Global estimates and determinants of antituberculosis drug pharmacokinetics in children and adolescents: a systematic review and individual patient data meta-analysis.

BACKGROUND: Suboptimal exposure to antituberculosis (anti-TB) drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line anti-TB drug pharmacokinetics in children and adolescents at a global level. METHODS: We systematically searched MEDLINE, Embase and Web of Science (1990-2021) for pharmacokinetic studies of first-line anti-TB 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 from 0 to 24 h post-dose (AUC0-24) and peak plasma concentration (C max) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC0-24 and C max were assessed with linear mixed-effects models. RESULTS: Of 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means of steady-state AUC0-24 were summarised for isoniazid (18.7 (95% CI 15.5-22.6) h·mg·L-1), rifampicin (34.4 (95% CI 29.4-40.3) h·mg·L-1), pyrazinamide (375.0 (95% CI 339.9-413.7) h·mg·L-1) and ethambutol (8.0 (95% CI 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 AUC0-24 for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC0-24 for isoniazid and pyrazinamide. N-acetyltransferase 2 rapid acetylators had lower isoniazid AUC0-24 and slow acetylators had higher isoniazid AUC0-24 than intermediate acetylators. Determinants of C max were generally similar to those for AUC0-24. CONCLUSIONS: This study provides the most comprehensive estimates of plasma exposures to first-line anti-TB 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.

Antibiotic stewardship in a tertiary care NICU of northern India: a quality improvement initiative.

BACKGROUND: The 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. PROBLEM: Our 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. METHOD: A 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. RESULTS: The 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. CONCLUSION: In 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.

Pharmacokinetic study of isoniazid and pyrazinamide in children: impact of age and nutritional status.

OBJECTIVES: To evaluate pharmacokinetics of first-line antitubercular drugs, isoniazid (INH) and pyrazinamide (PZA), with revised WHO dosages and to assess its adequacy in relation to age and nutritional status. DESIGN: Observational study. SETTING: This study was conducted at Sarojini Naidu Medical College, Agra, and National Institute for Research in Tuberculosis, Chennai. PATIENTS: 40 subjects diagnosed with tuberculosis were registered in the study and started on daily first-line antitubercular regimen based on the revised WHO guidelines. INTERVENTIONS: Blood samples were collected at 0, 2, 4, 6 and 8 hours from these subjects after 15 days of treatment for drug estimations. MAIN OUTCOME MEASURE: The measurement of drug concentrations (maximum peak concentration (Cmax) and area under the time -concentration curve (AUC0-8 hours)) for INH and PZA. Appropriate statistical methods were used to evaluate the impact of age and nutritional status on pharmacokinetic variables. RESULTS: For INH, the difference in drug exposures in children <3 years (Cmax 3.18 µg/mL and AUC0-8 hours15.76 µg/mL hour) and children >3 years (Cmax3.05 µg/mL and AUC0-8 hours 14.37 µg/mL hour) was not significant (P=0.94, P=0.81, respectively). The drug levels in children with low body mass index (BMI) (Cmax3.08 µg/mL; AUC0-8 hours14.81 µg/mL hour) were also comparable with their normal counterparts (Cmax3.09 µg/mL, P=0.99; AUC0-8 hours 14.69 µg/mL hour, P=0.82). PZA drug exposures obtained in children less than 3 years (Cmax29.22 µg/mL, AUC0-8 hours 155.45 µg/mL hour) were significantly lower compared with drug levels in children above 3 years (Cmax 37.12 µg/mL, P=0.03; AUC 202.63 µg/mL hour, P value=0.01). Children with low BMI had significantly lower drug concentrations (Cmax 31.90 µg/mL, AUC0-8 hours167.64 µg/mL hour) when compared with normal counterparts (Cmax 37.60 µg/mL, P=0.02; AUC0-8 hours 208.77 µg/mL hour, P=0.01). CONCLUSIONS: 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.

Rotary drum composting of vegetable waste and tree leaves.

High rate composting studies on institutional waste, i.e. vegetable wastes, tree leaves, etc., were conducted on a demonstration-scale (3.5 m(3)) rotary drum composter by evaluating changes in some physico-chemical and biological parameters. During composting, higher temperature (60-70 degrees C) at inlet zone and (50-60 degrees C) at middle zone were achieved which resulted in high degradation in the drum. As a result, all parameters including TOC, C/N ratio, CO(2) evolution and coliforms were decreased significantly within few days of composting. Within a week period, quality compost with total nitrogen (2.6%) and final total phosphorus (6 g/kg) was achieved; but relatively higher final values of fecal coliforms and CO(2) evolution, suggested further maturation. Thus, two conventional composting methods namely windrow (M1) and vermicomposting (M2) tried for maturation of primary stabilized compost. By examining these methods, it was suggested that M2 was found suitable in delivering fine grained, better quality matured compost within 20 days of maturation period.