39.701 notificações em 11 cidades, sendo 66% delas de São Paulo e do Rio de Janeiro (Brasil). Encontramos um aumento significativo das notificações de tratamento preventivo de TB no início de 2021 (faixa de variação quinzenal percentual 1,4-49,6), com progressão sustentada em 7/11 cidades. No geral, as taxas medianas de conclusão foram de 65%. Na maioria dos municípios, houve queda gradual e constante das taxas de conclusão de tratamento, com exceção do Rio de Janeiro e Manaus (Amazonas, Brasil), onde a variação quinzenal percentual de 1,5 e 1,2, respectivamente, foi acompanhada de aumento sustentado. As notificações e proporções de tratamento preventivo de TB completados foram heterogêneas, o que reflete em parte a diversidade na resposta local à pandemia. No geral, as notificações se recuperaram e a queda acentuada de 2021 não é mais observada, o que sugere atrasos na notificação. Em conclusão, a redução das taxas de conclusão do tratamento preventivo da TB na maioria das cidades pode refletir atrasos na notificação, mas a diminuição sustentada e progressiva das notificações preocupa.

Resumen: Brasil fue seriamente afectado por el COVID-19, tanto con el número de muertes como económicamente, con la ausencia de una respuesta centralizada del Gobierno Federal. Las notificaciones de la tuberculosis (TB) redujeron en 2020, pero aumentaron parcialmente en 2021. Ya mostramos una reducción drástica (el 93%) en las notificaciones del tratamiento preventivo de la TB en las cinco ciudades brasileñas con más de 1.000 notificaciones en 2021. Nuestra hipótesis es que el tratamiento preventivo de la TB también aumentaría. Actualizamos el análisis anterior añadiendo otras ciudades que presentaron más de 1.000 notificaciones hasta 2022. Los datos agregados durante períodos de dos semanas se extrajeron del Sistema de Información de Notificaciones para Personas en Tratamiento por ILTB (IL-TB). Las notificaciones quincenales de cambio porcentual hasta octubre de 2022 y os resultados hasta julio de 2022 (en las dos semanas iniciales del tratamiento precoz de la tuberculosis) se analizaron a través del software Joinpoint. Se incluyeron 39.701 notificaciones en 11 ciudades, siendo el 66% de ellas en São Paulo y Rio de Janeiro, Brasil. Encontramos un aumento significativo de las notificaciones del tratamiento preventivo de la TB a principios de 2021 (rango de cambio porcentual quincenal 1,4-49,6), con progresión sostenida en siete de las once ciudades. En general, las tasas medias de finalización fueron del 65%. En la mayoría de los municipios, hubo una reducción gradual y constante de las tasas de finalización de tratamiento, salvo en Rio de Janeiro y Manaus (Amazonas, Brasil), donde el cambio porcentual quincenal de 1,5 y 1,2, respectivamente, estuvo acompañado de un aumento sostenido. Las notificaciones y proporciones de cumplimentación del tratamiento preventivo de la TB fueron heterogéneas, lo que refleja la heterogeneidad en la respuesta local a la pandemia. En general, las notificaciones aumentaron y ya no se observa la fuerte caída de 2021 lo que refleja en parte retrasos en la notificación. En conclusión, la reducción en las tasas de finalización del tratamiento preventivo de la TB en la mayoría de las ciudades puede reflejar retrasos en la notificación, pero la reducción sostenida y progresiva es una preocupación.

Is the Pharmacokinetics of First-Line Anti-TB Drugs a Cause of High Mortality Rates in TB Patients Admitted to the ICU? A Non-Compartmental Pharmacokinetic Analysis.

BACKGROUND: Patients with tuberculosis (TB) may develop multi-organ failure and require admission to intensive care. In these cases, the mortality rates are as high as 78% and may be caused by suboptimal serum concentrations of first-line TB drugs. This study aims to compare the pharmacokinetics of oral rifampin, isoniazid, pyrazinamide and ethambutol patients in intensive care units (ICU) to outpatients and to evaluate drug serum concentrations as a potential cause of mortality. METHODS: A prospective pharmacokinetic (PK) study was performed in Amazonas State, Brazil. The primary PK parameters of outpatients who achieved clinical and microbiological cure were used as a comparative target in a non-compartmental analysis. RESULTS: Thirteen ICU and twenty outpatients were recruited. The clearance and volume of distribution were lower for rifampin, isoniazid, pyrazinamide and ethambutol. ICU thirty-day mortality was 77% versus a cure rate of 89% in outpatients. CONCLUSIONS: ICU patients had a lower clearance and volume of distribution for rifampin, isoniazid, pyrazinamide and ethambutol compared to the outpatient group. These may reflect changes to organ function, impeded absorption and distribution to the site of infection in ICU patients and have the potential to impact clinical outcomes.

Implementation of an integrated care strategy for child contacts of tuberculosis patients: a quasi-experimental study protocol.

BACKGROUND: Childhood tuberculosis continues to be a major public health problem. Although the visibility of the epidemic in this population group has increased, further research is needed. OBJECTIVE: To design, implement and evaluate an integrated care strategy for children under five years old who are household contacts of bacteriologically confirmed pulmonary tuberculosis patients in Medellín and the Metropolitan Area. METHODS: A quasi-experimental study in which approximately 300 children who are household contacts of bacteriologically confirmed pulmonary tuberculosis patients from Medellín and the Metropolitan Area will be evaluated and recruited over one year. A subgroup of these children, estimated at 85, who require treatment for latent tuberculosis, will receive an integrated care strategy that includes: some modifications of the current standardized scheme in Colombia, with rifampicin treatment daily for four months, follow-up under the project scheme with nursing personnel, general practitioners, specialists, professionals from other disciplines such as social work, psychology, and nutritionist. Additionally, transportation and food assistance will be provided to encourage treatment compliance. This strategy will be compared with isoniazid treatment received by a cohort of children between 2015 and 2018 following the standardized scheme in the country. The study was approved by the CIB Research Ethics Committee and UPB. CLINICALTRIALS: gov identifier NCT04331262. DISCUSSION: This study is expected to contribute to the development of integrated care strategies for the treatment of latent tuberculosis in children. The results will have a direct impact on the management of childhood tuberculosis contributing to achieving the goals proposed by the World Health Organization's End TB Strategy. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04331262 . Implementation of an Integrated Care Strategy for Children Contacts of Patients with Tuberculosis. Registered 2 April 2020.

Biofilm-forming microorganisms causing hospital-acquired infections from intravenous catheter: A systematic review.

The high prevalence of nosocomial infections is related to the use of medical insertion devices such as central venous catheters (CVCs). Most of the microorganisms causing nosocomial infections are biofilm producers, this characteristic allows them to adhere to abiotic surfaces and cause initial catheter infections that can lead to bloodstream infections. Our main goal in this systematic review was to evaluate the prevalence of biofilm among CVC-related infections, particularly among Intensive Care Unit (ICU) patients, in the studies applying different in vitro and in vivo methodologies. All studies reporting clinical isolates from patients with catheter-related nosocomial infections and biofilm evaluation published up to 24 June 2022 in the PubMed and Scopus databases were included. Twenty-five studies met the eligibility criteria and were included in this systematic review for analysis. Different methodologies were applied in the assessment of biofilm-forming microorganisms including in vitro assays, catheter-infected in vitro, and in vivo mouse models. The present study showed that between 59 and 100% of clinical isolates were able to form biofilms, and the prevalence rate of biofilm formation varied significantly between studies from different countries and regions. Among the clinical isolates collected in our study set, a wide variety of microorganisms including Gram-positive strains, Gram-negative strains, and Candida albicans were found. Many authors studied resistance mechanisms and genes related to biofilm development and surface adherence properties. In some cases, the studies also evaluated biofilm inhibition assays using various kinds of catheter coatings.

Tuberculosis treatment without rifampin in kidney/kidney-pancreas transplantation: A case series report.

BACKGROUND: The best approach to tuberculosis (TB) treatment in transplanted patients is still unknown. Current guidelines are based on evidence either extrapolated from other populations or observational. Rifampin-containing regimens have strong pharmacokinetic interactions with immunosuppressive regimens, with high rates of organ dysfunction and ∼20% mortality. This report describes the results obtained using non-rifampin-containing regimens to treat confirmed TB in adult patients with kidney/kidney-pancreas transplantation. METHODS: Retrospective data analysis from confirmed TB cases in adult kidney/kidney-pancreas transplant recipients (2006-2019), treated "de novo" with non-rifampin-containing regimens. RESULTS: Fifty-seven patients had confirmed TB. Thirty patients were treated "de novo" with non-rifampin-containing regimens. These patients' mean age was 49.24 (±11.50) years. Induction immunosuppression was used in 22 patients. Maintenance immunosuppression was tacrolimus-mycophenolate-steroids in 13 (43%), sirolimus-mycophenolate-steroids in 6 (20%), and other immunosuppressive regimens in 11 (36%). Belatacept was used in four patients. TB localizations: pulmonary 43%; disseminated 23%; extrapulmonary 33%. Twenty-seven (90%) patients completed treatment with isoniazid, ethambutol, and levofloxacin (12 months, 23; 9 months, 3; 6 months, 1); 12 of these patients also received pyrazinamide for the first 2 months and were cured with functioning grafts. One patient (3%) lost the graft while on treatment. Two patients (7%) died while on TB treatment. Median (range) follow-up after completion of TB treatment was 32 (8-150) months. No TB relapses were observed. CONCLUSIONS: Results with non-rifampin-containing TB treatments in this case series were better (in terms of mortality and graft dysfunction) than those previously described with rifampin-containing regimens in transplanted patients.

Avances en tuberculosis en el 54° congreso chileno de enfermedades respiratorias. 1ra parte: nuevos esquemas acortados para tuberculosis drogoresistente ¿son adecuados para todos? / New shortened schemes for drug-resistant tuberculosis: are they suitable for everyone?

En esta presentación se realiza un recorrido a través de los diferentes esquemas terapéuticos de la tuberculosis drogo-resistente. Se muestra como los investigadores utilizan los nuevos fármacos disponibles y desarrollan diferentes esquemas cada vez más acortados y de administración por vía oral exclusiva, con la intención de lograr una mayor eficacia de curación de la tuberculosis resistente, con menos efectos colaterales y menor letalidad. La búsqueda de esquemas con una duración similar a las terapias de casos sensibles de tuberculosis (esquemas primarios de 6 meses) es el objetivo principal. Las pruebas moleculares como el Xpert ayudan enormemente a seleccionar los esquemas de terapia, según el perfil de susceptibilidad de los casos (resistencia a isoniazida, rifampicina, fluorquinolonas y combinaciones). Las terapias actuales de la tuberculosis drogo-resistente se basan en nuevos fármacos como fluorquinolonas, bedaquilina y linezolid, pero otros fármacos como pretomanid y delamanid también están siendo recomendados.

This presentation takes a tour through the different therapeutic schemes of drug-resistant tuberculosis. It shows how researchers use the new drugs available and develop different increasingly shortened schedules and exclusive oral administration, with the intention of achieving greater efficacy in curing resistant tuberculosis, with fewer side effects and lower lethality. The search for regimens with a duration similar to therapies of sensitive cases of tuberculosis (primary regimens of 6 months) is the main objective. Molecular tests, such as Xpert, greatly help in selecting therapy regimens, according to the susceptibility profile of the cases (resistance to isoniazid, rifampicin, fluorquinolones and combinations). Current drug-resistant tuberculosis therapies are based on new drugs such as fluorquinolones, bedaquiline and linezolid, but other drugs such as pretomanid and delamanid are also being recommended.

Novel approaches in the treatment of Hansen's disease (Leprosy): a case series of multidrug therapy of monthly rifampin, moxifloxacin, and minocycline (RMM) in the United States.

The World Health Organization (WHO) recommends multidrug therapy (MDT) for the treatment of paucibacillary and multibacillary forms of leprosy, also known as Hansen's disease (HD). MDT combinations of dapsone, rifampin, and clofazimine have reduced the prevalence of the disease but are not without adverse effects impacting regimen adherence. Hence, an urgent need exists to consider alternative MDT regimens with an improved safety profile that promotes treatment adherence. Herein, we described a case series of 10 patients with HD (nine patients with multibacillary leprosy and one with pure neural leprosy) treated with monthly rifampin, moxifloxacin, and minocycline (RMM). The United States National Hansen's Disease Program (NHDP) diagnosed and treated patients across US institutions. All patients received a regimen of 12-24 months of RMM. We reviewed the clinical outcomes, adherence, rate of completion, and adverse events of patients treated with monthly RMM from January 2019 to August 2022. Nine patients had multibacillary leprosy, with some having type-2 reactions. One patient had pure neural leprosy with a reversal reaction. In this case series, we identified that all patients completed the RMM regimen without treatment interruptions. None of the patients experienced any skin hyperpigmentation or any significant side effects. All patients tolerated the monthly RMM regimen with rapid improvement of skin lesions and without logistic hurdles. Based on previous clinical evidence and the results of this case series, the NHDP and other programs should consider the RMM regimen as first-line therapy.

SLCO1B1 and SLC10A1 polymorphism and plasma rifampin concentrations in patients with co-morbidity tuberculosis-diabetes mellitus in Baja California, Mexico.

Rifampicin is one of the most important drugs for the treatment of tuberculosis (TB). Polymorphisms in SLCO1B1 and SLC10A1 genes are associated with impaired transporter function of drug compounds such as rifampicin. The relationship between genetic variation, clinical comorbidities, and rifampicin exposures in TB patients has not been completely elucidated. The aim of this study was to investigate the prevalence of SLCO1A1 and SLCO1B1 polymorphisms in TB and TB-DM patients and to determine their relationship with rifampicin pharmacokinetics on patients from México. Blood samples were collected in two hospitals in Baja California, Mexico from February through December 2017. Sampling included 19 patients with TB, 11 with T2DM and 17 healthy individuals. Polymorphisms genotype rs2306283, rs11045818, rs11045819, rs4149056, rs4149057, rs72559746,rs2291075 and rs4603354 of SLCO1B1 and rs4646285 and rs138880008 of SLC10A1 were analyzed by Sanger's sequencing. None of the SLCO1B1 and SLC10A1 variants were significantly associated with rifampicin Cmax. TB and T2DM patients with suboptimal Cmax rifampicin levels showed wild alleles in rs11045819 and rs2291075 in SLCO1B1 SLC10A1 and SLC10A1. This is the first study to analyze SLC10A1 and SLCO1B1 polymorphisms in TB and TB-T2DM patients and healthy individuals in Mexico. Further research to confirm and extend these findings is necessary.

Lesión renal aguda y anemia hemolítica autoinmune inducida por rifampicina, una complicación poco frecuente y potencialmente mortal / Acute kidney injury and hemolytic anemia induced by rifampin, an infrequent and deadly complication

La rifampicina es un medicamento ampliamente utilizado para el tratamiento de diversas infecciones bacterianas con un amplio espectro de efectos adversos que varían desde reacciones leves hasta potencialmente fatales; la anemia hemolítica es un efecto adverso escasamente reportado en la literatura pero que puede tener un desenlace potencialmente fatal, reportamos así un caso de anemia hemolítica autoinmune asociada a lesión renal aguda en una paciente joven en segunda fase de tratamiento para tuberculosis pulmonar.

Summary Rifampicin is a widely used drug for the treatment of various infectious diseases with a broad spectrum of adverse reaction ranging from mild to life-threatening manifestations; hemolytic anemia is an adverse effect rarely reported in the literature, but it can have a potentially fatal outcome. Thus, we report a case of autoimmune hemolytic anemia associated with acute kidney injury in a young patient in the second phase of treatment for pulmonary tuberculosis.

An uncommon case of brucellosis with ocular presentation / Um caso incomum de brucelose com apresentação ocular

ABSTRACT We report an unusual case of brucellosis presented with headache, diminished vision, papillitis and multiple peripapillary hemorrhages accompanied by subretinal fluid extending up to macula. Diagnosis of brucellosis was made based on positive polymerase chain reaction of cerebrospinal fluid sample for Brucella species DNA, accompanied by a raised titer of anti-brucella antibodies. Patient showed remarkable improvement on triple drug therapy in form of doxycycline, rifampicin and ceftriaxone.

RESUMO Relatamos um caso incomum de brucelose apresentada com cefaleia, visão diminuída, papilite e múltiplas hemorragias peripapilares acompanhadas por fluido sub-retinal, estendendo-se até a mácula. O diagnóstico de brucelose foi feito com base na reação em cadeia da polimerase positiva de amostra de líquido cefalorraquidiano para DNA de espécies de Brucella, acompanhada por um título elevado de anticorpos antibrucela. O paciente apresentou melhora notável com a terapia tripla com drogas na forma de doxiciclina, rifampicina e ceftriaxona.

Mycolicibacterium fortuitum genomic epidemiology, resistome and virulome

BACKGROUND Mycolicibacterium fortuitum is an opportunistic pathogen associated with human and animal infection worldwide. Studies concerning this species are mainly represented by case reports, some of them addressing drug susceptibility with a focus on a specific geographic region, so there is a gap in relation to the global epidemiological scenario. OBJECTIVES We aimed determine the global epidemiological scenario of M. fortuitum and analyse its traits associated with pathogenicity. METHODS Based on publicly available genomes of M. fortuitum and a genome from Brazil (this study), we performed a genomic epidemiology analysis and in silico and in vitro characterisation of the resistome and virulome of this species. FINDINGS Three main clusters were defined, one including isolates from the environment, human and animal infections recovered over nearly a century. An apparent intrinsic resistome comprises mechanisms associated with macrolides, beta-lactams, aminoglycosides and antitubercular drugs such as rifampin. Besides, the virulome presented Type VII secretion systems (T7SS), including ESX-1, ESX-3, ESX-4 and ESX-4-bis, some of which play a role on the virulence of Mycobacteriaceae species. MAIN CONCLUSIONS Here, M. fortuitum was revealed as a reservoir of an expressive intrinsic resistome, as well as a virulome that may contribute to its success as a global opportunist pathogen.

Coverage and fidelity of the Xpert MTB/RIF™ implementation in a high-burden area for pulmonary tuberculosis in Colombia / [Cobertura y fidelidad de la prueba Xpert MTB/RIF™ en un área de alta carga de tuberculosis pulmonar en Colombia].

Introduction: The Xpert MTB/RIF™ is a rapid molecular test that diagnoses tuberculosis and rifampin resistance. Since 2010, it is recommended by the World Health Organization (WHO) and although it was introduced in Colombia since 2012, the results of its implementation are unknown. Objective: To describe the coverage and fidelity in the implementation of the Xpert MTB/RIF™ in patients with pulmonary tuberculosis in a city with a high burden for the disease in Colombia. Materials and methods: We conducted a retrospective, descriptive study of cases from a tuberculosis program in Cali between 2013 and 2019. We estimated the coverage as the total number of tests used compared to the cases registered in the program and the fidelity based on international Xpert MTB/RIF™ implementation protocols. We performed a multivariate analysis of multiple correspondences between the test and the sociodemographic variables. Results: We included 6,328 patients with pulmonary tuberculosis of whom 181 were drugresistant. The Xpert MTB/RIF™ coverage was 10,3% (n=655) with an annual variation between 0.2% and 23%. Loyalty among the highest risk groups of MDR-TB was 46.8%. The use of the test was related to being an Afro-Colombian man between 41 and 60 years of age. Conclusions: The coverage of the Xpert MTB/RIF in Cali is low and its use does not follow the recommended prioritization for its implementation. Implementation strategies are required for its proper use to contribute to the goal of ending tuberculosis.

Introducción. La prueba Xpert MTB/RIF™ es una prueba molecular rápida para el diagnóstico de la tuberculosis y la resistencia a la rifampicina. Desde el 2010 es la recomendada por la Organización Mundial de la Salud (OMS) y, aunque fue introducida en Colombia en el 2012, se desconocen los resultados de su uso. Objetivo. Describir la cobertura y la fidelidad en el uso de la prueba Xpert MTB/RIF™ en pacientes con tuberculosis pulmonar en una ciudad con alta carga de la enfermedad en Colombia. Materiales y métodos. Se hizo un estudio retrospectivo descriptivo de casos del programa de tuberculosis en Cali entre el 2013 y el 2019. La cobertura se estimó como el total de pruebas empleadas en los casos registrados en el programa. La fidelidad se midió con base en los protocolos internacionales de uso de la Xpert MTB/RIF™. Además, se hizo un análisis de correspondencias múltiples entre la prueba y las variables sociodemográficas. Resultados. Se incluyeron 6.328 pacientes con tuberculosis pulmonar, de los cuales 181 eran resistentes a los fármacos. La cobertura total de la Xpert MTB/RIF™ durante el periodo de estudio fue de 10,3 % (n=655), con una variación anual entre 0,2 y 23 %. La fidelidad fue de 46,8 % para los grupos de mayor riesgo de tuberculosis multirresistente (TB-MDR). El uso de la prueba se relacionó con la condición de ser hombre, afrocolombiano, y tener entre 41 y 60 años de edad. Conclusiones. La cobertura de la prueba Xpert MTB/RIF™ en Cali es baja y su uso no responde a la priorización recomendada para su implementación. Se requieren estrategias para promover su uso adecuado, de manera que contribuya a la meta de poner fin a la tuberculosis.

Cobertura y fidelidad de la prueba Xpert MTB/RIF™ en un área de alta carga de tuberculosis pulmonar en Colombia / Coverage and fidelity of the Xpert MTB/RIF™ implementation in a high-burden area for pulmonary tuberculosis in Colombia

Resumen. Introducción. La prueba Xpert MTB/RIF™ es una prueba molecular rápida para el diagnóstico de la tuberculosis y la resistencia a la rifampicina. Desde el 2010 es la recomendada por la Organización Mundial de la Salud (OMS) y, aunque fue introducida en Colombia en el 2012, se desconocen los resultados de su uso.Objetivo. Describir la cobertura y la fidelidad en el uso de la prueba Xpert MTB/RIF™ en pacientes con tuberculosis pulmonar en una ciudad con alta carga de la enfermedad en Colombia.Materiales y métodos. Se hizo un estudio retrospectivo descriptivo de casos del programa de tuberculosis en Cali entre el 2013 y el 2019. La cobertura se estimó como el total de pruebas empleadas en los casos registrados en el programa. La fidelidad se midió con base en los protocolos internacionales de uso de la Xpert MTB/RIF™. Además, se hizo un análisis de correspondencias múltiples entre la prueba y las variables sociodemográficas.Resultados. Se incluyeron 6.328 pacientes con tuberculosis pulmonar, de los cuales 181 eran resistentes a los fármacos. La cobertura total de la Xpert MTB/RIF™ durante el periodo de estudio fue de 10,3 % (n=655), con una variación anual entre 0,2 y 23 %. La fidelidad fue de 46,8 % para los grupos de mayor riesgo de tuberculosis multirresistente (TB-MDR). El uso de la prueba se relacionó con la condición de ser hombre, afrocolombiano, y tener entre 41 y 60 años de edad.Conclusiones. La cobertura de la prueba Xpert MTB/RIF™ en Cali es baja y su uso no responde a la priorización recomendada para su implementación. Se requieren estrategias para promover su uso adecuado, de manera que contribuya a la meta de poner fin a la tuberculosis.

Abstract. Introduction:The Xpert MTB/RIF™ is a rapid molecular test that diagnoses tuberculosis and rifampin resistance. Since 2010, it is recommended by the World Health Organization (WHO) and although it was introduced in Colombia since 2012, the results of its implementation are unknown.Objective: To describe the coverage and fidelity in the implementation of the Xpert MTB/RIF™ in patients with pulmonary tuberculosis in a city with a high burden for the disease in Colombia.Materials and methods: We conducted a retrospective, descriptive study of cases from a tuberculosis program in Cali between 2013 and 2019. We estimated the coverage as the total number of tests used compared to the cases registered in the program and the fidelity based on international Xpert MTB/RIF™ implementation protocols. We performed a multivariate analysis of multiple correspondences between the test and the sociodemographic variables.Results: We included 6,328 patients with pulmonary tuberculosis of whom 181 were drug-resistant. The Xpert MTB/RIF™ coverage was 10,3% (n=655) with an annual variation between 0.2% and 23%. Loyalty among the highest risk groups of MDR-TB was 46.8%. The use of the test was related to being an Afro-Colombian man between 41 and 60 years of age.Conclusions: The coverage of the Xpert MTB/RIF in Cali is low and its use does not follow the recommended prioritization for its implementation. Implementation strategies are required for its proper use to contribute to the goal of ending tuberculosis.

Acute tubulointerstitial nephritis due to the use of rifampicin. case report

ABSTRACT Introduction: Rifampin is a cornerstone for the first phase of the treatment of pulmonary tuberculosis. This report presents the case of a patient with allergic tubulointerstitial nephritis (ATIN) due to rifampin, situation that has not been reported in Colombia. Case presentation: A male patient with a history of pulmonary tuberculosis treated with rifampin developed acute kidney injury. On admission, no evidence of abnormalities or history to explain the injury was found, but he did present tubular acidosis and associated Fanconi syndrome. The kidney injury was temporarily consistent with rifampicin use, and a kidney biopsy confirmed ATIN. The drug was suspended, resulting in improved kidney function. Discussion: ATIN as a side effect of rifampin is a scarcely reported disease. The risk of developing this condition should be considered when starting and restarting treatments with this medication. Conclusion: ATIN is one of the side effects of tuberculosis treatment. Albeit rare, it should be considered when starting tuberculosis medications.

RESUMEN Introducción. La rifampicina es un medicamento fundamental en la primera fase del tratamiento en la tuberculosis pulmonar; sin embargo, esta puede causar nefritis tubulointersticial aguda (NTIA) en raras ocasiones. Presentación del caso. Paciente masculino con antecedentes de tuberculosis y en tratamiento con rifampicina, quien desarrolló lesión renal aguda. Al ingreso, el sujeto no registró anormalidades o antecedentes que explicaran lesión renal, pero sí presentaba acidosis tubular y síndrome de Fanconi asociado. La lesión renal concordó temporalmente con el uso de rifampicina y una biopsia de riñón confirmó NTIA. Se ordenó suspender el medicamento, con lo cual la función renal mejoró. Discusión. La NTIA como un efecto secundario de la rifampicina es una enfermedad poco reportada, por tanto, al iniciar y al reiniciar el manejo con este medicamento se debe tener en cuenta el riesgo de desarrollarla. Conclusión. La NTIA es uno de los efectos secundarios del tratamiento de la tuberculosis y, aunque es raro, debe tenerse en cuenta al iniciar el esquema de medicamentos para la tuberculosis.

Possible Binding of Piperine in Mycobacterium tuberculosis RNA Polymerase and Rifampin Synergism.

The activity of rifampin (RIF) and piperine was evaluated at the relative transcript levels of 12 efflux pumps (EPs), and an additional mechanism was proposed to be behind the synergic interactions of piperine plus RIF in Mycobacterium tuberculosis AutoDock v4.2.3 and Molegro v6 programs were used to evaluate PIP binding in M. tuberculosis RNA polymerase (RNAP). A hypothesis has been raised that piperine interferes in M. tuberculosis growth through RNAP inhibition, differently from what was previously endorsed for EP inhibition only.

Nefritis intersticial aguda inducida por rifampicina en un paciente con tuberculosis pulmonar / Rifampicin-induced acute interstitial nephritis in a patient with pulmonary tuberculosis

La tuberculosis (TB) constituye un grave problema de salud en el mundo y está relacionada con problemáticas sociales que dificultan su control y erradicación como la pobreza, la marginalidad y el hacinamiento. Aunque la toxicidad hepática por rifampicina es bien conocida, la nefrotoxicidad es una complicación poco frecuente y grave del tratamiento antituberculosis. El deterioro de la función renal, determinado por nefritis tubulointersticial aguda o necrosis tubular aguda o ambos, por lo general aparece en pacientes que reciben tratamiento intermitente; no obstante, algunos autores han informado casos ocurridos durante la terapia continua con rifampicina.Con frecuencia la lesión renal aguda inducida por rifampicina tiene un curso favorable con tratamiento y una recuperación completa de la función renal en un lapso de tres meses. El siguiente reporte describe un paciente en tratamiento por TB Pulmonar, que desarrolló toxicidad renal inducida por rifampicina

Validación e implementación de GeneXpert MTB/RIF para diagnóstico de tuberculosis en Ecuador / Validation and implementation of GeneXpert MTB/RIF for diagnosis of Tuberculosis in Ecuador

El objetivo del estudio fue la validación e implementación de GeneXpert MTB/RIF para uso rutinario en la detección rápida de tuberculosis, y sensibilidad a la rifampicina en muestras clínicas; para esto se recogieron 1592 muestras respiratorias y fueron analizadas en el laboratorio del Instituto Nacional de Investigación en Salud Pública Guayaquil. El análisis de los resultados de GeneXpert en comparación con la baciloscopía mostraron una sensibilidad inicial de 99,8% y especificidad de 93,2%; el análisis de discrepancias utilizando los resultados del cultivo como método de referencia mostró que los resultados de GeneXpert considerados falsos negativos resultaron ser verdaderos negativos, lo mismo sucede con los falsos positivos que corresponden a verdaderos positivos. Recalculada la sensibilidad y especificidad del GeneXpert se tuvo 99,8% y 100% correspondientemente. La comparación con pruebas de sensibilidad a drogas mostró una sensibilidad de 91,4% y una especificidad del 95,5% para el sistema GeneXpert MTB/RIF. Se concluye que la implementación del sistema GeneXpert en Ecuador permitió dar solución a ciertos problemas asociados con la aplicación de las metodologías de diagnóstico convencionales, disminuyendo los tiempos de espera, e incrementando la sensibilidad y especificidad en el diagnóstico de la tuberculosis resistente a drogas, generando una valiosa oportunidad de diagnóstico temprano.

The objective of the study was the validation and implementation of GeneXpert MTB/RIF for routine use in the rapid detection of tuberculosis and sensitivity to rifampicin in clinical samples; for this, 1592 respiratory samples were collected and analyzed in the laboratory of Instituto Nacional de Investigación en Salud Pública Guayaquil. The analysis of the results of GeneXpert in comparison with smear microscopy showed an initial sensitivity of 99.8% and specificity of 93.2%; The analysis of discrepancies using the results of the culture as a reference method showed that the GeneXpert results considered false negatives turned out to be true negatives, the same happens with the false positives that correspond to true positives. Recalculated the sensitivity and specificity of the Xpert was 99.8% and 100% correspondingly. The comparison with the drugs susceptibility test showed a sensitivity of 91.4% and a specificity of 95.5% for the GeneXpert MTB/RIF system. It is concluded that the implementation of the Xpert system allows solution to certain problems associated with the application of conventional diagnostic methodologies, decreasing the waiting times, and increasing the sensitivity and specificity in the diagnosis of drug-resistant tuberculosis, thus generating a valuable opportunity for early diagnosis.