Delivery of long-term-injectable agents for TB by lay carers: pragmatic randomised trial.

BACKGROUND: People with recurrent or drug-resistant TB require long courses of intramuscular injections. We evaluate a novel system in which patient-nominated lay carers were trained to deliver intramuscular injections to patients in their own homes. METHODS: A pragmatic, individually randomised non-inferiority trial was conducted at two hospitals in Malawi. Adults starting TB retreatment were recruited. Patients randomised to the intervention received home-based care from patient-nominated lay people trained to deliver intramuscular streptomycin. Patients receiving standard care were admitted to hospital for 2 months of streptomycin. The primary outcome was successful treatment (alive and on treatment) at the end of the intervention. RESULTS: Of 456 patients screened, 204 participants were randomised. The trial was terminated early due to futility. At the end of the intervention, 97/101 (96.0%) in the hospital arm were still alive and on treatment compared with 96/103 (93.2%) in the home-based arm (risk difference -0.03 (95% CI -0.09 to 0.03); p value 0.538). There were no differences in the proportion completing 8 months of anti-TB treatment; or the proportion experiencing 2-month sputum culture conversion. The mean cost of hospital-based management was US$1546.3 per person, compared to US$729.2 for home-based management. Home-based care reduced risk of catastrophic household costs by 84%. CONCLUSIONS: Although this trial failed to meet target recruitment, the available data demonstrate that training patient-nominated lay people has potential to provide a feasible solution to the operational challenges associated with delivering long-term-injectable drugs to people with recurrent or drug-resistant TB in resource-limited settings, and substantially reduce costs. Further data under operational conditions are required. TRIAL REGISTRATION NUMBER: ISRCTN05815615.

How should assent to research be sought in low income settings? Perspectives from parents and children in Southern Malawi.

BACKGROUND: Paediatric research in low-income countries is essential to tackle high childhood mortality. As with all research, consent is an essential part of ethical practice for paediatric studies. Ethics guidelines recommend that parents or another proxy provide legal consent for children to participate, but that children should be involved in the decision through providing assent. However, there remain uncertainties about how to judge when children are ready to give assent and about appropriate assent processes. Malawi does not yet have detailed guidelines on assent. Understanding perspectives among children and their parents can assist in developing contextually-appropriate assent guidance. METHODS: Qualitative research was conducted with children and parents in three settings in Southern Malawi (low- and high-income urban and rural), to take account of any variations between socioeconomic and cultural contexts. In each setting, interviews were conducted with parents and their children who had participated in paediatric research to understand their experiences of assent and views on appropriate assent practice. Focus groups were also conducted with children and parents, to understand broader social perspectives. RESULTS: We found widespread support for involving children in decisions on research participation. Participants identified a range of factors that affect children's capacity to give assent, including intellectual capacity, emotional development, life experience and cultural norms. Age was often mentioned as a consideration, but deemed an unreliable sole indicator of capacity to assent. In relation to appropriate assent processes, participants emphasised considerations such as supporting effective understanding and minimizing harms. Views on how to achieve these aims varied; for example, there were different ideas about the appropriate order in which to approach children and parents, and about whose decision to respect in the event of disagreement. CONCLUSIONS: Parents and children agreed about the value of involving children in decisions on research, and about the need to promote children's decision-making capacity while respecting parents' interests in children's welfare. Developing practical guidance that meets these principles is challenging, particularly given the need for flexible approaches that suit different study types, children's capacities and family environments. Further discussion within the Malawi research and ethics community will help develop contextually-appropriate guidelines.

A qualitative study exploring hand hygiene practices in a neonatal unit in Blantyre, Malawi: implications for controlling healthcare-associated infections.

Background: Neonatal sepsis causes morbidity and mortality in sub-Saharan Africa. Antimicrobial resistance exacerbates outcomes. Poor Infection Prevention and Control practices (IPC) by healthcare workers and caregivers drive infection transmission. The Chatinkha Neonatal Unit in Malawi has experienced Klebsiella pneumoniae outbreaks of neonatal sepsis. We aimed to identify barriers to optimal IPC, focusing on hand hygiene. Methods: We used a focused ethnography to meet the study aim. Combining participant observation over a seven-month period with semi structured interviews with health care workers and patient carers (23) to provide an in-depth understanding of activities relating to hygiene and IPC existing on the ward. To analyse the data, we drew on the framework approach. Results: We found that staff and caregivers had a good understanding and recognition of the importance of ideal IPC, but faced substantial structural limitations and scarce resources, which hindered the implementation of best practices. We present two key themes: (1) structural and health systems barriers that shaped IPC. These included scarce material resources and overwhelming numbers of patients meant the workload was often unmanageable. (2) individual barriers related to the knowledge of frontline workers and caregivers, which were shaped by training and communication practices on the ward. We highlight the importance of addressing both structural and individual barriers to improve IPC practices and reduce the burden of neonatal sepsis in resource-limited settings. Conclusion: For IPC to be improved, interventions need to address the chronic shortages of material resources and create an enabling environment for HCWs and patient caregivers.

Effect of resistance to third-generation cephalosporins on morbidity and mortality from bloodstream infections in Blantyre, Malawi: a prospective cohort study.

BACKGROUND: The burden of antimicrobial resistance is a major threat to global health; however, prospective clinical outcome data from Africa are scarce. In Malawi, third-generation cephalosporins are the antibiotics of choice in patients admitted to hospital despite a rapid proliferation of resistance to these drugs. We aimed to quantify the effect of resistance to third-generation cephalosporins on mortality and length of hospital stay among patients with bloodstream infections. METHODS: We did a prospective cohort study of patients admitted to Queen Elizabeth Central Hospital in Blantyre, Malawi. Patients of all ages who had positive blood cultures for Enterobacterales were included, with the exception of those from the genus Salmonella, and were followed up for 180 days. We characterised blood culture isolates using whole-genome sequencing and used Cox regression models to estimate the effect of resistance to third-generation cephalosporins on length of hospital stay, in-hospital mortality, and survival. FINDINGS: Between Jan 31, 2018, and Jan 13, 2020, we recruited 326 patients, from whom 220 (68%) of 326 isolates were resistant to third-generation cephalosporins. The case fatality proportion was 45% (99 of 220) in patients with bloodstream infections that were resistant to third-generation cephalosporins, and 34% (36 of 106) in patients with bloodstream infections that were sensitive to third-generation cephalosporins. Resistance to third-generation cephalosporins was associated with an increased probability of in-hospital mortality (hazard ratio [HR] 1·44, 95% CI 1·02-2·04), longer hospital stays (1·5 days, 1·0-2·0) and decreased probability of discharge alive (HR 0·31, 0·22-0·45). Whole-genome sequencing showed a high diversity of sequence types of both Escherichia coli and Klebsiella pneumoniae. Although isolates associated with death were distributed across clades, we identified three E coli clades (ST410, ST617, and ST648) that were isolated from 14 patients who all died. INTERPRETATION: Resistance to third-generation cephalosporins is associated with increased mortality and longer hospital stays in patients with bloodstream infections in Malawi. These data show the urgent need for allocation of resources towards antimicrobial resistance mitigation strategies in Africa. FUNDING: Wellcome Trust and Wellcome Asia and Africa Programme.

Poor outcomes in recurrent tuberculosis: More than just drug resistance?

BACKGROUND: Approximately 11% of people reported to have tuberculosis (TB) have previously received treatment. Clinical outcomes are consistently poor on retreatment regimens, however reasons for this are unclear. This study aimed to explore factors which may contribute to unsuccessful outcomes in retreatment TB. METHODS AND FINDINGS: A prospective cohort of consecutive patients starting WHO Category II retreatment regimen was recruited at a central hospital in Malawi. Participants were evaluated at baseline, after completion of the intensive phase at 2-months, and at the end of the 8-month treatment course. Patients were assessed for respiratory co-morbidity; anaemia; renal impairment; diabetes; Anti-retroviral (ART) failure; and drug toxicity. Amongst 158 patients entering TB care at the point of a recurrent episode, only 92 (58%) had a microbiologically confirmed diagnosis. The prevalence of drug resistance was low (9.6%). Of the 158 patients, 131 (83%) were HIV-positive, of whom 96 (73%) were on ART. Of 63 patients on ART >1 year, 24 (38%) had ART failure. Chronic lung disease was found in 88% on CT thorax, including scarring (80%), bronchiectasis (61%), COPD (22%), and destroyed lung (19%). Spirometry revealed restrictive deficit in 60%, and obstructive deficit in 7% of patients. Anaemia and renal impairment were common (34% and 45% respectively). Ototoxicity developed in 32%, and nephrotoxicity in 15%. 40% of patients reported peripheral neuropathy. Liver injury developed in 4%. CONCLUSIONS: If outcomes are to be improved in retreatment TB, there is an urgent need to address the impact of other co-morbid medical conditions including chronic lung disease, HIV and ART failure.