Surveillance of adverse events in the treatment of drug-resistant tuberculosis: first global report.

The World Health Organization (WHO) recommends that countries implement pharmacovigilance and collect information on active drug safety monitoring (aDSM) and management of adverse events.The aim of this prospective study was to evaluate the frequency and severity of adverse events to anti-tuberculosis (TB) drugs in a cohort of consecutive TB patients treated with new (i.e. bedaquiline, delamanid) and repurposed (i.e. clofazimine, linezolid) drugs, based on the WHO aDSM project. Adverse events were collected prospectively after attribution to a specific drug together with demographic, bacteriological, radiological and clinical information at diagnosis and during therapy. This interim analysis included patients who completed or were still on treatment at time of data collection.Globally, 45 centres from 26 countries/regions reported 658 patients (68.7% male, 4.4% HIV co-infected) treated as follows: 87.7% with bedaquiline, 18.4% with delamanid (6.1% with both), 81.5% with linezolid and 32.4% with clofazimine. Overall, 504 adverse event episodes were reported: 447 (88.7%) were classified as minor (grade 1-2) and 57 (11.3%) as serious (grade 3-5). The majority of the 57 serious adverse events reported by 55 patients (51 out of 57, 89.5%) ultimately resolved. Among patients reporting serious adverse events, some drugs held responsible were discontinued: bedaquiline in 0.35% (two out of 577), delamanid in 0.8% (one out of 121), linezolid in 1.9% (10 out of 536) and clofazimine in 1.4% (three out of 213) of patients. Serious adverse events were reported in 6.9% (nine out of 131) of patients treated with amikacin, 0.4% (one out of 221) with ethionamide/prothionamide, 2.8% (15 out of 536) with linezolid and 1.8% (eight out of 498) with cycloserine/terizidone.The aDSM study provided valuable information, but implementation needs scaling-up to support patient-centred care.

Multidrug-resistant tuberculosis and culture conversion with bedaquiline.

BACKGROUND: Bedaquiline (Sirturo, TMC207), a diarylquinoline that inhibits mycobacterial ATP synthase, has been associated with accelerated sputum-culture conversion in patients with multidrug-resistant tuberculosis, when added to a preferred background regimen for 8 weeks. METHODS: In this phase 2b trial, we randomly assigned 160 patients with newly diagnosed, smear-positive, multidrug-resistant tuberculosis to receive either 400 mg of bedaquiline once daily for 2 weeks, followed by 200 mg three times a week for 22 weeks, or placebo, both in combination with a preferred background regimen. The primary efficacy end point was the time to sputum-culture conversion in liquid broth. Patients were followed for 120 weeks from baseline. RESULTS: Bedaquiline reduced the median time to culture conversion, as compared with placebo, from 125 days to 83 days (hazard ratio in the bedaquiline group, 2.44; 95% confidence interval, 1.57 to 3.80; P<0.001 by Cox regression analysis) and increased the rate of culture conversion at 24 weeks (79% vs. 58%, P=0.008) and at 120 weeks (62% vs. 44%, P=0.04). On the basis of World Health Organization outcome definitions for multidrug-resistant tuberculosis, cure rates at 120 weeks were 58% in the bedaquiline group and 32% in the placebo group (P=0.003). The overall incidence of adverse events was similar in the two groups. There were 10 deaths in the bedaquiline group and 2 in the placebo group, with no causal pattern evident. CONCLUSIONS: The addition of bedaquiline to a preferred background regimen for 24 weeks resulted in faster culture conversion and significantly more culture conversions at 120 weeks, as compared with placebo. There were more deaths in the bedaquiline group than in the placebo group. (Funded by Janssen Pharmaceuticals; TMC207-C208 ClinicalTrials.gov number, NCT00449644.).

Population Pharmacokinetics of Delamanid and its Main Metabolite DM-6705 in Drug-Resistant Tuberculosis Patients Receiving Delamanid Alone or Coadministered with Bedaquiline.

BACKGROUND AND OBJECTIVE: Delamanid is a nitroimidazole, a novel class of drug for treating tuberculosis, and is primarily metabolized by albumin into the metabolite DM-6705. The aims of this analysis were to develop a population pharmacokinetic (PK) model to characterize the concentration-time course of delamanid and DM-6705 in adults with drug-resistant tuberculosis and to explore a potential drug-drug interaction with bedaquiline when coadministered. METHODS: Delamanid and DM-6705 concentrations after oral administration, from 52 participants (of whom 26 took bedaquiline concurrently and 20 were HIV-1 positive) enrolled in the DELIBERATE trial were analyzed using nonlinear mixed-effects modeling. RESULTS: Delamanid PK were described by a one-compartment disposition model with transit compartment absorption (mean absorption time of 1.45 h [95% confidence interval 0.501-2.20]) and linear elimination, while the PK of DM-6705 metabolite were described by a one-compartment disposition model with delamanid clearance as input and linear elimination. Predicted terminal half-life values for delamanid and DM-6705 were 15.1 h and 7.8 days, respectively. The impact of plasma albumin concentrations on delamanid metabolism was not significant. Bedaquiline coadministration did not affect delamanid PK. Other than allometric scaling with body weight, no patients' demographics were significant (including HIV). CONCLUSIONS: This is the first joint PK model of delamanid and its DM-6705 metabolite. As such, it can be utilized in future exposure-response or exposure-safety analyses. Importantly, albumin concentrations, bedaquiline coadministration, and HIV co-infection (dolutegravir coadministration) did not have an effect on delamanid and DM-6705 PK.

QT effects of bedaquiline, delamanid, or both in patients with rifampicin-resistant tuberculosis: a phase 2, open-label, randomised, controlled trial.

BACKGROUND: Bedaquiline and delamanid are the first drugs of new classes registered for tuberculosis treatment in 40 years. Each can prolong the QTc interval, with maximum effects occurring weeks after drug initiation. The cardiac safety and microbiological activity of these drugs when co-administered are not well-established. Our aim was to characterise the effects of bedaquiline, delamanid, or both on the QTc interval, longitudinally over 6 months of multidrug treatment, among patients with multidrug-resistant or rifampicin-resistant tuberculosis taking multidrug background therapy. METHODS: ACTG A5343 is a phase 2, open-label, randomised, controlled trial in which adults with multidrug-resistant or rifampicin-resistant tuberculosis receiving multidrug background treatment were randomly assigned 1:1:1 by centrally, computer-generated randomisation, by means of permuted blocks to receive bedaquiline, delamanid, or both for 24 weeks. Participants were enrolled at TASK in Cape Town and the South African Tuberculosis Vaccine Initiative in Worcester, both in South Africa, and Hospital Maria Auxiliadora in Peru. Individuals with QTc greater than 450 ms were excluded. HIV-positive participants received dolutegravir-based antiretroviral therapy. Clofazimine was disallowed, and levofloxacin replaced moxifloxacin. ECG in triplicate and sputum cultures were done fortnightly. The primary endpoint was mean QTcF change from baseline (averaged over weeks 8-24); cumulative culture conversation at week 8-24 was an exploratory endpoint. Analyses included all participants who initiated study tuberculosis treatment (modified intention-to-treat population). This trial is registered with ClinicalTrials.gov, NCT02583048 and is ongoing. FINDINGS: Between Aug 26, 2016 and July 13, 2018, of 174 screened, 84 participants (28 in each treatment group, and 31 in total with HIV) were enrolled. Two participants did not initiate study treatment (one in the delamanid group withdrew consent and one in the bedaquiline plus delamanid group) did not meet the eligibility criterion). Mean change in QTc from baseline was 12·3 ms (95% CI 7·8-16·7; bedaquiline), 8·6 ms (4·0-13·1; delamanid), and 20·7 ms (16·1-25·3) (bedaquiline plus delamanid). There were no grade 3 or 4 adverse QTc prolongation events and no deaths during study treatment. Cumulative culture conversion by week 8 was 21 (88%) of 24 (95% CI 71-97; bedaquiline), 20 (83%) of 24 (65-95; delamanid), and 19 (95%) of 20 (79-100; bedaquiline plus delamanid) and was 92% (77-99) for bedaquiline, 91% (76-99), for delamanid, and 95% (79-100) for bedaquiline plus delamanid at 24 weeks. INTERPRETATION: Combining bedaquiline and delamanid has a modest, no more than additive, effect on the QTc interval, and initial microbiology data are encouraging. This study provides supportive evidence for use of these agents together in patients with multidrug-resistant or rifampicin-resistant tuberculosis with normal baseline QTc values. FUNDING: Division of AIDS, National Institutes of Health.

A pilot study of safety of sulfamethoxazole, trimethoprim and guaifenesin in pediatric and adult patients with acute bronchitis.

OBJECTIVE: This exploratory study assessed the safety of the combination of sulfamethoxazole, trimethoprim and guaifenesin (STG) in adult and pediatric patients with acute bronchitis according to local labelling in Peru. RESULTS: We enrolled 51 pediatric and 52 adult participants diagnosed with acute bronchitis and indication of STG. The mean ages were 7.6 years (SD ± 3.2 years) and 42.8 years (SD ± 16.1) and the proportion of female patients were 51% and 65%, respectively. The duration of treatment in pediatric patients was < 5 days in 2% of patients, 5 days in 13.7%, 6-7 days, in 82.4% and > 7 days in 2% while in adults patients it was < 5 days in 17%, 5 days in 69.2%; 6-7 days in 28.8% of patients. Adverse events (AEs) were registered in 9.6% and 19.2% of pediatric and adult patients, respectively. These AEs had definite relation of causality with the study drugs in 2 adults (20% of AEs) and possible causality with the study drugs in 4 pediatric (80% of AEs) and 2 adult cases (20% of AEs). Our results provide valuable data to develop trials of pharmacovigilance where different statistical parameters should be considered to calculate an adequate sample size in studies evaluating STG in pediatric or adult patients. Trial registration NCT02879981 and NCT02902640.

Percutaneous implantation of cerebral microdialysis catheters by twist-drill craniostomy in neurocritical patients: description of the technique and results of a feasibility study in 97 patients.

Cerebral microdialysis is increasingly used to monitor several types of neurocritical patients. This study presents the technique used in our unit for percutaneous implantation of cerebral microdialysis catheters using a small twist-drill craniostomy that can be performed in the intensive care unit (ICU). We also present the results of this technique in 89 head-injured patients and in eight patients with a malignant middle cerebral artery (MCA) infarction. One hundred and twenty-two cerebral microdialysis catheters were implanted in the 97 patients included in this study. One cerebral microdialysis catheter was implanted in the less damaged hemisphere of 67 head-injured patients with a diffuse brain injury. An additional microdialysis catheter was inserted in the pericontusional parenchyma of 22 patients with brain contusions. In five of the eight patients with a malignant MCA infarction, only one microdialysis probe was inserted in the penumbral zone. In the remaining three patients, two cerebral microdialysis catheters were implanted in the same hemisphere (one in the ischemic core and the other in the penumbra). Technical problems were detected in 18 (15%) of the 122 microdialysis catheters implanted and were more frequent during the initial period of using microdialysis in our unit. In four patients (3% of implanted catheters), follow-up computed tomography (CT) scans showed a small intracerebral blood collection (always

Deteccion y manejo de tres pacientes con agamaglobulinemia ligada al cromosoma X / Detection and management of three patients with X-linked agammaglobulinemia

La agammaglobulinemia ligada al cromosoma X (XLA) es una inmunodeficiencia primaria caracterizada por disminución de linfocitos B circulantes y por la reducción de los niveles plasmáticos de varios isotipos de inmunoglobulinas. Los individuos afectados, tienen mayor susceptibilidad de presentar infecciones bacterianas del tracto respiratorio, así como infecciones por enterovirus. En este reporte se describe la historia clínica de tres pacientes de sexo masculino vinculados al servicio clínico del grupo de inmunodeficiencias primarias de la Universidad de Antioquia, en quienes se estableció el diagnóstico de XLA. Gracias a esto los pacientes se beneficiaron de una terapéutica con gamaglobulina intravenosa, lo que ha mejorado sustancialmente su calidad de vida.

Prevalencia de hipertensión arterial en Carampoma Huarochiri - Lima - Perú (3400 m.s.n.m.) / Arterial hypertension of prevalence in Carampoma Huarochiri - Lima - Peru

Objetivos: determinar la prevalencia de hipertensión en Carampoma (Huarochirí, Lima - Perú), población de altura. Materiales y Métodos: Se realizó un estudio descriptivo en la ciudad de Carampoma (3400 msnm.) durante el mes de febrero de 1998. Se registró la presión arterial en 108 sujetos mayores de 18 años. Resultados: la prevalencia de hipertensión fue de 11.1 por ciento (12 pacientes), un 83.3 por ciento estuvieron en estadio I, el 25 por ciento tuvo hipertensión sistólica aislada. La prevalencia de hipertensión en hombres fue de 10.52 por ciento y en mujeres fue de 11.42 por ciento. La prevalencia fue mayor en el grupo de pacientes mayores de 60 años (15 por ciento). La prevalencia de hipertensión sistólica aislada fue de 7.5 por ciento en el grupo de pacientes mayores de 60 años. Cuando la prevalencia de hipertensión arterial fue comparada por sexo y edad se encontró que la prevalencia en pacientes mayores de 60 años fue de 21.42 por ciento para las mujeres y 0 por ciento para los hombres, mientras que en los pacientes menores de 60 años fue de 15.38 por ciento para los hombres y 4.76 por ciento para las mujeres. Conclusiones: la prevalencia de hipertensión en la ciudad de Carampoma fue de 11.1 por ciento la mayoría de los pacientes estuvieron dentro del estadio I. La prevalencia de hipertensión arterial aislada fue mayor en pacientes mayores de 60 años. La prevalencia de hipertensión se incrementa con la edad. La Hipertensión fue más prevalente en hombres que en las mujeres en el grupo de pacientes menores de 60 años y se encontró una relación inversa en el grupo de pacientes mayores de 60 años.