Exploring stakeholders perspectives on TB contact investigation in Cali, Colombia: a qualitative study.

Introduction: Contact investigation is a proven intervention for tuberculosis (TB) case finding and prevention. Although widely endorsed by national public health authorities and the World Health Organization, many countries struggle to implement it effectively. The objective of the study is to describe and characterize the barriers and facilitators of TB contact investigation in Cali, Colombia from the perspective and experience of the key stakeholders involved. Methods: We collected data from group discussions during two workshop sessions with clinic and public health staff involved in TB contact investigation (June 2019 and March 2020 respectively) and semi-structured interviews with TB cases and their household contacts (July 2019 to April 2020). We undertook an inductive thematic analysis with the RADaR technique to characterize the barriers and facilitators of the TB contact investigation process. Results: The two workshops included 21 clinics and 12 public health staff. We also conducted 26 semi-structured interviews with TB cases and their household contacts. Using thematic analysis, we identified four common themes: Healthcare Operations, Essential Knowledge, Time Limitations and Competing Responsibilities, and Interpersonal Interactions. The main barriers to conducting household visits were low data quality, stigma and mistrust, safety concerns for health workers, and limited resources. The main barriers to TB uptake by contacts were competing responsibilities, low TB risk perceptions among contacts, and difficulty accessing diagnostic tests for contacts. In contrast, good communication and social skills among health workers and accurate TB knowledge facilitated successful household visits and TB test uptake, according to key stakeholders. Conclusion: This study provides a deeper understanding of TB contact investigation barriers and facilitators in a high-prevalence urban setting in a middle-income country from the perspective and experience of key stakeholders. The study shed light on the barriers that hinder household contacts engagement and TB test uptake such as issues of systemic capacity and TB knowledge. Also, highlighted facilitators such as the importance of interpersonal communication skills among health workers in the public and private sector. The insights from this study can serve as a valuable resource for public health organizations seeking to enhance their contact investigation efforts and improve TB control in similar settings.

First Report of Acanthocheilonema reconditum Outbreak in Canines with Clinical Signs of Anemia from Southwestern Colombia.

Different nematodes affect canines, however Acanthocheilonema reconditum was considered mostly a non-pathogenic parasite. Climate change, animal migration, and other factors transformed the dynamics of vector-borne diseases, including filariasis. Since 2016, a sudden increase in the number of dogs with microfilaremia was reported by different veterinary centers in Cali, southwest Colombia. The objective of this study was to molecularly identify the etiologic agent of this filariasis outbreak detected in this city, using PCR−RFLP and evaluating dogs' clinical signs. From 2018−2019, canine filariasis cases were prospectively evaluated after a microscopic test, recruiting 82 cases and 43 healthy controls from 2971 samples. Acanthocheilonema reconditum (Nematoda, Onchocercidae) was identified in 61.3% of the cases (49/82) by PCR−RFLP. Sanger sequencing of the 5.8S ribosomal RNA gene and internal transcribed spacer-2 fragment was additionally performed on seven cases, confirming A. reconditum in all of them. The filariasis cases are statistically associated with male dogs who have clinical signs of anemia, low levels of hemoglobin and hematocrit (p < 0.0001), and high levels of plasma proteins (p < 0.001). This emerging canine disease constitutes an important public health concern among veterinarians and active surveillance is advised to explore its zoonotic potential.

Quinta arremetida de COVID-19 y el uso de mascarillas en espacios abiertos y cerrados / Fifth peak of COVID-19 and use of masks in open and enclosed spaces

Introduction: COVID-19 pandemic requires permanent adaptations in management depending on the epidemiological situation. Objective: To analyze the epidemiological behavior of COVID-19 in Cali (Colombia) after ending the face mask mandate in open and enclosed spaces between March 1 and July 11 of 2022. Materials and methods: An observational descriptive study of COVID-19 cases and cumulative incidence (CI) for 7 days with two temporary milestones: refusal of the obligatory use of face masks in open and enclosed environments, using data published by the National Institute of Health. The temporary tendency was evaluated with the Mann-Kendall non parametric test. Results: Differences were found between the first and second milestone; 922 cases in 75 days vs. 12,037 in 59 days; Tau=-0.22 vs. 0.57, S=-608 vs. 968, Var(S)=47,574.66 versus 233,280.66; Sen slope=-0.10 (IC95%: -0.18 and -0.03) versus 7.39 (IC95%: 5.23 and 8.88). After the second milestone, the CI increased with a positive tendency (S=23, p=0.006). Conclusions: The significant increases of COVID-19 cases and the CI coincided with the ending of the face mask mandate in enclosed spaces. Therefore, it is advisable to return to the use of face masks in enclosed spaces, strengthen infodemic management, promote vaccination, and improve natural ventilation.

Introducción: La pandemia COVID-19 demanda permanentes adaptaciones en la gestión según la situación epidemiológica. Objetivo: Analizar el comportamiento epidemiológico de COVID-19 en Cali (Colombia) post levantamiento de obligatoriedad de usar mascarillas en ambientes abiertos y cerrados, entre marzo 1 y julio 11/2022. Materiales y métodos: Estudio observacional descriptivo de casos de COVID-19 e incidencia acumulada (IA) para 7 días, con dos hitos temporales: desistimiento del uso mandatorio de mascarillas en ambientes abiertos y cerrados, usando datos publicados por el Instituto Nacional de Salud. Se evaluó la tendencia temporal con la prueba no paramétrica Mann-Kendall. Resultados: Se demostraron diferencias entre el primer y segundo hito: 922 casos en 75 días versus 12.037 en 59 días; Tau=-0,22 versus 0,57, S=-608 versus 968, Var(S)=47.574,66 versus 233.280,66; pendiente de Sen=-0,10 (IC95%: -0,18 y -0,03) versus 7,39 (IC95%: 5,23 y 8,88). Luego del segundo hito, la IA aumentó con tendencia positiva (S=23, p=0,006). Conclusiones: El aumento significativo de casos de COVID-19 y de IA coincidió con el levantamiento de la medida de usar mascarillas en espacios cerrados. Por tanto, se apoya el regresar al uso de mascarillas en espacios cerrados, reforzar la gestión infodémica, promover la vacunación y acrecentar la ventilación natural.

Vulnerabilidad social, un blanco fatal de la coinfección tuberculosis-VIH en Cali / Social vulnerability, a fatal scenario for TB-HIV coinfection

Resumen Objetivo: Describir la proporción, características clínicas, demográficas y programáticas de casos fatales de coinfección TB/VIH de Cali-Colombia, en 2017. Material y Método: Estudio de corte transversal, con información de las bases de datos del programa de tuberculosis, las historias clínicas y unidades de análisis de mortalidad disponibles. Resultados: Se depuraron 257 casos fatales por TB, el 24,5% (63/257) falleció con coinfección TB/VIH. La mediana de edad fue 43 años (Rango Intercuartílico: 30-52), 73% (46/63) eran hombres, 76,2% (48/63) no pertenecían al régimen contributivo, 28,6% eran habitantes de calle. 81,2% (39/48) eran casos nuevos de TB, 76,6% (37/47), inició tratamiento; al 74,6% (47/63) se les realizó unidad de análisis de mortalidad. La presentación pulmonar fue frecuente (75,9%-44/58), en 60% de los registros se observó desnutrición (Índice de Masa Corporal <20), en 39,7% (25/63) dependencia al alcohol, tabaco o farmacodependencia. Conclusiones: La mortalidad asociada a TB/VIH es prevenible, pero en 2017 representó la cuarta parte de la mortalidad por TB en Cali. Hombres adultos con condiciones de vulnerabilidad social, diagnosticados en estados avanzados de enfermedad, fueron blanco de fatalidad. Mejorar los sistemas de información e integrar los programas de TB/VIH, deben ser estrategias prioritarias para la salud pública en Colombia.

Abstract Objective: To describe the proportion, clinical, demographic and programmatic characteristics of fatal cases of TB/HIV coinfection from Cali-Colombia, in 2017. Material and Method: Cross-sectional study, with information from the TB program databases, clinical records and mortality analysis units available. Results: 257 TB fatal cases were cleared in Cali in 2017, 24.5% (63/257) of these died with TB/HIV coinfection. The median age was 43 years (Interquartile Range: 30-52), 73% (46/63) were men, 76.2% (48/63) did not belong to the contributory health regimen, 28.6% were homeless. 81.2% (39/48) were new TB cases, 76.6% (37/47) started treatment; 74.6% (47/63) had mortality analysis register. Pulmonary presentation was frequent (75.9% -44 / 58), in 60% of the registries malnutrition was observed (Body Mass Index <20), in 39.7% (25/63), dependence on alcohol, tobacco or drug dependence was registered. Conclusions: Mortality associated with TB/HIV is preventable, but in 2017 it represented a quarter of the TB mortality in Cali. Adult men with conditions of social vulnerability, diagnosed in advanced stages of disease, were fatally targeted. Improving information systems and integrating TB/HIV programs should be priority strategies for public health in Colombia.

Determinación de la persistencia y diagnóstico tardío de lepra en el Valle del Cauca de 2010 a 2016 / Determination of persistence and delayed diagnosis of leprosy in Valle del Cauca from 2010 to 2016 / Determinação da persistência e diagnóstico tardio de lepra no Valle del Cauca de 2010 a 2016

Resumen Objetivo: Describir la frecuencia, las características clínico-demográficas y los factores relacionados con el retraso diagnóstico, con tratamientos incompletos y con el desarrollo de discapacidad entre el ingreso y el egreso de pacientes inscritos en el "Programa de Control de la Enfermedad de Hansen del Valle del Cauca", de 2010 a 2016. Metodología: Se realizó un estudio observacional descriptivo de una cohorte retrospectiva de pacientes con lepra. Resultados: La incidencia promedio fue de 0,99 casos / 100 000 habitantes. La mediana de edad fue 54 años (rango intercuartílico: 39-65); el 58,82 % fueron hombres, el 49,73 % pertenecía al régimen subsidiado. El 83,68 % fueron casos nuevos, de los cuales, el 76,47 % eran multibacilares (47,9 % con lepra lepromatosa). El 59,54 % manifestó discapacidad y el 10,54 % tuvo leprorreacciones. El 50% presentó retraso diagnóstico, y el 9,09 %, abandonó tratamiento. Se encontró dependencia significativa entre retraso diagnóstico y discapacidad al ingreso (or: 2,09, ic 95 %: 1,28-3,41, p= 0,003), y entre la no finalización del tratamiento y ser previamente tratado (or: 2,82, ic 95 %: 1,28-6,18, p= 0,009). Conclusión: La lepra continúa siendo frecuente en el Valle del Cauca. El retraso diagnóstico y el ingreso con alguna discapacidad connotan captación tardía de los pacientes y en estadios avanzados. El abandono y la discapacidad al egreso se suman a la complejidad de la situación. Se evidencia la necesidad de fortalecer las intervenciones actuales dirigidas hacia el paciente, sus contactos domiciliarios, el personal de salud y la comunidad en general.

Abstract Objective: To describe the frequency, clinical-demographic characteristics and factors related to delayed diagnosis, incomplete treatments, and development of disability from admission to discharge of patients enrolled in the "Hansen's Disease Control Program of Valle del Cauca", from 2010 to 2016. Methodology: A descriptive observational study of a retrospective cohort of patients with leprosy was conducted. Results: The average incidence was 0.99 cases / 100 000 inhabitants. The median age was 54 years (interquartile range: 39-65); 58.82% were men, 49.73 % belonged to the subsidized regime. 83.68% were new cases, of which 76.47% were multibacillary (47.9% with lepromatous leprosy). 59.54% were disabled, and 10.54% experienced leprotic reactions. 50% had a delayed diagnosis, and 9.09 % abandoned treatment. Significant dependence was found between delayed diagnosis and disability at admission (OR: 2.09, CI 95 %: 1.28-3.41, p = 0.003), and between non-completion of treatment and prior treatment (OR: 2.82, CI 95 %: 1.28-6.18, p = 0.009). Conclusion: Leprosy continues to be frequent in Valle del Cauca. Delayed diagnosis and disability at admission imply late identification of patients in advanced stages. Abandonment and disability are additional factors in this complex situation. It is evident the need to strengthen current interventions aimed at the patient, their home contacts, healthcare workers, and the community.

Resumo Objetivo: Descrever a frequência, as características clínico-demográficas e os fatores relacionados com o atraso do diagnóstico, com tratamentos incompletos e com o desenvolvimento de incapacidade entre a ingresso e o egresso de pacientes inscritos no "Programa de Controle da Enfermidade de Hansen do Valle del Cauca", de 2010 a 2016. Metodologia: Foi realizado um estudo observacional descritivo de uma coorte retrospectiva de pacientes com lepra. Resultados: A incidência média foi de 0,99 casos/100000 habitantes. A média de idade foi de 54 anos (intervalo interquartil: 39-65); 58,82% foram homens, 49,73% pertenciam ao regime subsidiado. Um total de 83,68% foram de novos casos, dos quais, 76,47% eram multibacilares (47,9% com lepra lepromatosa). Um 59,54% manifestaram incapacidade e 10,54% tiveram lepro-reações. Um 50% apresentaram atraso no diagnóstico e 9,09% abandonaram o tratamento. Encontrou-se significativa dependência entre atraso no diagnóstico e incapacidade no ingresso (OR: 2,09, IC95%: 1,28-3,41, p= 0,003), e entre a não-finalização do tratamento e ser previamente tratado (OR: 2,82, IC95%: 1,28-6,18, p= 0,009). Conclusão: A lepra continua sendo frequente no Valle del Cauca. O atraso no diagnóstico e o ingresso com alguma incapacidade indicam captação tardia dos pacientes e em estágios avançados. O abandono e a incapacidade ao ingresso são somados à complexidade da situação. É evidente a necessidade de fortalecer as intervenções atuais dirigidas ao paciente, seus contatos domiciliares o pessoal de saúde e a comunidade em geral.

Evaluation of the Antibacterial Activity of Crude Extracts Obtained From Cultivation of Native Endophytic Fungi Belonging to a Tropical Montane Rainforest in Colombia.

Bioactive secondary metabolite production from endophytic fungi has gained a recurring research focus in recent decades as these microorganisms represent an unexplored biological niche for their diverse biotechnological potential. Despite this focus, studies involving tropical endophytes remain scarce, particularly those isolated from medicinal plants of these ecosystems. In addition, the state of the art of the pharmaceutical industry has experienced stagnation in the past 30years, which has pushed pathogenic infections to get one step ahead, resulting in the development of resistance to existing treatments. Here, five fungal endophytes were isolated from the medicinal plant Otoba gracilipes (Myristicaceae), which corresponded to the genera Xylaria and Diaporthe, and screened to demonstrate the promissory potential of these microorganisms for producing bioactive secondary metabolites with broad-spectrum antibacterial activities. Thus, the evaluation of crude organic extracts obtained from the mycelia and exhaust medium allowed the elucidation of Xylaria sp. and Diaporthe endophytica potential toward providing crude extracellular extracts with promising bioactivities against reference strains of Escherichia coli (ATCC 25922) and Staphylococcus aureus (ATCC 25923), according to the determined half-maximum inhibitory concentration (IC50) with values down to 3.91 and 10.50mg/ml against each pathogen, respectively. Follow-up studies provided insights into the polarity nature of bioactive compounds in the crude extracts through bioactivity guided fractionation using a polymeric resin absorbent alternative extraction procedure. In addition, evaluation of the co-culturing methods demonstrated how this strategy can enhance endophytes biosynthetic capacity and improve their antibacterial potential with a 10-fold decrease in the IC50 values against both pathogens compared to the obtained values in the preliminary evaluations of Xylaria sp. and D. endophytica crude extracts. These results support the potential of Colombian native biodiversity to provide new approaches concerning the global emergence of antibiotics resistance and future production of undiscovered compounds different from the currently used antibiotics classes and simultaneously call for the value of preserving native habitats due to their promising ecosystemic applications in the biotechnological and pharmaceutical industries.

[Clinical behavior of infection and disease caused by non-tuberculous mycobacteria in Latin America: Scoping review]. / Comportamiento clínico de la infección y enfermedad causada por micobacterias no tuberculosas en Latinoamérica: Revisión de alcance.

Reports of infection and/or disease caused by non-tuberculous mycobacteria (NTM) are becoming increasingly frequent. This scope review describes the epidemiological and clinical trend of infection/disease caused by NTM in Latin America. OVID MEDLINE, Embase and LILACS databases were explored for relevant articles. After filtering, we included 44 articles, representing an overall population of 2,826 subjects diagnosed with NTM infection and disease; the majority of the publications included subjects from Brazil and Colombia (75%), cross-sectional studies were the most common (36.6%), most subjects were male (61.3%) and the median age of subjects was 40.1 years. Disease by NTM was reported in 37 publications, extrapulmonary presentation was the most frequent (54%), main comorbidities were other pulmonary diseases, HIV, cystic fibrosis, diabetes and malnutrition, as reported in 13 studies; tuberculosis diagnosis previous to NTM disease was reported in 15 articles. Aesthetic procedures were reported in 12 articles while clinical procedures were reported in 3 articles. Several NTM species were reported, being Mycobacterium avium (52%), M. abscessus (34%), M. chelonae (18%), M. fortuitum (16%) and M. kansasii (9.1%) the most frequent. Culture and molecular testing were the main methods for diagnosis and identification. Scientific literature on NTM from Latin American countries is scarce. There is an urgent need to conduct studies on the frequency and clinical impact of NTM infections, in order to accurately identify the current morbidity and mortality associated with NTM in Latin American. It is also important to strengthen the local diagnostic capacity and the existing networks focused on studying NTM.

Cada vez son más frecuentes los reportes de aislamientos y enfermedades producidas por micobacterias no tuberculosas (MNT). Esta revisión de alcance describe el comportamiento epidemiológico y clínico de la infección y enfermedad por MNT en Latinoamérica. Se realizó la búsqueda en las bases de datos MEDLINE vía OVID, Embase y LILACS. Después de la depuración, se incluyeron 44 artículos que representaron una población global de 2826 sujetos, a quienes se les diagnosticó infección y enfermedad por MNT; la mayoría de las investigaciones incluyeron sujetos de Brasil y Colombia (75%); los estudios transversales fueron los más frecuentes (36,6%), el sexo masculino fue el más afectado (61,3%), mientras que la mediana de edad fue 40,1 años. En 37 artículos se reportó enfermedad por MNT, siendo la localización extrapulmonar (54%) la más frecuente; las principales comorbilidades fueron las enfermedades pulmonares, VIH/sida, fibrosis quística, diabetes y desnutrición, reportadas en 13 estudios; en 15 artículos se reportó tuberculosis previa al evento por MNT. En 12 artículos se evidenciaron procedimientos estéticos; en tres, procedimientos clínicos previos. Se reportó variedad de especies de MNT, siendo Mycobacterium avium (52%), M. abscessus (34%), M. chelonae (18%), M. fortuitum (16%) y M. kansasii (9,1%) las más frecuentes. El método más usado para diagnosticar e identificar la enfermedad por MNT fue el cultivo, recientemente se agregaron también las pruebas moleculares. La literatura científica latinoamericana sobre la infección/enfermedad por MNT es escasa. Es apremiante conducir estudios de frecuencia e impacto clínico y fortalecer la capacidad diagnóstica y las redes de organizaciones existentes enfocadas al estudio de micobacterias para conocer la verdadera morbimortalidad asociada a las MNT en Latinoamérica.

Identification of Nontuberculous Mycobacteria in Drinking Water in Cali, Colombia.

Nontuberculous mycobacteria (NTM) are ubiquitous microorganisms naturally resistant to antibiotics and disinfectants that can colonize drinking water supply systems. Information regarding the spread of NTM in specifically South America and Colombia is limited. We aimed to identify and characterize NTM present in tap water samples from Cali, Colombia. Drinking water samples and faucet biofilm swabs were collected in 18 places, including the city's three main water treatment plants (WTPs). Filter-trapped material and eluates (0.45 µm) from swab washes were plated in 7H11 agar plates. Suspected colonies were evaluated microscopically, and NTM species were identified based on the rpoB gene. Antibiotic susceptibility testing was also performed. Fifty percent (9/18) of sampling points were positive for NTM (including two WTPs), from which 16 different isolates were identified: Mycobacterium mucogenicum (8/16), M. phocaicum (3/16), M. chelonae (2/16), M. mageritense (2/16), and M. fortuitum (1/16), all rapidly growing mycobacteria. A susceptibility profile was obtained from 68.75% (11/16) of the isolates. M. chelonae was the most resistant species. All NTM isolated are potentially responsible for human diseases; our findings might provide a baseline for exploring NTM transmission dynamics and clinical characterization, as well as potential associations between NTM species found in drinking water and isolates from patients.

Evaluating the Quality of Tuberculosis Contact Investigation in Cali, Colombia: A Retrospective Cohort Study.

Tuberculosis (TB) contact investigation facilitates earlier TB diagnosis and initiation of preventive therapy, but little data exist about the quality of its implementation. We conducted a retrospective cohort study to evaluate processes of TB contact investigation for index TB patients diagnosed in Cali, Colombia, in 2017, including dropout at each stage and overall yield. We constructed multivariable models to identify predictors of completing 1) the baseline household visit and 2) a follow-up clinic visit for TB evaluation among referred contacts. Sixty-eight percent (759/1,120) of registered TB patients were eligible for contact investigation; 77% (582/759) received a household visit. Odds of completing a household visit were significantly lower among men (adjusted odds ratio [aOR]: 0.6; 95% CI: 0.4-0.9; P = 0.009) and patients living in Cali's western zone (aOR: 0.5; 95% CI: 0.3-0.8; P = 0.008). Among 1880 screened contacts, 31% (n = 582) met the criteria for clinic referral, 47% (n = 271) completed a clinic visit, and 85% (231/271) completed testing. After adjusting for clustering by index patient, odds of completing referral were higher among contacts with cough (aOR: 22; 95% CI: 7.1-66; P < 0.001) and contacts living in the western zone (aOR: 4.1; 95% CI: 1.2-15; P = 0.03). The cumulative probability of a symptomatic contact from an eligible household completing TB evaluation was only 28%. The yield of active TB patients among contacts was only 0.3% (5/1880). Only 16% (17/103) of children aged < 5 years and none of the eight persons living with HIV, reported preventive therapy initiation. Routine monitoring of process indicators may facilitate quality improvement to close gaps in contact tracing and increase yield.

Comportamiento clínico de la infección y enfermedad causada por micobacterias no tuberculosas en Latinoamérica: Revisión de alcance

Cada vez son más frecuentes los reportes de aislamientos y enfermedades producidas por micobacterias no tuberculosas (MNT). Esta revisión de alcance describe el comportamiento epidemiológico y clínico de la infección y enfermedad por MNT en Latinoamérica. Se realizó la búsqueda en las bases de datos MEDLINE vía OVID, Embase y LILACS. Después de la depuración, se incluyeron 44 artículos que representaron una población global de 2826 sujetos, a quienes se les diagnosticó infección y enfermedad por MNT; la mayoría de las investigaciones incluyeron sujetos de Brasil y Colombia (75%); los estudios transversales fueron los más frecuentes (36,6%), el sexo masculino fue el más afectado (61,3%), mientras que la mediana de edad fue 40,1 años. En 37 artículos se reportó enfermedad por MNT, siendo la localización extrapulmonar (54%) la más frecuente; las principales comorbilidades fueron las enfermedades pulmonares, VIH/sida, fibrosis quística, diabetes y desnutrición, reportadas en 13 estudios; en 15 artículos se reportó tuberculosis previa al evento por MNT. En 12 artículos se evidenciaron procedimientos estéticos; en tres, procedimientos clínicos previos. Se reportó variedad de especies de MNT, siendo Mycobacterium avium (52%), M. abscessus (34%), M. chelonae (18%), M. fortuitum (16%) y M. kansasii (9,1%) las más frecuentes. El método más usado para diagnosticar e identificar la enfermedad por MNT fue el cultivo, recientemente se agregaron también las pruebas moleculares. La literatura científica latinoamericana sobre la infección/enfermedad por MNT es escasa. Es apremiante conducir estudios de frecuencia e impacto clínico y fortalecer la capacidad diagnóstica y las redes de organizaciones existentes enfocadas al estudio de micobacterias para conocer la verdadera morbimortalidad asociada a las MNT en Latinoamérica.

Reports of infection and/or disease caused by non-tuberculous mycobacteria (NTM) are becoming increasingly frequent. This scope review describes the epidemiological and clinical trend of infection/disease caused by NTM in Latin America. OVID MEDLINE, Embase and LILACS databases were explored for relevant articles. After filtering, we included 44 articles, representing an overall population of 2,826 subjects diagnosed with NTM infection and disease; the majority of the publications included subjects from Brazil and Colombia (75%), cross-sectional studies were the most common (36.6%), most subjects were male (61.3%) and the median age of subjects was 40.1 years. Disease by NTM was reported in 37 publications, extrapulmonary presentation was the most frequent (54%), main comorbidities were other pulmonary diseases, HIV, cystic fibrosis, diabetes and malnutrition, as reported in 13 studies; tuberculosis diagnosis previous to NTM disease was reported in 15 articles. Aesthetic procedures were reported in 12 articles while clinical procedures were reported in 3 articles. Several NTM species were reported, being Mycobacterium avium (52%), M. abscessus (34%), M. chelonae (18%), M. fortuitum (16%) and M. kansasii (9.1%) the most frequent. Culture and molecular testing were the main methods for diagnosis and identification. Scientific literature on NTM from Latin American countries is scarce. There is an urgent need to conduct studies on the frequency and clinical impact of NTM infections, in order to accurately identify the current morbidity and mortality associated with NTM in Latin American. It is also important to strengthen the local diagnostic capacity and the existing networks focused on studying NTM.

Genetic profiling of Mycobacterium tuberculosis revealed "modern" Beijing strains linked to MDR-TB from Southwestern Colombia.

Beijing strains of Mycobacterium tuberculosis (lineage 2) have been associated with drug-resistance and transmission of tuberculosis worldwide. Most of the Beijing strains identified in the Colombian Pacific coast have exhibited a multidrug resistant (MDR) phenotype. We sought to evaluate the clonality and sublineage of Beijing strains circulating in Southwestern Colombia. Thirty-seven Beijing strains were identified through spoligotyping out of 311 clinical isolates collected in 9 years from 2002-2010. Further analysis by MIRU-VNTR 24 loci was conducted for the Beijing strains. For sublineage classification, deletions of RD105, RD207, and RD131 and point mutations at fbpB, mutT2, and acs were evaluated. Drug-resistance associated mutations to first- and second-line anti-TB drugs were also evaluated. Additionally, two Beijing strains were Illumina-whole genome sequenced (one MDR and one drug-susceptible). Among the 37 Beijing strains characterized, 36 belonged to the SIT190 type from which 28 were MDR, four pre-extensively drug resistant (XDR) TB, and four XDR-TB. The remaining strain was SIT1 and drug susceptible. MIRU-VNTR analysis allowed the identification of three Beijing clusters and two unique strains. Beijing strains were confirmed as "modern" sublineage. The mutations rpoB S531L and katG S315T were the most common among MDR strains. Moreover, the two strains evaluated by whole genome sequencing (WGS) shared most of the genetic features with the sublineage 2.2.1 "modern" Beijing previously characterized from Asian strains. WGS analysis of the MDR strain revealed the presence of eight SNPs previously reported in other MDR "Beijing-like" strains from Colombia. The presence of "modern" Beijing strains in Southwestern Colombia, most of them with MDR phenotype, suggests a different origin of this M. tuberculosis sublineage compared to other Beijing strains found in neighboring South American countries. This work may serve as a genetic baseline to study the evolution and spread of M. tuberculosis Beijing strains in Colombia, which play an important role in the propagation of MDR-TB.

Risk of infection and disease progression in children exposed to tuberculosis at home, Colombia / Riesgo de infección y progresión de la enfermedad en niños expuestos a tuberculosis en el hogar, Colombia

Abstract Aim: To assess the risk of tuberculosis (infection and disease) in children less than 15 years' old who are household contacts of pulmonary tuberculosis patients in three Colombian cities (Medellín, Cali, and Popayán). Methods: A cohort of 1,040 children household contacts of 380 adults with smear-positive pulmonary tuberculosis was followed up for 24 months. Study period 2005-2009. Results: Tuberculin skin test was positive (≥10 mm) in 43.7% (95% CI: 39.2-48.2). Tuberculin skin test positivity was associated with age 10-14 years (Prevalence Ratio -PR= 1.43, 95% CI: 1.1-1.9), having a BCG vaccine scar (PR= 1.52, 95% CI: 1.1-2.1), underweight, closer proximity to the index case and exposure time >3 months. The annual risk of infection (tuberculin skin test induration increase of 6 mm or more per year) was 17% (95% CI: 11.8-22.2) and was associated with a bacillary load of the adult index case (Relative Risk -RR= 2.12, 95% CI: 1.0-4.3). The incidence rate of active tuberculosis was 12.4 cases per 1,000 persons-year. Children <5 years without BCG vaccine scar had a greater risk of developing active disease (Hazard Ratio -HR= 6.00, 95% CI: 1.3-28.3) than those with scar (HR= 1.33, 95% CI: 0.5-3.4). The risk of developing active tuberculosis augmented along with the increase from initial tuberculin skin test (tuberculin skin test 5-9 mm HR= 8.55, 95% CI: 2.5-29.2; tuberculin skin test ≥10 mm HR= 8.16, 95% CI: 2.0-32.9). Conclusions: There is a need for prompt interruption of adult-to-children tuberculosis transmission within households. Conducting proper contact investigation and offering chemoprophylaxis to infected children could reduce tuberculosis transmission.

Resumen Objetivo: Evaluar el riesgo de tuberculosis (infección y enfermedad) en niños menores de 15 años de edad convivientes de pacientes con tuberculosis pulmonar en tres ciudades colombianas (Medellín, Cali y Popayán). Métodos: Se siguió durante 24 meses una cohorte de 1,040 niños convivientes de 380 adultos con tuberculosis pulmonar bacilífera. Periodo de estudio 2005-2009. Resultados: La prueba de tuberculina fue positiva (≥10 mm) en el 43.7% (IC 95%: 39.2-48.2), y estuvo asociada con la edad de 10-14 años (Razón de Prevalencia-RP= 1.43, IC 95%: 1.1-1.9), tener cicatriz de la vacuna BCG (RP= 1.52, IC 95%: 1.1-2.1). El riesgo anual de infección (aumento de la induración en la prueba de tuberculina de 6 mm o más al año) fue 17% (IC 95%: 11.8-22.2), y estuvo asociado con mayor carga bacilar en el adulto con tuberculosis pulmonar (Riesgo Relativo-RR= 2.12, IC 95%: 1.0-4.3). La tasa de incidencia de tuberculosis activa fue de 12.4 casos por 1,000 años-persona de seguimiento. Los niños menores de 5 años sin cicatriz de vacuna BCG tuvieron un mayor riesgo de desarrollar tuberculosis activa (Razón de Peligro -HR= 6.00, IC 95%: 1.3-28.3), que quienes tenían cicatriz (HR= 1.33, IC 95%: 0.5-3.4). El riesgo de desarrollar tuberculosis activa aumentó conforme el aumento de la prueba de tuberculina inicial (prueba de tuberculina 5-9 mm HR= 8.55, IC 95%: 2.5-29.2; prueba de tuberculina ≥10 mm HR= 8.16, IC 95%: 2.0-32.9). Conclusión: Es necesario interrumpir rápidamente la transmisión de tuberculosis de adultos a niños en los hogares. Realizar investigaciones de contacto apropiadas y ofrecer quimioprofilaxis a los niños infectados podría reducir la transmisión de la tuberculosis.

Risk of infection and disease progression in children exposed to tuberculosis at home, Colombia.

AIM: To assess the risk of tuberculosis (infection and disease) in children less than 15 years' old who are household contacts of pulmonary tuberculosis patients in three Colombian cities (Medellín, Cali, and Popayán). METHODS: A cohort of 1,040 children household contacts of 380 adults with smear-positive pulmonary tuberculosis was followed up for 24 months. Study period 2005-2009. RESULTS: Tuberculin skin test was positive (≥10 mm) in 43.7% (95% CI: 39.2-48.2). Tuberculin skin test positivity was associated with age 10-14 years (Prevalence Ratio -PR= 1.43, 95% CI: 1.1-1.9), having a BCG vaccine scar (PR= 1.52, 95% CI: 1.1-2.1), underweight, closer proximity to the index case and exposure time >3 months. The annual risk of infection (tuberculin skin test induration increase of 6 mm or more per year) was 17% (95% CI: 11.8-22.2) and was associated with a bacillary load of the adult index case (Relative Risk -RR= 2.12, 95% CI: 1.0-4.3). The incidence rate of active tuberculosis was 12.4 cases per 1,000 persons-year. Children <5 years without BCG vaccine scar had a greater risk of developing active disease (Hazard Ratio -HR= 6.00, 95% CI: 1.3-28.3) than those with scar (HR= 1.33, 95% CI: 0.5-3.4). The risk of developing active tuberculosis augmented along with the increase from initial tuberculin skin test (tuberculin skin test 5-9 mm HR= 8.55, 95% CI: 2.5-29.2; tuberculin skin test ≥10 mm HR= 8.16, 95% CI: 2.0-32.9). CONCLUSIONS: There is a need for prompt interruption of adult-to-children tuberculosis transmission within households. Conducting proper contact investigation and offering chemoprophylaxis to infected children could reduce tuberculosis transmission.

OBJETIVO: Evaluar el riesgo de tuberculosis (infección y enfermedad) en niños menores de 15 años de edad convivientes de pacientes con tuberculosis pulmonar en tres ciudades colombianas (Medellín, Cali y Popayán). MÉTODOS: Se siguió durante 24 meses una cohorte de 1,040 niños convivientes de 380 adultos con tuberculosis pulmonar bacilífera. Periodo de estudio 2005-2009. Resultados: La prueba de tuberculina fue positiva (≥10 mm) en el 43.7% (IC 95%: 39.2-48.2), y estuvo asociada con la edad de 10-14 años (Razón de Prevalencia-RP= 1.43, IC 95%: 1.1-1.9), tener cicatriz de la vacuna BCG (RP= 1.52, IC 95%: 1.1-2.1). El riesgo anual de infección (aumento de la induración en la prueba de tuberculina de 6 mm o más al año) fue 17% (IC 95%: 11.8-22.2), y estuvo asociado con mayor carga bacilar en el adulto con tuberculosis pulmonar (Riesgo Relativo-RR= 2.12, IC 95%: 1.0-4.3). La tasa de incidencia de tuberculosis activa fue de 12.4 casos por 1,000 años-persona de seguimiento. Los niños menores de 5 años sin cicatriz de vacuna BCG tuvieron un mayor riesgo de desarrollar tuberculosis activa (Razón de Peligro -HR= 6.00, IC 95%: 1.3-28.3), que quienes tenían cicatriz (HR= 1.33, IC 95%: 0.5-3.4). El riesgo de desarrollar tuberculosis activa aumentó conforme el aumento de la prueba de tuberculina inicial (prueba de tuberculina 5-9 mm HR= 8.55, IC 95%: 2.5-29.2; prueba de tuberculina ≥10 mm HR= 8.16, IC 95%: 2.0-32.9). CONCLUSIÓN: Es necesario interrumpir rápidamente la transmisión de tuberculosis de adultos a niños en los hogares. Realizar investigaciones de contacto apropiadas y ofrecer quimioprofilaxis a los niños infectados podría reducir la transmisión de la tuberculosis.

The stability of antimycobacterial drugs in media used for drug susceptibility testing.

The emergence of drug-resistant tuberculosis and disease caused by nontuberculous mycobacteria has increased the need for accurate drug susceptibility testing of mycobacteria. The stability of the tested drugs in relevant test media have been understudied. We assessed the stability of isoniazid, rifampicin, clarithromycin, linezolid and amikacin in Middlebrook 7H9 medium and that of clarithromycin, amikacin and cefoxitin in the cation-adjusted Mueller Hinton broth. We used ultra-performance liquid chromatography (UPLC) methods for rifampicin and isoniazid and a microbiological assay for rifampicin, clarithromycin, amikacin, cefoxitin and linezolid. Rifampicin and isoniazid concentrations in Middlebrook 7H9 medium had decreased by 92% and 54% after 7 days. The microbiological assay revealed decreases in drug concentration of ≥75% (rifampicin, clarithromycin, cefoxitin) and 60% (linezolid) after 14 days. With the exception of amikacin, all antimycobacterial drugs were unstable during 14 days of incubation in the preferred media for DST. Drug stability may influence minimum inhibitory concentration measurements.

Systematic Review and Meta-analyses of the Effect of Chemotherapy on Pulmonary Mycobacterium abscessus Outcomes and Disease Recurrence.

In pharmacokinetic/pharmacodynamic models of pulmonary Mycobacterium abscessus complex, the recommended macrolide-containing combination therapy has poor kill rates. However, clinical outcomes are unknown. We searched the literature for studies published between 1990 and 2017 that reported microbial outcomes in patients treated for pulmonary M. abscessus disease. A good outcome was defined as sustained sputum culture conversion (SSCC) without relapse. Random effects models were used to pool studies and estimate proportions of patients with good outcomes. Odds ratios (OR) and 95% confidence intervals (CI) were computed. Sensitivity analyses and metaregression were used to assess the robustness of findings. In 19 studies of 1,533 patients, combination therapy was administered to 508 patients with M. abscessus subsp. abscessus, 204 with M. abscessus subsp. massiliense, and 301 with M. abscessus with no subspecies specified. Macrolide-containing regimens achieved SSCC in only 77/233 (34%) new M. abscessus subsp. abscessus patients versus 117/141 (54%) M. abscessus subsp. massiliense patients (OR, 0.108 [95% CI, 0.066 to 0.181]). In refractory disease, SSCC was achieved in 20% (95% CI, 7 to 36%) of patients, which was not significantly different across subspecies. The estimated recurrent rates per month were 1.835% (range, 1.667 to 3.196%) for M. abscessus subsp. abscessus versus 0.683% (range, 0.229 to 1.136%) for M. abscessus subsp. massiliense (OR, 6.189 [95% CI, 2.896 to 13.650]). The proportion of patients with good outcomes was 52/223 (23%) with M. abscessus subsp. abscessus versus 118/141 (84%) with M. abscessus subsp. massiliense disease (OR, 0.059 [95% CI, 0.034 to 0.101]). M. abscessus subsp. abscessus pulmonary disease outcomes with the currently recommended regimens are atrocious, with outcomes similar to those for extensively drug-resistant tuberculosis. Therapeutically, the concept of nontuberculous mycobacteria is misguided. There is an urgent need to craft entirely new treatment regimens.

Failure of the Amikacin, Cefoxitin, and Clarithromycin Combination Regimen for Treating Pulmonary Mycobacterium abscessus Infection.

In a hollow-fiber model, we mimicked the drug exposures achieved in the lungs of humans treated with standard amikacin, clarithromycin, and cefoxitin combination therapy for Mycobacterium abscessus infection. At optimal dosing, a kill rate of -0.09 (95% confidence interval, -0.04 to 0.03) log10 CFU per ml/day was achieved over the first 14 days, after which there was regrowth due to acquired drug resistance. Thus, the standard regimen quickly failed. A new regimen is needed.

Moxifloxacin's Limited Efficacy in the Hollow-Fiber Model of Mycobacterium abscessus Disease.

Current regimens used to treat pulmonary Mycobacterium abscessus disease have limited efficacy. There is an urgent need for new drugs and optimized combinations and doses. We performed hollow-fiber-system studies in which M. abscessus was exposed to moxifloxacin lung concentration-time profiles similar to human doses of between 0 and 800 mg/day. The minimum bactericidal concentration and MIC were 8 and 2 mg/liter, respectively, in our M. abscessus strain, suggesting bactericidal activity. Measurement of the moxifloxacin concentrations in each hollow-fiber system revealed an elimination rate constant (kel) of 0.11 ± 0.05 h(-1) (mean ± standard deviation) (half-life of 9.8 h). Inhibitory sigmoid maximal effect (Emax) modeling revealed that the highest Emax was 3.15 ± 1.84 log10 CFU/ml on day 3, and the exposure mediating 50% of Emax (EC50) was a 0- to 24-h area under the concentration time curve (AUC0-24)-to-MIC ratio of 41.99 ± 31.78 (r(2) = 0.99). The EC80 was an AUC0-24/MIC ratio of 102.11. However, no moxifloxacin concentration killed the bacteria to burdens below the starting inoculum. There was regrowth beyond day 3 in all doses, with replacement by a resistant subpopulation that had an MIC of >32 mg/liter by the end of the experiment. A quadratic function best described the relationship between the AUC0-24/MIC ratio and the moxifloxacin-resistant subpopulation. Monte Carlo simulations of 10,000 patients revealed that the 400- to 800-mg/day doses would achieve or exceed the EC80 in ≤12.5% of patients. The moxifloxacin susceptibility breakpoint was 0.25 mg/liter, which means that almost all M. abscessus clinical strains are moxifloxacin resistant by these criteria. While moxifloxacin's efficacy against M. abscessus was poor, formal combination therapy studies with moxifloxacin are still recommended.

Tigecycline Is Highly Efficacious against Mycobacterium abscessus Pulmonary Disease.

Mycobacterium abscessus causes chronic pulmonary infections that are extremely difficult to cure. The currently recommended combination therapy is associated with high failure rates and relapse. Tigecycline has been explored in salvage regimens, with a response rate of 43% in those who received at least a month of therapy. We performed a dose-response study in a hollow-fiber system model of pulmonary M. abscessus infection in which we recapitulated tigecycline human pulmonary concentration-time profiles of 8 different doses for 21 days. We identified the maximal kill or efficacy in CFU per milliliter and the ratio of the 0- to 24-h area under the concentration-time curve to MIC (AUC/MIC) associated with 80% efficacy (EC80). The tigecycline efficacy was 5.38 ± 2.35 log10 CFU/ml, and the drug achieved the unprecedented feat of a bacterial level of 1.0 log10 CFU/ml below the pretreatment inoculum (1-log kill) of M. abscessus in the hollow-fiber system. The EC80 AUC/MIC ratio was 36.65, while that for a 1-log kill was 44.6. Monte Carlo experiments with 10,000 patients were used to identify the clinical dose best able to achieve the EC80 or 1-log kill. The standard dose of 100 mg/day had a cumulative fraction of response of 51% for the EC80 and 46% for 1-log kill. For both the EC80 target and 1-log kill, the optimal tigecycline clinical dose was identified as 200 mg/day. The susceptibility breakpoint was ≤0.5 mg/liter. Tigecycline is the most active single agent evaluated to date, and we propose that 200 mg/day be examined as the backbone of new combination therapy regimens to replace current treatment.

Clofazimine Prevents the Regrowth of Mycobacterium abscessus and Mycobacterium avium Type Strains Exposed to Amikacin and Clarithromycin.

Multidrug therapy is a standard practice when treating infections by nontuberculous mycobacteria (NTM), but few treatment options exist. We conducted this study to define the drug-drug interaction between clofazimine and both amikacin and clarithromycin and its contribution to NTM treatment. Mycobacterium abscessus and Mycobacterium avium type strains were used. Time-kill assays for clofazimine alone and combined with amikacin or clarithromycin were performed at concentrations of 0.25× to 2× MIC. Pharmacodynamic interactions were assessed by response surface model of Bliss independence (RSBI) and isobolographic analysis of Loewe additivity (ISLA), calculating the percentage of statistically significant Bliss interactions and interaction indices (I), respectively. Monte Carlo simulations with predicted human lung concentrations were used to calculate target attainment rates for combination and monotherapy regimens. Clofazimine alone was bacteriostatic for both NTM. Clofazimine-amikacin was synergistic against M. abscessus (I = 0.41; 95% confidence interval [CI], 0.29 to 0.55) and M. avium (I = 0.027; 95% CI, 0.007 to 0.048). Based on RSBI analysis, synergistic interactions of 28.4 to 29.0% and 23.2 to 56.7% were observed at 1× to 2× MIC and 0.25× to 2× MIC for M. abscessus and M. avium, respectively. Clofazimine-clarithromycin was also synergistic against M. abscessus (I = 0.53; 95% CI, 0.35 to 0.72) and M. avium (I = 0.16; 95% CI, 0.04 to 0.35), RSBI analysis showed 23.5% and 23.3 to 53.3% at 2× MIC and 0.25× to 0.5× MIC for M. abscessus and M. avium, respectively. Clofazimine prevented the regrowth observed with amikacin or clarithromycin alone. Target attainment rates of combination regimens were >60% higher than those of monotherapy regimens for M. abscessus and M. avium. The combination of clofazimine with amikacin or clarithromycin was synergistic in vitro. This suggests a potential role for clofazimine in treatment regimens that warrants further evaluation.

Amikacin Pharmacokinetics/Pharmacodynamics in a Novel Hollow-Fiber Mycobacterium abscessus Disease Model.

The treatment of pulmonary Mycobacterium abscessus disease is associated with very high failure rates and easily acquired drug resistance. Amikacin is the key drug in treatment regimens, but the optimal doses are unknown. No good preclinical model exists to perform formal pharmacokinetics/pharmacodynamics experiments to determine these optimal doses. We developed a hollow-fiber system model of M. abscessus disease and studied amikacin exposure effects and dose scheduling. We mimicked amikacin human pulmonary pharmacokinetics. Both amikacin microbial kill and acquired drug resistance were linked to the peak concentration-to-MIC ratios; the peak/MIC ratio associated with 80% of maximal kill (EC80) was 3.20. However, on the day of the most extensive microbial kill, the bacillary burden did not fall below the starting inoculum. We performed Monte Carlo simulations of 10,000 patients with pulmonary M. abscessus infection and examined the probability that patients treated with one of 6 doses from 750 mg to 4,000 mg would achieve or exceed the EC80. We also examined these doses for the ability to achieve a cumulative area under the concentration-time curve of 82,232 mg · h/liter × days, which is associated with ototoxicity. The standard amikacin doses of 750 to 1,500 mg a day achieved the EC80 in ≤ 21% of the patients, while a dose of 4 g/day achieved this in 70% of the patients but at the cost of high rates of ototoxicity within a month or two. The susceptibility breakpoint was an MIC of 8 to 16 mg/liter. Thus, amikacin, as currently dosed, has limited efficacy against M. abscessus. It is urgent that different antibiotics be tested using our preclinical model and new regimens developed.