Pharmacokinetics of anti-TB drugs in Malawian children: reconsidering the role of ethambutol

Background Current guidelines for dosing of anti-TB drugs in children advocate higher doses for rifampicin and isoniazid despite limited availability of paediatric data on the pharmacokinetics of these drugs, especially from Africa, where the burden of childhood disease remains high. Methods Thirty children aged 6 months to 15 years underwent intensive pharmacokinetic sampling for first-line anti-TB drugs at Queen Elizabeth Central Hospital, Blantyre, Malawi. Rifampicin, isoniazid, pyrazinamide and ethambutol were dosed at 10, 5, 25 and 20 mg/kg, respectively. Plasma drug concentrations were determined using sensitive, validated bioanalytical methods and summary pharmacokinetic parameters were estimated using non-compartmental analysis. Results The median (IQR) Cmax was 2.90 (2.08–3.43), 3.37 (2.55–4.59), 34.60 (32.30–40.90) and 1.20 (0.85–1.68) mg/L while the median (IQR) AUC0–∞ was 16.92 (11.10–22.74), 11.48 (7.35–18.93), 333.50 (279.50–487.2) and 8.65 (5.96–11.47) mg·h/L for rifampicin, isoniazid, pyrazinamide and ethambutol, respectively. For all drugs, pharmacokinetic parameters relating to drug absorption and exposure were lower than those published for adults, though similar to existing paediatric data from sub-Saharan Africa. Weight and/or dose predicted at least one measure of exposure for all drugs. Age-related decreases in CL/F for rifampicin and pyrazinamide and a biphasic elimination pattern of isoniazid were observed. Predicted AUC0–∞ for rifampicin dosed at 15 mg/kg was comparable to that of adults while the dose required to achieve ethambutol exposure similar to that in adults was 55 mg/kg or higher. Conclusions These data support recently revised WHO recommendations for dosing of anti-TB drugs in children, but dosing of ethambutol in children also appears inadequate by comparison with adult pharmacokinetic data

Feasibility Study of the World Health Organization Health Care Facility-Based Antimicrobial Stewardship Toolkit for Low- and Middle-Income Countries

Antimicrobial stewardship (AMS) has emerged as a systematic approach to optimize antimicrobial use and reduce antimicrobial resistance. To support the implementation of AMS programs, the World Health Organization developed a draft toolkit for health care facility AMS programs in low- and middle-income countries. A feasibility study was conducted in Bhutan, the Federated States of Micronesia, Malawi, and Nepal to obtain local input on toolkit content and implementation of AMS programs. This descriptive qualitative study included semi-structured interviews with national- and facility-level stakeholders. Respondents identified AMS as a priority and perceived the draft toolkit as a much-needed document to further AMS program implementation. Facilitators for implementing AMS included strong national and facility leadership and clinical staff engagement. Barriers included lack of human and financial resources, inadequate regulations for prescription antibiotic sales, and insufficient AMS training. Action items for AMS implementation included improved laboratory surveillance, establishment of a stepwise approach for implementation, and mechanisms for reporting and feedback. Recommendations to improve the AMS toolkit\u27s content included additional guidance on defining the responsibilities of the committees and how to prioritize AMS programming based on local context. The AMS toolkit was perceived to be an important asset as countries and health care facilities move forward to implement AMS programs

Diagnosis of childhood tuberculosis and host RNA expression in Africa

Improved diagnostic tests for tuberculosis in children are needed. We hypothesized that transcriptional signatures of host blood could be used to distinguish tuberculosis from other diseases in African children who either were or were not infected with the human immunodeficiency virus (HIV

Use of bubble continuous positive airway pressure (bCPAP) in the management of critically ill children in a Malawian paediatric unit: An observational study

INTRODUCTION: In low-resource countries, respiratory failure is associated with a high mortality risk among critically ill children. We evaluated the role of bubble continuous positive airway pressure (bCPAP) in the routine care of critically ill children in Lilongwe, Malawi. // METHODS: We conducted an observational study between 26 February and 15 April 2014, in an urban paediatric unit with approximately 20 000 admissions/year (in-hospital mortality <5% approximately during this time period). Modified oxygen concentrators or oxygen cylinders provided humidified bCPAP air/oxygen flow. Children up to the age of 59 months with signs of severe respiratory dysfunction were recruited. Survival was defined as survival during the bCPAP-treatment and during a period of 48 hours following the end of the bCPAP-weaning process. // RESULTS: 117 children with signs of respiratory failure were included in this study and treated with bCPAP. Median age: 7 months. Malaria rapid diagnostic tests were positive in 25 (21%) cases, 15 (13%) had severe anaemia (Hb < 7.0 g/dL); 55 (47%) children had multiorgan failure (MOF); 22 (19%) children were HIV-infected/exposed. 28 (24%) were severely malnourished. Overall survival was 79/117 (68%); survival was 54/62 (87%) in children with very severe pneumonia (VSPNA) but without MOF. Among the 19 children with VSPNA (single-organ failure (SOF)) and negative HIV tests, all children survived. Survival rates were lower in children with MOF (including shock) (45%) as well as in children with severe malnutrition (36%) and proven HIV infection or exposure (45%). // CONCLUSIONS: Despite the limitations of this study, the good outcome of children with signs of severe respiratory dysfunction (SOF) suggests that it is feasible to use bCPAP in the hospital management of critically ill children in resource-limited settings. The role of bCPAP and other forms of non-invasive ventilatory support as a part of an improved care package for critically ill children with MOF at tertiary and district hospital level in low-resource countries needs further evaluation. Critically ill children with nutritional deficiencies and/or HIV infection/exposure need further study to determine bCPAP efficacy

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 (AUC(0-24)) and peak plasma concentration (C (max)) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC(0-24) 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 AUC(0-24) 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 AUC(0-24) for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC(0-24) for isoniazid and pyrazinamide. N-acetyltransferase 2 rapid acetylators had lower isoniazid AUC(0-24) and slow acetylators had higher isoniazid AUC(0-24) than intermediate acetylators. Determinants of C (max) were generally similar to those for AUC(0-24). 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