Tuberculosis in Spain: An opinion paper / Tuberculosis en España: Un documento de opinión

This document is the result of the deliberations of the Committee on Emerging Pathogens and COVID-19 of the Il lustrious Official College of Physicians of Madrid (ICOMEM) regarding the current situation of tuberculosis, particularly in Spain. We have reviewed aspects such as the evolution of its incidence, the populations currently most exposed and the health care circuits for the care of these patients in Spain. We have also discussed latent tuberculosis, the reality of extrapul monary disease in the XXI century and the means available in daily practice for the diagnosis of both latent and active forms. The contribution of molecular biology, which has changed the perspective of this disease, was another topic of discussion. The paper tries to put into perspective both the classical drugs and their resistance figures and the availability and indications of the new ones. In addition, the reality of direct observa tion in the administration of antituberculosis drugs has been discussed. All this revolution is making it possible to shorten the treatment time for tuberculosis, a subject that has also been reviewed. If everything is done well, the risk of relapse of tuberculosis is small but it exists. On the other hand, many special situations have been discussed in this paper, such as tuberculosis in pediatric age and tuberculosis as a cause for concern in surgery and intensive care. The status of the BCG vaccine and its present indications as well as the future of new vaccines to achieve the old dream of eradicating this disease have been discussed. Finally, the ethical and medicolegal impli cations of this disease are not a minor issue and our situation in this regard has been reviewed (AU)

El presente documento es el resultado de las deliberacio nes del Comité sobre Patógenos Emergentes y COVID-19 del Ilustre Colegio Oficial de Médicos de Madrid (ICOMEM) en re lación a la situación actual de la tuberculosis, particularmente en España. Hemos revisado aspectos tales como la evolución de su incidencia, las poblaciones actualmente más expuestas y los circuitos sanitarios para la atención a estos pacientes en España. Se ha discutido también la tuberculosis latente, la rea lidad de la enfermedad extrapulmonar en el siglo XXI y los me dios de que en la práctica diaria se dispone para el diagnóstico tanto de las formas latentes como de las activas. La aportación de la biología molecular que ha cambiado la perspectiva de es ta enfermedad ha constituido otro de los temas de debate. El documento trata de poner en perspectiva tanto los fármacos clásicos y sus cifras de resistencia como la disponibilidad e in dicaciones de los nuevos. Junto a esto, se ha discutido la rea lidad de la observación directa en la administración de fárma cos antituberculosos. Toda esta revolución está posibilitando el acortamiento del tiempo de tratamiento de la tuberculosis tema que ha sido igualmente revisado. Si todo se hace bien, el riesgo de recaída de la tuberculosis es pequeño pero existen te. Por otra parte, muchas situaciones especiales han merecido discusión en este documento como por ejemplo la tuberculosis en edad pediátrica y la tuberculosis como causa de preocupa ción en cirugía y cuidados intensivos. Se ha discutido tanto la situación de la vacuna BCG y sus indicaciones presentes, co mo el futuro de nuevas vacunas que permitan alcanzar el viejo sueño de erradicar esta enfermedad. Finalmente, las implica ciones éticas y medicolegales que esta enfermedad plantea no son un tema menor y se ha revisado nuestra situación en este particular (AU)

Safety of antituberculosis agents used for multidrug-resistant tuberculosis among patients attending the Jamot Hospital of Yaounde, Cameroon.

Background: Recognized in 1994 as a global emergency by the World Health Organization, tuberculosis (TB) remains an ongoing health threat. In Cameroon, the mortality rate is estimated at 2.9%. Treatment of multidrug-resistant TB (MDR-TB) defined as the resistance to the two most effective antiTB drugs, and requires therapy of more than 7 drugs taken on a daily basis during 9-12 months. This study aimed to evaluate the safety profile of treatment regimens used for MDR-TB at Jamot Hospital of Yaounde (JHY). Methods: This was a retrospective cohort study of patients treated for MDR-TB at HJY from January 1, 2017, to December 31, 2019. Patients characteristics of the cohort, drugs regimen were collected and described. All possible adverse drug reactions (ADR) were described clinically and by severity grade. Results: During the study period, 107 patients were included, and 96 (89.7%) experienced at least one ADR. Most parts of the patients (90) experienced mild or moderate ADR. Hearing loss was the most frequent ADR, and led mostly in aminoglycosides dose reduction (n = 30, 96.7%). Gastrointestinal events were commonly observed during the study period. Conclusion: Our findings suggested that ototoxicity was a prominent safety issue during the study period. The implementation of the new short treatment regimen could be effective in reducing the burden of ototoxicity among MDR-TB patients. Nevertheless, new safety issues could emerge.

Stable, compounded bedaquiline suspensions to support practical implementation of pediatric dosing in the field.

BACKGROUND: Bedaquiline (BDQ) tablets are indicated as part of a combination regimen for the treatment of multidrug-resistant TB in adults, adolescents and children. A dispersible tablet formulation is now approved but is not currently available in all settings. The aim of this study was to develop stable extemporaneous liquid formulations of BDQ that can be stored at room temperature or 30°C for several weeks, to support pragmatic pediatric dosing in the field and reduce wastage.METHODS: BDQ tablets were suspended in simple syrup and a sugar-free vehicle. Each 20 mg/mL formulation was stored at room temperature or 30°C for 30 days in amber dispensing bottles. Appearance, BDQ potency, pH and microbial counts were determined on Days 0, 15 and 30.RESULTS: The BDQ potency in both formulations remained at 98-101% of the theoretical concentration for 30 days. The appearance, pH and microbial count of sugar-free formulation did not change during the 30-day storage. The simple syrup formulation was stable for 15 days as microbial growth was observed on Day 30.CONCLUSIONS: BDQ may be prepared in syrup or sugar-free suspensions: syrup suspensions can be stored for 15 days at room temperature and 30C, whereas sugar-free suspensions can be stored for 30 days at room temperature and 30C. This information will support practical BDQ dosing for children in the field.

Determining the Delamanid Pharmacokinetics/Pharmacodynamics Susceptibility Breakpoint Using Monte Carlo Experiments.

Antimicrobial susceptibility testing, based on clinical breakpoints that incorporate pharmacokinetics/pharmacodynamics (PK/PD) and clinical outcomes, is becoming a new standard in guiding individual patient therapy as well as for drug resistance surveillance. However, for most antituberculosis drugs, breakpoints are instead defined by the epidemiological cutoff values of the MIC of phenotypically wild-type strains irrespective of PK/PD or dose. In this study, we determined the PK/PD breakpoint for delamanid by estimating the probability of target attainment for the approved dose administered at 100 mg twice daily using Monte Carlo experiments. We used the PK/PD targets (0- to 24-h area under the concentration-time curve to MIC) identified in a murine chronic tuberculosis model, hollow fiber system model of tuberculosis, early bactericidal activity studies of patients with drug-susceptible tuberculosis, and population pharmacokinetics in patients with tuberculosis. At the MIC of 0.016 mg/L, determined using Middlebrook 7H11 agar, the probability of target attainment was 100% in the 10,000 simulated subjects. The probability of target attainment fell to 25%, 40%, and 68% for PK/PD targets derived from the mouse model, the hollow fiber system model of tuberculosis, and patients, respectively, at the MIC of 0.031 mg/L. This indicates that an MIC of 0.016 mg/L is the delamanid PK/PD breakpoint for delamanid at 100 mg twice daily. Our study demonstrated that it is feasible to use PK/PD approaches to define a breakpoint for an antituberculosis drug.

A 24-Week, All-Oral Regimen for Rifampin-Resistant Tuberculosis.

BACKGROUND: In patients with rifampin-resistant tuberculosis, all-oral treatment regimens that are more effective, shorter, and have a more acceptable side-effect profile than current regimens are needed. METHODS: We conducted an open-label, phase 2-3, multicenter, randomized, controlled, noninferiority trial to evaluate the efficacy and safety of three 24-week, all-oral regimens for the treatment of rifampin-resistant tuberculosis. Patients in Belarus, South Africa, and Uzbekistan who were 15 years of age or older and had rifampin-resistant pulmonary tuberculosis were enrolled. In stage 2 of the trial, a 24-week regimen of bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) was compared with a 9-to-20-month standard-care regimen. The primary outcome was an unfavorable status (a composite of death, treatment failure, treatment discontinuation, loss to follow-up, or recurrence of tuberculosis) at 72 weeks after randomization. The noninferiority margin was 12 percentage points. RESULTS: Recruitment was terminated early. Of 301 patients in stage 2 of the trial, 145, 128, and 90 patients were evaluable in the intention-to-treat, modified intention-to-treat, and per-protocol populations, respectively. In the modified intention-to-treat analysis, 11% of the patients in the BPaLM group and 48% of those in the standard-care group had a primary-outcome event (risk difference, -37 percentage points; 96.6% confidence interval [CI], -53 to -22). In the per-protocol analysis, 4% of the patients in the BPaLM group and 12% of those in the standard-care group had a primary-outcome event (risk difference, -9 percentage points; 96.6% CI, -22 to 4). In the as-treated population, the incidence of adverse events of grade 3 or higher or serious adverse events was lower in the BPaLM group than in the standard-care group (19% vs. 59%). CONCLUSIONS: In patients with rifampin-resistant pulmonary tuberculosis, a 24-week, all-oral regimen was noninferior to the accepted standard-care treatment, and it had a better safety profile. (Funded by Médecins sans Frontières; TB-PRACTECAL ClinicalTrials.gov number, NCT02589782.).

Evaluation of patient's experiences with daily DOTS.

BACKGROUND/AIMS: Past few decades have seen major revisions in the Tuberculosis (TB) control programs time and again with a goal to strengthen the delivery of services and achieve elimination of the disease. Daily Directly Observed Treatment, Short-course (DOTS) Fixed dose combination (FDC) was one such major leap and aimed to simplify the treatment regimen, reduce pill burden, avoid drug monotherapy, improve compliance, reduce chances of drug resistance, decrease stigma and make the treatment more patient friendly. We intended to study the impact and acceptance of this changed FDC daily DOTS at the grass root level. Clinical and microbiological parameters were also studied alongwith. METHODS: Prospective study was conducted in the Department of Pulmonary Medicine, Government Medical College and Hospital, Chandigarh from October, 2018 to October, 2020.138 sputum smear positive patients were enrolled at the time of initiation of treatment and studied till end of intensive phase (IP). Baseline socio-demographic and clinical details, any adverse drug reactions (ADR's), their subsequent management and sputum smear conversion at end IP were noted. Various patient and disease related factors were studied in relation to sputum smear conversion and ADR's. At end IP, experiences of the patients with the newly introduced daily regimen were assessed by using a structured questionnaire. The data was tabulated and statistically analyzed. RESULTS: Mean age of the patients was 39.31 ± 1.5 years. Majority were males, literate, married, employed, from urban background and moderately built. During IP, 59 (42.8%) patients experienced ADR's. 31/59 patients needed admission while 28/59 patients were managed on outpatient basis. 31/59 patients improved with symptomatic management, while 28/59 patients required change in anti tubercular drugs for a short period of time. All the patients were shifted back to FDC daily DOTS after a few days. Though 59 patients reported ADR's, only 44/59 patients missed their doses. Rest 15/59 patients continued with the treatment despite mild ADR's and reported for management without missing any dose. Follow-up smear at end IP was negative in 130/138 patients (94.2%). 93.5% patients preferred their family member as the DOTS provider. More than 90% of the patients were satisfied with basic provisions like treatment room privacy, cleanliness, safe drinking water and sign boards at DOTS centre. Satisfaction with the health care worker (HCW) (assessed by enquiring about the behavior of the HCW, explanation given about the disease and treatment, pre-treatment counseling, occurrence of ADR's, consequences of irregular treatment, warning signs for consultation, advise on nutrition requirement and follow-up information) was reported by 97.8% patients. Sputum conversion rates were significantly higher in unemployed (p = 0.043). Non-adherence to treatment was significantly associated with ADR's (p < 0.001). Sputum conversion rates and ADR's were unaffected by education, rural/urban background, BMI, co-morbidities, addiction and previous history of anti-tubercular treatment. CONCLUSION: Daily DOTS achieved appreciable sputum conversion rates at end IP. Non-adherence to treatment and ADR's were managed well with adequate psychosocial support, counseling, timely monitoring and treatment. FDC daily DOTS emerged as a highly acceptable regimen owing to various comprehensive measures adopted at the grass root level.

Non-adherence to anti-tubercular treatment during COVID-19 pandemic in Raipur district Central India.

BACKGROUND: Non-adherence is major factor in failure of any drug regimen. The significance of non-adherence is so much that WHO states that increasing the effectiveness of Adherence Interventions may have far greater impact on health of population than any improvement in specific medical treatments. Incidence of non-adherence to Anti Tubercular Treatment (ATT) usually ranges from 8.4% to 55.8%. This study aims to find out the reasons of Non-adherence to ATT in patients receiving anti-tubercular treatment at DIRECTLY OBSERVED TREATMENT SHORTCOURSE (DOTS) Centre at District Tuberculosis Centre (DTC), Kalibadi, Raipur during COVID-19 pandemic. METHODS: A cross sectional study was conducted at Department of Pharmacology, Pt. JNM Medical College and DTC Kalibadi Raipur. 55 Patients taking ATT fulfilling inclusion and exclusion criteria were interviewed using structured questionnaire. The data obtained was analysed to know causes of non-adherence. RESULTS: Study was carried out between March & April 2020. In our study, 80% subjects were male and 20% were female. The main reasons for Non-adherence were Side-effects of drug in 36% cases, missing medication intentionally in 34% cases, lack of encouragement by family members in 32% cases, patient's unawareness of consequences of skipping medication in 25% cases, unaware of treatment duration in 22%, not feeling any change, forgetting to take medication, and burden of concomitant medication besides ATT, each in 20% cases, 13% cases had difficulty in procuring medication due to lockdown, 5% cases did not go to collect their medicine due to fear of contracting COVID-19 infection. CONCLUSIONS: Our study shows reasons for Non-adherence are multi-factorial with drug side -effects & intentionally skipping medication being major factors.

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.

Using the Food and Drug Administration´s Sentinel System for surveillance of TB infection.

BACKGROUND: We examined patterns in care for individuals treated for latent TB infection (LTBI) in the US Food and Drug Administration´s Sentinel System.METHODS: Using administrative claims data, we identified patients who filled standard LTBI treatment prescriptions during 2008-2019. In these cohorts, we assessed LTBI testing, clinical management, and treatment duration.RESULTS: Among 113,338 patients who filled LTBI prescriptions, 80% (90,377) received isoniazid (INH) only, 19% (21,235) rifampin (RIF) only, and 2% (1,726) INH + rifapentine (RPT). By regimen, the proportion of patients with documented prior testing for TBI was 79%, 54%, and 91%, respectively. Median therapy duration was 84 days (IQR 35-84) for the 3-month once-weekly INH + RPT regimen, 60 days (IQR 30-100) for the 6- to 9-month INH regimen, and 30 days (IQR 2-60) for the 4-month RIF regimen.CONCLUSIONS: Among the cohorts, INH-only was the most commonly prescribed LTBI treatment. Most persons who filled a prescription for LTBI treatment did not have evidence of completing recommended treatment duration. These data further support preferential use of shorter-course regimens such as INH + RPT.

Comparison of three short-course rifamycin-based regimens for the prevention of tuberculosis in patients with end-stage kidney disease: Study protocol for a randomised clinical trial (RIFAKiD-TB trial).

BACKGROUND AND PURPOSE: Screening for and treatment of latent tuberculosis (TB) in patients with end-stage kidney disease (ESKD) are recommended. However, there is limited evidence on safety and treatment completion in this population. The objective of the study is to evaluate three short-course rifamycin-based regimens for the treatment of latent TB in ESKD patients. METHODS: Study design and setting. This is a prospective, open label, randomized clinical trial, that will be conducted at seven teaching hospitals in Spain. Study population, randomization, and interventions. Consecutive adult patients with ESKD requiring treatment for a latent TB infection will be randomly allocated (1:1:1) to receive one of the three treatment regimens of the study: three months of daily isoniazid plus rifampicin (3HR); three months of once-weekly isoniazid plus rifapentine (3HP); or four months of daily rifampicin (4R). Participants will be followed regularly through pre-established visits and a blood test schedule from enrolment to a month after finishing the assigned treatment. Outcomes. The primary outcome will be treatment completion, while the secondary outcomes will be discontinuation of the assigned treatment due to adverse events, related or unrelated to the study treatment; definitive discontinuation of the assigned treatment because of adverse events related to the treatment of the study, and death. Sample size. Two hundred and twenty-five subjects (75 per arm) will be enrolled, which will enable the demonstration, if it exists, of an increase of 0.16 in treatment completion rates either in the 3HP or 4R arm with respect to the 3HR arm. DISCUSSION: Results of this clinical trial will contribute to evidence-based recommendations on the management of latent TB infection in ESKD patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05021731.

Medicinal plant use and adherence problems to TB treatment.

BACKGROUND: Good adherence is essential in the treatment of TB. The aim of this study was to describe medication consumption patterns and to assess factors associated with adherence to TB treatment among TB patients in Lomé, Togo.METHODS: A cross-sectional study was conducted among TB patients in 10 health structures in Lomé from September 2019 to January 2020. TB patients aged ≥18 years and under treatment for at least 2 months were eligible for this study. Adherence to TB treatment was assessed using the Girerd compliance test.RESULTS: A total of 195 TB patients (61.5% male) with a median age of 35 years (IQR 27-44) were recruited. TB-HIV coinfection was 11.3%. Polypharmacy (≥5 medications/day) and using medicinal plants were observed in respectively 6.2% and 42.6% of patients. Prevalence of TB treatment adherence problems was 68.2% (95% CI 61.2-74.7). Being <35 years (aOR 2.79; P = 0.005) and taking medicinal plants (aOR 4.31; P < 0.001) were associated with TB treatment adherence problems.CONCLUSION: Treatment adherence problems, a major obstacle to TB elimination, are highly prevalent in TB patients in Lomé, and were associated with the use of medicinal plants. Reasons for the use of medicinal plants should be documented in order to propose appropriate interventions to reinforce adherence to TB treatment.

Clinical standards for the dosing and management of TB drugs.

BACKGROUND: Optimal drug dosing is important to ensure adequate response to treatment, prevent development of drug resistance and reduce drug toxicity. The aim of these clinical standards is to provide guidance on 'best practice´ for dosing and management of TB drugs.METHODS: A panel of 57 global experts in the fields of microbiology, pharmacology and TB care were identified; 51 participated in a Delphi process. A 5-point Likert scale was used to score draft standards. The final document represents the broad consensus and was approved by all participants.RESULTS: Six clinical standards were defined: Standard 1, defining the most appropriate initial dose for TB treatment; Standard 2, identifying patients who may be at risk of sub-optimal drug exposure; Standard 3, identifying patients at risk of developing drug-related toxicity and how best to manage this risk; Standard 4, identifying patients who can benefit from therapeutic drug monitoring (TDM); Standard 5, highlighting education and counselling that should be provided to people initiating TB treatment; and Standard 6, providing essential education for healthcare professionals. In addition, consensus research priorities were identified.CONCLUSION: This is the first consensus-based Clinical Standards for the dosing and management of TB drugs to guide clinicians and programme managers in planning and implementation of locally appropriate measures for optimal person-centred treatment to improve patient care.

A case report. Rediscovering tuberculostatics drugs: skin rash and pyrazinamide

No disponible