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.

The revised WHO drug dosages were found to be adequate for INH with respect to age and nutritional status, whereas PZA showed significantly lower drug levels in children <3 years and in malnourished children.

BackgroundThe overuse of antibiotics in newborns leads to increased mortality and morbidities. Implementation of a successful antibiotic stewardship programme (ASP) is necessary to decrease inappropriate use of antibiotics and its adverse effects.ProblemOur neonatal intensive care unit (NICU) is a tertiary referral centre of north India, consisting of all outborn babies mostly with sepsis caused by high rate of multidrug-resistant organisms (MDROs). So antibiotics are not only life-saving but also used excessively with a high antibiotic usage rate (AUR) of 574 per 1000 patient days.MethodA quality improvement (QI) study was conducted using the Plan–Do–Study–Act (PDSA) approach to reduce AUR by at least 20% from January 2019 to December 2020. Various strategies were made : such as making a unit protocol, education and awareness of NICU nurses and doctors, making check points for both starting and early stoppage of antibiotics, making specific protocol to start vancomycin, and reviewing yearly antibiotic policy as per antibiogram.ResultsThe total AUR, AUR (culture negative) and AUR (vancomycin) was reduced by 32%, 20% and 29%, respectively, (p<0.01). The proportion of newborns who never received antibiotics increased from 22% to 37% (p<0.045) and the proportion of culture-negative/screen-negative newborns where antibiotics were stopped within 48 hours increased from 16% to 54% (p<0.001). The compliance with the unit protocol in starting and upgrading antibiotic was 75% and 82%, respectively. In early 2020, there was a sudden upsurge in AUR due to central line-related bloodstream infection breakout. However, we were able to control it, and all the PDSA cycles were reinforced. Finally, we could reattain our goals, and also able to sustain it until next 1 year. There was no significant difference in overall necrotising enterocolitis and mortality rates.ConclusionIn a centre such as ours, where sepsis is a leading cause of neonatal deaths, restricting antibiotic use is a huge challenge. However, we have demonstrated implementation of an efficient ASP with the help of a dedicated team and effective PDSA cycles. Also, we have emphasised the importance of sustainability in success of any QI study.

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