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.</p

Estimations of electron-positron pair production at high-intensity laser interaction with high-Z targets

Electron-positron pairs' generation occuring in the interaction of $10^{18}$-$10^{20}$~W/cm$^2$ laser radiation with high-Z targets are examined. Computational results are presented for the pair production and the positron yield from the target with allowance for the contribution of pair production processes due to electrons and bremsstrahlung photons. Monte-Carlo simulations using the PRIZMA code confirm the estimates obtained. The possible positron yield from high-Z targets irradiated by picosecond lasers of power $10^2$-$10^3$~TW is estimated to be $10^9$-$10^{11}$

Colistin dry powder inhalation with the Twincer (TM):An effective and more patient friendly alternative to nebulization

BACKGROUND: Nebulization of antimicrobial drugs such as tobramycin and colistin is a cornerstone in the treatment of patients with cystic fibrosis (CF) infected with Pseudomonas aeruginosa. However, nebulization has a high treatment burden. The Twincer™ is a dry powder inhaler specifically developed for the inhalation of antibiotics such as colistin. The aim of this study was to compare patient outcomes and experience with colistin dry powder by the Twincer with nebulization of colistin or tobramycin in adult CF patients in a real-life setting. METHODS: This was a retrospective study from 01-01-2015 until 01-07-2018. Effectiveness was evaluated by comparing FEV1 decline and exacerbation rate during a mean of 4.1 years of nebulization therapy prior to the initiation of the Twincer against the same values during a mean of 1.7 years of treatment with the Twincer. RESULTS: Twenty-one patients were evaluated, of whom twelve could be included in the effectiveness analysis, with a total of twenty patient years. Of all patients 71.4% preferred therapy with the Twincer over nebulization. Twincer use resulted in high treatment adherence with an average adherence rate of 92.5%. There was no significant difference in annual decline in FEV1%pred prior to and after start changing from nebulization to the use of the Twincer powder inhaler (median decline -1.56 [-5.57-5.31] and 1.35 [-8.45-6.36]) respectively, p = 0.45 (linear mixed effect model)). No significant difference was found in the number of intravenous or combined total intravenous and oral antibiotic courses during Twincer therapy compared to when using nebulization (1.68 and 2.49 courses during Twincer therapy versus 1.51 and 2.94 courses during nebulization, p = 0.88 and p = 0.63). CONCLUSION: Colistin dry powder inhalation with the Twincer is a more patient friendly alternative to nebulization, and we did not observe significant differences in the clinical outcome, regarding lung function and exacerbation rates

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

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

In Vitro Susceptibility of Mycobacterium tuberculosis to Amikacin, Kanamycin, and Capreomycin

Amikacin, kanamycin and capreomycin are listed among the most important 2nd line drugs for multidrug resistant tuberculosis. Although amikacin and kanamycin are administered in the same dose and show the same pharmacokinetics, they have different WHO breakpoints suggesting that the two drugs have a different minimal inhibitory concentrations (MIC). The aim of this paper was to investigate possible differences in MIC between the aminoglycosides and capreomycin.Using the direct concentration method, a concentration range of amikacin, kanamycin and capreomycin (0.25, 0.50, 1.0, 2.0, 4.0, 8.0, 16.0, 32.0 and 64.0 mg/L) was tested against 57 clinical Mycobacterium tuberculosis strains. The 7H10 agar plates were examined for mycobacterial growth after 14 days.At 2 mg/L, 48 strains (84%) were inhibited by amikacin and only five strains (9%) were inhibited by kanamycin (p < 0.05, Wilcoxon Signed Rank Test). The median MICs of amikacin, kanamycin and capreomycin were 2, 4 and 8 mg/L, respectively. No difference was observed between multidrug resistant and fully susceptible strains in the MIC-distribution of amikacin, kanamycin and capreomycin.The results indicate that amikacin is more active against M. tuberculosis than kanamycin and capreomycin in the absolute concentration method. The impact of this difference on clinical outcome in daily practice requires a prospective study including pharmacokinetic and pharmacodynamics evaluations

Bedaquiline as part of combination therapy in adults with pulmonary multi-drug resistant tuberculosis

Introduction: Few innovative anti-microbial products have been brought to market in recent years to combat the global multidrug resistant-tuberculosis (MDR-TB) epidemic. Bedaquiline, a novel oral diarylquinoline, was approved by the US FDA as a part of combination therapy in adults with pulmonary MDR-TB based on phase II trials.Area covered: Pubmed searches were conducted using search terms bedaquiline, diarylquinoline, R207910, and TMC207 was performed. Supplementary sources included World Health Organization, Clinicaltrial.gov, US Food and Drug Administration. Bedaquiline is an ATP synthase inhibitor specific for M. tuberculosis and some nontuberculous mycobacteria. It is metabolized by CYP3A4 and it's drug exposure can be influenced by inducers and inhibitors of this enzyme. Phase II studies showed promising results on efficacy of bedaquiline when being used in combination with a background regimen for MDR-TB. Main safety concerns include QTc prolongation and hepatotoxicity. Phase III trials are ongoing to confirm efficacy findings from phase II studies and provide additional evidence of safety and efficacy.Expert commentary: Critical data for long-term efficacy and safety are incomplete and scarce, supporting the cautious use of bedaquiline

Prospective evaluation of improving fluoroquinolone exposure using centralised therapeutic drug monitoring (TDM) in patients with tuberculosis (PERFECT): a study protocol of a prospective multicentre cohort study

Introduction Global multidrug-resistant tuberculosis (MDR-TB) treatment success rates remain suboptimal. Highly active WHO group A drugs moxifloxacin and levofloxacin show intraindividual and interindividual pharmacokinetic variability which can cause low drug exposure. Therefore, therapeutic drug monitoring (TDM) of fluoroquinolones is recommended to personalise the drug dosage, aiming to prevent the development of drug resistance and optimise treatment. However, TDM is considered laborious and expensive, and the clinical benefit in MDR-TB has not been extensively studied. This observational multicentre study aims to determine the feasibility of centralised TDM and to investigate the impact of fluoroquinolone TDM on sputum conversion rates in patients with MDR-TB compared with historical controls. Methods and analysis Patients aged 18 years or older with sputum smear and culture-positive pulmonary MDR-TB will be eligible for inclusion. Patients receiving TDM using a limited sampling strategy (t=0 and t=5 hours) will be matched to historical controls without TDM in a 1:2 ratio. Sample analysis and dosing advice will be performed in a centralised laboratory. Centralised TDM will be considered feasible if &gt;80% of the dosing recommendations are returned within 7 days after sampling and 100% within 14 days. The number of patients who are sputum smear and culture-negative after 2 months of treatment will be determined in the prospective TDM group and will be compared with the control group without TDM to determine the impact of TDM. Ethics and dissemination Ethical clearance was obtained by the ethical review committees of the 10 participating hospitals according to local procedures or is pending (online supplementary file 1). Patients will be included after obtaining written informed consent. We aim to publish the study results in a peer-reviewed journal. Trial registration number ClinicalTrials.gov Registry (NCT03409315)