Antimicrobial resistance (AMR) is a multifaceted complex problem with momentous consequences for individuals as well as health-care systems. Understanding the gravity of the problem, the World Health Assembly has adopted the Global Action Plan on AMR in the year 2015 as a part of the tripartite collaboration with World Health Organization, Food and Agricultural Organization, and World Organization for Animal Health. India's National Action Plan (NAP) for AMR was released in April 2017 by the Union Ministry of Health and Family Welfare. The objectives of the NAP include improving awareness, enhancing surveillance measures, strengthening infection prevention and control, research and development, promoting investments, and collaborative activities to control AMR. On the basis of the NAP, various states have begun the process of initiating their State Action Plans. The aim of this article is to highlight some of the main components of the NAP and to make family physicians, general practitioners, and other stakeholders aware of the issue of AMR and its factors and what can be done. The article also discusses some of the challenges in implementation of NAP such as varied perceptions about antibiotic use and AMR among key stakeholders, inappropriate antibiotic use owing to a number of reasons, lack of diagnostic facilities, widespread use of antibiotics in various sectors, environmental contamination because of pharmaceutical industry, agricultural and hospital waste, gaps in infection prevention and control, and difficulty in enforcing regulations. Similar to other low-middle income countries (LMICs), lack of sufficient finances remains a major challenge in NAP implementation in India as well. Overall, a strong political will, inter-sectoral co-ordination between public and private sectors and comprehensive strengthening of the healthcare systems are necessary to achieve the desired forward momentum.

Introduction: Implementing a sustainable and effective Antimicrobial Stewardship (AMS) programme in secondary level hospitals, in Low-Middle Income Country (LMIC) contexts, has numerous challenges. It is important to understand these challenges so that the stewardship initiatives can be tailored according to the unique requirements thrown up by these healthcare facilities. This study explores the experiences of implementing AMS in secondary level hospitals in the state of Kerala, India. Methods: A qualitative study was planned to map the challenges in implementing AMS in the secondary level hospitals. Toward the end of the 1 year followup period, the nodal officers at each hospital were interviewed using a semi-structured interview guide. The in-depth interviews were transcribed and later subjected to content analysis using N-Vivo 11.0, a popular software tool used for qualitative analysis. Results: Many physicians cite perceived patient satisfaction as one of the reasons for increased antibiotic use, as many patients consider antibiotics as standard of care. Also, the distance traveled by the patient and advancing age are factors which increase antibiotic use. The physician factors which determine use include empiric treatment needs, outbreak of diseases, absence of education programmes in antibiotic usage to fill in the knowledge gap and fear of litigation. The promotional activities by companies and antibiotics being a major source of income for small hospitals, affects use patterns. The factors which determine antibiotic selection includes conformism, experience of the physician, perceived resistance to certain antibiotics, emergence of specific diseases, and promotional activities related to antimicrobial agents. The challenges in implementing a sustainable stewardship programme is multifactorial. It includes competition between doctors, time constraints faced by physicians, absence of a champion, sub-optimal interdepartmental cooperation, absence of supporting facilities, dysfunctional regulatory systems, and unreliability of antibiograms. Discussion: AMS in resource-limited setting is going to be a challenge, especially in terms of financing, access to technologies and capacity building. Political and regulatory Mathew et al. Challenges in Antimicrobial Stewardship Implementation willpower of international partnerships should be effectively harnessed for designing solutions for LMIC contexts. Also, models for stewardship from elsewhere should undergo an adaptation process before implementation in low resource settings.

Aims Pharmacokinetic studies in the past have shown inadequate antituberculosis drug levels in children with the currently available dosing regimens. This study attempted to investigate the pharmacokinetics of isoniazid and rifampicin, when used in children, and to optimize their dosing regimens. Methods Data were collected from 41 children, aged 2–16 years, who were being treated with antituberculosis drugs for at least 2 months. Concentration measurements were done for 6 h and analysed using a nonlinear, mixed‐effects model. Results Isoniazid pharmacokinetics were described by a one‐compartment disposition model with a transit absorption model (fixed, n = 5). A mixture model was used to identify the slow and fast acetylator subgroups. Rifampicin was described by a one‐compartment disposition model with a transit absorption model (fixed, n = 9). Body weight was added to the clearance and volume of distribution of both the drugs using an allometric function. Simulations with the isoniazid model showed that 84.9% of the population achieved therapeutic peak serum concentration with the planned fixed‐dose combination regimen. Simulations with the rifampicin model showed that only about 28.8% of the simulated population achieve the therapeutic peak serum concentration with the fixed‐dose combination regimen. A novel regimen for rifampicin, with an average dose of 35 mg kg–1, was found to provide adequate drug exposure in most children. Conclusions The exposure to isoniazid is adequate with present regimens. For rifampicin, a novel dosing regimen was developed to ensure adequate drug concentrations in children. However, further studies are required to assess the dose–effect relationship of higher doses of rifampicin.

No abstract

BackgroundSuboptimal exposure to antituberculosis drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line antituberculosis drug pharmacokinetics in children and adolescents at a global level.MethodsWe systematically searched MEDLINE, Embase, and Web of Science (1990–2021) for pharmacokinetic studies of first-line antituberculosis drugs in children and adolescents. Individual patient data were obtained from authors of eligible studies. Summary estimates of total/extrapolated area under the plasma concentration-time curve (AUC0–24) and peak plasma concentration (Cmax) were assessed with random-effects models, normalised with current WHO-recommended paediatric doses. Determinants of AUC0–24and Cmaxwere assessed with linear mixed-effects models.ResultsOf 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means (95% CIs) of steady-state AUC0–24were summarised for isoniazid (18.7 [15.5−22.6] h·mg·L−1), rifampicin (34.4 [29.4−40.3] h·mg·L−1), pyrazinamide (375.0 [339.9−413.7] h·mg·L−1), and ethambutol (8.0 [6.4−10.0] h·mg·L−1). Our multivariate models indicated that younger age (especially <2 years) and HIV-positive status were associated with lower AUC0–24for all antituberculosis drugs, while severe malnutrition was associated with lower AUC0–24for isoniazid and pyrazinamide. N-acetyltransferase2rapid acetylators had lower isoniazid AUC0–24and slow acetylators had higher isoniazid AUC0–24than intermediate acetylators. Determinants of Cmaxwere generally similar to those for AUC0–24.ConclusionThis study provides the most comprehensive estimates of plasma exposures to first-line antituberculosis drugs in children and adolescents. Key determinants of drug exposures were identified. These may be relevant for population-specific dose adjustment or individualised therapeutic drug monitoring.