TB therapeutic drug monitoring - analysis of opportunities in Romania and Ukraine.

INTRODUCTION: Therapeutic drug monitoring (TDM) could improve TB treatment outcomes by avoiding drug toxicity or underdosing. In this study, we describe the patient burden in three TB centres in Romania and Ukraine with a TDM indication, as per the current guidelines, in order to estimate the feasibility of implementing TDM.METHODS: A retrospective multi-centre study was conducted at the Iasi Lung Hospital (Iasi, Romania), Bucharest Marius Nasta Institute (Bucharest, Romania) and Chernivtsi TB Centre (Chernivtsi, Ukraine) in adult hospitalised TB patients.RESULTS: A total of 927 participants were admitted, of whom 37.8% had at least one indication for TDM, the most frequent being slow response to TB treatment (202/345, 58.6%); 55.5% had at least one cavity present on chest X-ray. Patients with a TDM indication stayed in the hospital for a median of 67 days and took on average 2 months more to reach a successful TB outcome.CONCLUSION: TDM could be a valuable tool to improve management of selected TB patients. The decision on whether to perform TDM is often delayed by 2 months due to waiting for culture results after treatment initiation. A randomised control trial should be performed in order to define TDM's precise role in TB therapy.

Isoniazid and rifampicin exposure during treatment in drug-susceptible TB.

BACKGROUND: Observational real-world studies on therapeutic drug monitoring (TDM) in relation to pharmacokinetic (PK) target values are lacking. This study aims to describe the PK of rifampicin (RIF) and isoniazid (INH) in a real-world setting of patients with drug-susceptible TB in relation to frequently used threshold values.METHODS: A total of 116 patients with TB using standard doses of RIF and INH and who had TDM as part of clinical care were included. Maximum plasma concentration (Cmax) and 24 h area under the concentration time curve (AUC24) at standard and revised doses were described in relation to the threshold values (Cmax ≥8 mg/L for RIF and ≥3 mg/L for INH).RESULTS: For RIF (100 patients), median Cmax and median AUC24 were respectively 7.9 mg/L (IQR 6.0-11.0) and 35.8 mg*h/L (IQR 27.4-57.3) at the first TDM measurement after a standard dose of 600 mg. For INH (90 patients), median Cmax and median AUC24 were respectively 2.9 mg/L (IQR 1.3-2.5) and 12.5 mg*h/L (IQR 8.7-18.9) at the first TDM after a standard dose 300 mg. Overall, more than 50% of study participants had drug exposure below threshold values at the first TDM.CONCLUSION: Our study shows that the measured Cmax values for both RIF and INH were frequently below the pre-specified targets, emphasising the need for better justification of drug exposure targets. These TDM results highlight the need for validating PK targets of anti-TB drugs associated with clinically relevant outcomes.

Diagnosis, treatment and transmission of rifampicin-resistant TB in the Netherlands, 2010-2019.

BACKGROUND: New tools for diagnosis and treatment of rifampicin-resistant (RR-) and multidrug-resistant (MDR-) TB have become available in the last decade, including better tests confirming transmission.OBJECTIVE: To analyse transmission risks of MDR/RR-TB in the Netherlands.METHODS: Analysis of national data of patients with MDR/RR-TB notified in 2010-2019, including contact investigation and genotyping data.RESULTS: Patients with MDR/RR-TB (n = 121) were more often female (adjusted odds ratio [aOR] 1.5), foreign-born, previously treated for TB (aOR 5.2) and co-infected with HIV (aOR 2.3) than patients with no MDR/RR-TB. Treatment outcomes were satisfactory, with at least 79% completing treatment. After additional whole-genome sequencing (WGS), five molecular clusters of 16 patients remained. Patients in three clusters could not be epidemiologically linked and were unlikely to have been infected in the Netherlands. The remaining eight (6.6%) patients with MDR/RR-TB belonged to two clusters, and were likely the result of transmission in the Netherlands. Among close contacts of patients with smear-positive pulmonary MDR/RR-TB, 13.4% (n = 38) had TB infection and 1.1% (n = 3) had TB disease. Only six contacts with TB infection were treated with a quinolone-based preventive treatment regimen.CONCLUSION: MDR/RR-TB is effectively controlled in the Netherlands. Preventive treatment options could be considered more frequently in contacts clearly infected by an index patient with MDR-TB.

eHealth in TB clinical management.

BACKGROUND: The constant expansion of internet and mobile technologies has created new opportunities in the field of eHealth, or the digital delivery of healthcare services. This TB meta-analysis aims to examine eHealth and its impact on TB clinical management in order to formulate recommendations for further development.METHODS: A systematic search was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses framework in PubMed and Embase of articles published up to April 2021. Screening, extraction and quality assessment were performed by two independent researchers. Studies evaluating an internet and/or mobile-based eHealth intervention with an impact on TB clinical management were included. Outcomes were organised following the five domains described in the WHO "Recommendations on Digital Interventions for Health System Strengthening" guideline.RESULTS: Search strategy yielded 3,873 studies, and 89 full texts were finally included. eHealth tended to enhance screening, diagnosis and treatment indicators, while being cost-effective and acceptable to users. The main challenges concern hardware malfunction and software misuse.CONCLUSION: This study offers a broad overview of the innovative field of eHealth applications in TB. Different studies implementing eHealth solutions consistently reported on benefits, but also on specific challenges. eHealth is a promising field of research and could enhance clinical management of TB.

Tolerability and pharmacokinetic evaluation of inhaled dry powder hydroxychloroquine in healthy volunteers.

RATIONALE: Inhaled antimicrobials enable high local concentrations where needed and, compared to orally administration, greatly reduce the potential for systemic side effects. In SARS-CoV-2 infections, hydroxychloroquine sulphate (HCQ) administered as dry powder via inhalation could be safer than oral HCQ allowing higher and therefore more effective pulmonary concentrations without dose limiting toxic effects. OBJECTIVES: To assess the local tolerability, safety and pharmacokinetic parameters of HCQ inhalations in single ascending doses of 5, 10 and 20 mg using the Cyclops dry powder inhaler. METHODS: Twelve healthy volunteers were included in the study. Local tolerability and safety were assessed by pulmonary function tests, electrocardiogram and recording adverse events. To estimate systemic exposure, serum samples were collected before and 0.5, 2 and 3.5 h after inhalation. RESULTS AND DISCUSSION: Dry powder HCQ inhalations were well tolerated by the participants, except for transient bitter taste in all participants and minor coughing irritation. There was no significant change in QTc-interval or drop in FEV1 post inhalation. The serum HCQ concentration remained below 10 µg/L in all samples. CONCLUSION: Single doses of inhaled dry powder HCQ up to 20 mg are safe and well tolerated. Our data support that further studies with inhaled HCQ dry powder to evaluate pulmonary pharmacokinetics and efficacy are warranted.

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.

Clinical standards for drug-susceptible pulmonary TB.

BACKGROUND: The aim of these clinical standards is to provide guidance on 'best practice´ for diagnosis, treatment and management of drug-susceptible pulmonary TB (PTB).METHODS: A panel of 54 global experts in the field of TB care, public health, microbiology, and pharmacology were identified; 46 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 46 participants.RESULTS: Seven clinical standards were defined: Standard 1, all patients (adult or child) who have symptoms and signs compatible with PTB should undergo investigations to reach a diagnosis; Standard 2, adequate bacteriological tests should be conducted to exclude drug-resistant TB; Standard 3, an appropriate regimen recommended by WHO and national guidelines for the treatment of PTB should be identified; Standard 4, health education and counselling should be provided for each patient starting treatment; Standard 5, treatment monitoring should be conducted to assess adherence, follow patient progress, identify and manage adverse events, and detect development of resistance; Standard 6, a recommended series of patient examinations should be performed at the end of treatment; Standard 7, necessary public health actions should be conducted for each patient. We also identified priorities for future research into PTB.CONCLUSION: These consensus-based clinical standards will help to improve patient care by guiding clinicians and programme managers in planning and implementation of locally appropriate measures for optimal person-centred treatment for PTB.

Pulmonary tuberculosis in intensive care setting, with a focus on the use of severity scores, a multinational collaborative systematic review.

BACKGROUND AND AIM: Tuberculosis (TB) is associated with a high mortality in the intensive care unit (ICU), especially in subjects with Acute Respiratory Distress Syndrome (ARDS) requiring mechanical ventilation. Despite its global burden on morbidity and mortality, TB is an uncommon cause of ICU admission, however mortality is disproportionate to the advances in diagnosis and treatment made. Herein we report a systematic review of published studies. METHODS: Our Literature search was conducted to identify studies on outcomes of individuals with TB admitted to ICU. We report and review in-hospital mortality, predictors of poorer outcomes, usefulness of severity scoring systems and potential benefits of intravenous antibiotics. Searches from Pubmed, Embase, Cochrane and Medline were conducted from inception to March 2020. Only literature in English was included. RESULTS: Out of 529 potentially relevant articles, 17 were included. Mortality across all studies ranged from 29-95% with an average of 52.9%. All severity scores underestimated average mortality. The most common indication for ICU admission was acute respiratory failure (36.3%). Negative predictors of outcome included hospital acquired infections, need of mechanical ventilation and vasopressors, delay in initiation of anti-TB treatment, more than one organ failure and a higher severity score. Low income, high incidence countries showed a 23.4% higher mortality rate compared to high income, low TB incidence countries. CONCLUSION: Mortality in individuals with TB admitted to ICU is high. Earlier detection and treatment initiation is needed.

Clinical standards for the assessment, management and rehabilitation of post-TB lung disease.

BACKGROUND: Increasing evidence suggests that post-TB lung disease (PTLD) causes significant morbidity and mortality. The aim of these clinical standards is to provide guidance on the assessment and management of PTLD and the implementation of pulmonary rehabilitation (PR).METHODS: A panel of global experts in the field of TB care and PR was identified; 62 participated in a Delphi process. A 5-point Likert scale was used to score the initial ideas for standards and after several rounds of revision the document was approved (with 100% agreement).RESULTS: Five clinical standards were defined: Standard 1, to assess patients at the end of TB treatment for PTLD (with adaptation for children and specific settings/situations); Standard 2, to identify patients with PTLD for PR; Standard 3, tailoring the PR programme to patient needs and the local setting; Standard 4, to evaluate the effectiveness of PR; and Standard 5, to conduct education and counselling. Standard 6 addresses public health aspects of PTLD and outcomes due to PR.CONCLUSION: This is the first consensus-based set of Clinical Standards for PTLD. Our aim is to improve patient care and quality of life by guiding clinicians, programme managers and public health officers in planning and implementing adequate measures to assess and manage PTLD.

The long-term safety of chronic azithromycin use in adult patients with cystic fibrosis, evaluating biomarkers for renal function, hepatic function and electrical properties of the heart.

Background: Azithromycin maintenance therapy is widely used in cystic fibrosis (CF), but little is known about its long-term safety. We investigated whether chronic azithromycin use is safe regarding renal function, hepatic cell toxicity and QTc-interval prolongation.Methods: Adult CF patients (72 patients using azithromycin for a cumulative period of 364.8 years and 19 controls, 108.8 years) from two CF-centers in the Netherlands with azithromycin (non)-use for at least three uninterrupted years were studied retrospectively.Results: There was no difference in mean decline of estimated glomerular filtration rate (eGFR), nor in occurrence of eGFR-events. No drug-induced liver injury could be attributed to azithromycin. Of the 39 azithromycin users of whom an ECG was available, 4/39 (10.3%) had borderline and 4/39 (10.3%) prolonged QTc-intervals, with 7/8 patients using other QTc-prolonging medication. Of the control patients 1/6 (16.7%) had a borderline QTc-interval, without using other QTc-prolonging medication. No cardiac arrhythmias were observed.Conclusion: We observed no renal or hepatic toxicity, nor cardiac arrythmias during azithromycin use in CF patients for a mean study duration of more than 5 years. One should be aware of possible QTc-interval prolongation, in particular in patients using other QTc-interval prolonging medication.

Outcome of treatment of MDR-TB or drug-resistant patients treated with bedaquiline and delamanid: Results from a large global cohort.

The World Health Organization (WHO) recommends countries introduce new anti-TB drugs in the treatment of multidrug-resistant tuberculosis. The aim of the study is to prospectively evaluate the effectiveness of bedaquiline (and/or delamanid)- containing regimens in a large cohort of consecutive TB patients treated globally. This observational, prospective study is based on data collected and provided by Global Tuberculosis Network (GTN) centres and analysed twice a year. All consecutive patients (including children/adolescents) treated with bedaquiline and/or delamanid were enrolled, and managed according to WHO and national guidelines. Overall, 52 centres from 29 countries/regions in all continents reported 883 patients as of January 31st 2021, 24/29 countries/regions providing data on 100% of their consecutive patients (10-80% in the remaining 5 countries). The drug-resistance pattern of the patients was severe (>30% with extensively drug-resistant -TB; median number of resistant drugs 5 (3-7) in the overall cohort and 6 (4-8) among patients with a final outcome). For the patients with a final outcome (477/883, 54.0%) the median (IQR) number of months of anti-TB treatment was 18 (13-23) (in days 553 (385-678)). The proportion of patients achieving sputum smear and culture conversion ranged from 93.4% and 92.8% respectively (whole cohort) to 89.3% and 88.8% respectively (patients with a final outcome), a median (IQR) time to sputum smear and culture conversion of 58 (30-90) days for the whole cohort and 60 (30-100) for patients with a final outcome and, respectively, of 55 (30-90) and 60 (30-90) days for culture conversion. Of 383 patients treated with bedaquiline but not delamanid, 284 (74.2%) achieved treatment success, while 25 (6.5%) died, 11 (2.9%) failed and 63 (16.5%) were lost to follow-up.