Addressing antimicrobial resistance through community engagement: a framework for developing contextually relevant and impactful behaviour change interventions.

Background: Community engagement (CE) interventions often explore and promote behaviour change around a specific challenge. Suggestions for behaviour change should be co-produced in partnership with the community. To facilitate this, it is essential that the intervention includes key content that unpacks the challenge of interest via multiple sources of knowledge. However, where community lived experience and academic evidence appear misaligned, tensions can appear within the co-production dynamic of CE. This is specifically so within the context of antimicrobial resistance (AMR) where ideal behaviours are often superseded by what is practical or possible in a particular community context. Methods: Here we describe a framework for the equitable development of contextually appropriate, clearly evidenced behavioural objectives for CE interventions. This framework explores different sources of knowledge on AMR, including the potentially competing views of different stakeholders. Findings: The framework allows key content on AMR to be selected based upon academic evidence, contextual appropriateness and fit to the chosen CE approach. A case study of the framework in action exemplifies how the framework is applicable to a range of contexts, CE approaches and One Health topics beyond just AMR. Conclusions: Within CE interventions, academic evidence is crucial to develop well-informed key content. However, this formative work should also involve community members, ensuring that their contextual knowledge is valued. The type of CE approach also needs careful consideration because methodological constraints may limit the breadth and depth of information that can be delivered within an intervention, and thus the scope of key content.

Co-designing community-based interventions to tackle antimicrobial resistance (AMR): what to include and why.

Antimicrobial resistance (AMR) is a social and biological problem. Although resistance to antimicrobials is a natural phenomenon, many human behaviors are increasing the pressure on microbes to develop resistance which is resulting in many commonly used treatments becoming ineffective. These behaviors include unregulated use of antimicrobial medicines, pesticides and agricultural chemicals, the disposal of heavy metals and other pollutants into the environment, and human-induced climatic change. Addressing AMR thus calls for changes in the behaviors which drive resistance. Community engagement for antimicrobial resistance (CE4AMR) is an international and interdisciplinary network focused on tackling behavioural drivers of AMR at community level. Since 2019 this network has worked within Low-Middle Income Countries (LMICs), predominantly within Southeast Asia, to tackle behavioral drivers of AMR can be mitigated through bottom-up solutions championed by local people. This commentary presents seven Key Concepts identified from across the CE4AMR portfolio as integral to tackling AMR. We suggest it be used to guide future interventions aimed at addressing AMR via social, participatory, and behavior-change approaches.

SD-Bioline malaria rapid diagnostic test performance and time to become negative after treatment of malaria infection in Southwest Nigerian Children.

Context and Aim: Given the challenges of microscopy, we compared its performance with SD-Bioline malaria rapid diagnostic test (MRDT) and polymerase chain reaction (PCR) and evaluated the time it took for positive results to become negative after treatment of children with acute uncomplicated malaria. Subjects and Methods: We present the report of 485 participants with complete MRDT, microscopy, and PCR data out of 511 febrile children aged 3-59 months who participated in a cohort study over a 12-month period in rural and urban areas of Ibadan, Nigeria. MRDT-positive children received antimalaria and tested at every visit over 28 days. Speciation was also carried out by PCR. Results: With microscopy as the gold standard, SD-Bioline™ had 95.2% sensitivity, 66.4% specificity, 67.5% positive predictive value (PPV), and 94.9 negative predictive value (NPV), while with PCR the findings were 84.3% sensitivity, 66.5% specificity, 72.7% PPV, and 80.1% NPV. PCR speciation of malaria parasites revealed 91.6% Plasmodium falciparum, 18.9% Plasmodium malariae, and 4.4% Plasmodium ovale. Among the 47 children with P. malariae infections, 66.0% were coinfected with P. falciparum, while 54.6% cases of P. ovale occurred as coinfections with P. falciparum. The median time to a negative MRDT was 23.2 days, while the median time to a negative malaria microscopy was 3.8 days. The two survival curves were significantly different. Conclusions: The SD-BiolineTM MRDT performed well, with remarkable persistence of rapid test-positive for an average of 23 days post treatment. The prevalence of P. malaria is somewhat greater than expected.

Résumé Contexte et objectif: Compte tenu des défis de la microscopie, nous avons comparé le test de diagnostic rapide du paludisme SD-Bioline (MRDT) avec la réaction en chaîne par polymérase (PCR) et évalué le temps qu'il a fallu pour que des résultats positifs deviennent négatifs après le traitement d'enfants atteints de paludisme aigu non compliqué. Sujets et méthodes: Nous présentons le rapport de 485 participants avec des données complètes de MRDT, de microscopie et de PCR sur 511 enfants fébriles âgés de 3 à 59 mois qui ont participé à une étude de cohorte sur une période de 12 mois dans les zones rurales et urbaines d'Ibadan, Nigeria. Les enfants positifs au MRDT ont reçu un antipaludique et ont été testés à chaque visite pendant 28 jours. La spéciation a également été réalisée par PCR. Résultats: Avec la microscopie comme référence, SD-Bioline TM avait une sensibilité de 95,2 %, une spécificité de 66,4 %, une valeur prédictive positive (VPP) de 67,5 % et une valeur prédictive négative (VPN) de 94,9 %, tandis qu'avec la PCR, les résultats étaient de 84,3 % de sensibilité, 66,5 % de spécificité, 72,7 % de VPP et 80,1 % de VPN. La spéciation par PCR des parasites du paludisme a révélé 91,6 % de Plasmodium falciparum, 18,9 % de Plasmodium malariae et 4,4 % de Plasmodium ovale. Parmi les 47 enfants atteints d'infections à P. malariae, 66,0 % étaient co-infectés par P. falciparum, tandis que 54,6 % des cas de P. ovale se sont produits sous forme de co-infections par P. falciparum. Le délai médian jusqu'à un MRDT négatif était de 23,2 jours, tandis que le délai médian jusqu'à une microscopie négative du paludisme était de 3,8 jours. Les deux courbes de survie étaient significativement différentes. Conclusions: Le SD-BiolineTM MRDT a donné de bons résultats, avec une infection à P. malariae un peu plus élevée que attendu dans la population et persistance remarquable des résultats positifs aux tests de diagnostic rapide pendant une moyenne de plus de 23. Mots-clés: Paludisme, microscopie, Nigéria, réaction en chaîne par polymérase, test de diagnostic rapide, spéciationjours après le traitement.

Non-Malaria Causes of Fever among under-5 Children with Negative Results for Malaria Rapid Diagnostic Test in South-Western Nigeria.

BACKGROUND: Although the global malaria burden is decreasing, there are still concerns about overdiagnosis of malaria and the danger of misdiagnosis of non-malaria causes of fever. Clinicians continue to face the challenge of differentiating between these causes despite the introduction of malaria rapid diagnostic tests (mRDTs). AIM: To determine the prevalence and causes of non-malaria-caused fever in children in South-Western Nigeria. METHODS: Secondary analysis of data obtained to evaluate the effect of restricting antimalarial treatment to positive mRDT children in rural and urban areas of southwest Nigeria. Clinical examinations, laboratory tests for malaria parasites (including thick blood film and mRDT) and bacterial identification were performed on children aged 3-59 months (n = 511). The non-malaria group comprised febrile children who had both negative mRDT and microscopy results, while the malaria group included those who were positive for either mRDT or microscopy. We compared the causes of fever among children with non-malaria fever and those with malaria. RESULTS: The prevalence of non-malaria fever and bacteria-malaria co-infection was 37.2% and 2.0%, respectively. Non-malarial pathogens identified were viral (54.7%) and bacterial (32.1%) infections. The bacterial infections included bacteriaemia (2.7%), urinary tract infections (21.6%), skin infections (11.6%) and otitis media (2.6%). The leading bacterial isolates were Staphylococcus aureus, Pseudomonas aeruginosa and Streptococcus pneumoniae. CONCLUSION: The high prevalence and wide range of non-malarial infections reinforces the need for point-of-care tests to identify bacterial and viral infections to optimize the treatment of febrile illnesses in malaria-endemic areas.

Current malaria infection, previous malaria exposure, and clinical profiles and outcomes of COVID-19 in a setting of high malaria transmission: an exploratory cohort study in Uganda.

BACKGROUND: The potential effects of SARS-CoV-2 and Plasmodium falciparum co-infection on host susceptibility and pathogenesis remain unknown. We aimed to establish the prevalence of malaria and describe the clinical characteristics of SARS-CoV-2 and P falciparum co-infection in a high-burden malaria setting. METHODS: This was an exploratory prospective, cohort study of patients with COVID-19 who were admitted to hospital in Uganda. Patients of all ages with a PCR-confirmed diagnosis of SARS-CoV-2 infection who had provided informed consent or assent were consecutively enrolled from treatment centres in eight hospitals across the country and followed up until discharge or death. Clinical assessments and blood sampling were done at admission for all patients. Malaria diagnosis in all patients was done by rapid diagnostic tests, microscopy, and molecular methods. Previous P falciparum exposure was determined with serological responses to a panel of P falciparum antigens assessed using a multiplex bead assay. Additional evaluations included complete blood count, markers of inflammation, and serum biochemistries. The main outcome was overall prevalence of malaria infection and malaria prevalence by age (including age categories of 0-20 years, 21-40 years, 41-60 years, and >60 years). The frequency of symptoms was compared between patients with COVID-19 with P falciparum infection versus those without P falciparum infection. The frequency of comorbidities and COVID-19 clinical severity and outcomes was compared between patients with low previous exposure to P falciparum versus those with high previous exposure to P falciparum. The effect of previous exposure to P falciparum on COVID-19 clinical severity and outcomes was also assessed among patients with and those without comorbidities. FINDINGS: Of 600 people with PCR-confirmed SARS-CoV-2 infection enrolled from April 15, to Oct 30, 2020, 597 (>99%) had complete information and were included in our analyses. The majority (502 [84%] of 597) were male individuals with a median age of 36 years (IQR 28-47). Overall prevalence of P falciparum infection was 12% (95% CI 9·4-14·6; 70 of 597 participants), with highest prevalence in the age groups of 0-20 years (22%, 8·7-44·8; five of 23 patients) and older than 60 years (20%, 10·2-34·1; nine of 46 patients). Confusion (four [6%] of 70 patients vs eight [2%] of 527 patients; p=0·040) and vomiting (four [6%] of 70 patients vs five [1%] of 527 patients; p=0·014] were more frequent among patients with P falciparum infection than those without. Patients with low versus those with high previous P falciparum exposure had a increased frequency of severe or critical COVID-19 clinical presentation (16 [30%] of 53 patients vs three [5%] of 56 patients; p=0·0010) and a higher burden of comorbidities, including diabetes (12 [23%] of 53 patients vs two [4%] of 56 patients; p=0·0010) and heart disease (seven [13%] of 53 patients vs zero [0%] of 56 patients; p=0·0030). Among patients with no comorbidities, those with low previous P falciparum exposure still had a higher proportion of cases of severe or critical COVID-19 than did those with high P falciparum exposure (six [18%] of 33 patients vs one [2%] of 49 patients; p=0·015). Multivariate analysis showed higher odds of unfavourable outcomes in patients who were older than 60 years (adjusted OR 8·7, 95% CI 1·0-75·5; p=0·049). INTERPRETATION: Although patients with COVID-19 with P falciparum co-infection had a higher frequency of confusion and vomiting, co-infection did not seem deleterious. The association between low previous malaria exposure and severe or critical COVID-19 and other adverse outcomes will require further study. These preliminary descriptive observations highlight the importance of understanding the potential clinical and therapeutic implications of overlapping co-infections. FUNDING: Malaria Consortium (USA).

A feasibility study to assess non-clinical community health workers' capacity to use simplified protocols and tools to treat severe acute malnutrition in Niger state Nigeria.

BACKGROUND: Severe acute malnutrition (SAM) is a major determinant of childhood mortality and morbidity. Although integrated community case management (iCCM) of childhood illnesses is a strategy for increasing access to life-saving treatment, malnutrition is not properly addressed in the guidelines. This study aimed to determine whether non-clinical Community Health Workers (called Community-Oriented Resource Persons, CORPs) implementing iCCM could use simplified tools to treat uncomplicated SAM. METHODS: The study used a sequential multi-method design and was conducted between July 2017 and May 2018. Sixty CORPs already providing iCCM services were trained and deployed in their communities with the target of enrolling 290 SAM cases. Competency of CORPs to treat and the treatment outcomes of enrolled children were documented. SAM cases with MUAC of 9 cm to < 11.5 cm without medical complications were treated for up to 12 weeks. Full recovery was at MUAC≥12.5 cm for two consecutive weeks. Supervision and quantitative data capturing were done weekly while qualitative data were collected after the intervention. RESULTS: CORPs scored 93.1% on first assessment and increment of 0.11 (95% CI, 0.05-0.18) points per additional supervision conducted. The cure rate from SAM to full recovery, excluding referrals from the denominator in line with the standard for reporting SAM recovery rates, was 73.5% and the median length of treatment was 7 weeks. SAM cases enrolled at 9 cm to < 10.25 cm MUAC had 31% less likelihood of recovery compared to those enrolled at 10.25 cm to < 11.5 cm. CORPs were not burdened by the integration of SAM into iCCM and felt motivated by children's recovery. Operational challenges like bad terrains for supervision, supply chain management and referrals were reported by supervisors, while Government funding was identified as key for sustainability. CONCLUSION: The study demonstrated that with training and supportive supervision, CORPs in Nigeria can treat SAM among under-fives, and refer complicated cases using simplified protocols as part of an iCCM programme. This approach seemed acceptable to all stakeholders, however, the effect of the extra workload of integrating SAM into iCCM on the quality of care provided by the CORPs should be assessed further.

Prevalence and seroprevalence of Plasmodium infection in Myanmar reveals highly heterogeneous transmission and a large hidden reservoir of infection.

Malaria incidence in Myanmar has significantly reduced over recent years, however, completeness and timeliness of incidence data remain a challenge. The first ever nationwide malaria infection and seroprevalence survey was conducted in Myanmar in 2015 to better understand malaria epidemiology and highlight gaps in Annual Parasite Index (API) data. The survey was a cross-sectional two-stage stratified cluster-randomised household survey conducted from July-October 2015. Blood samples were collected from household members for ultra-sensitive PCR and serology testing for P. falciparum and P. vivax. Data was gathered on demography and a priori risk factors of participants. Data was analysed nationally and within each of four domains defined by API data. Prevalence and seroprevalence of malaria were 0.74% and 16.01% nationwide, respectively. Prevalent infection was primarily asymptomatic P. vivax, while P. falciparum was predominant in serology. There was large heterogeneity between villages and by domain. At the township level, API showed moderate correlation with P. falciparum seroprevalence. Risk factors for infection included socioeconomic status, domain, and household ownership of nets. Three K13 P. falciparum mutants were found in highly prevalent villages. There results highlight high heterogeneity of both P. falciparum and P. vivax transmission between villages, accentuated by a large hidden reservoir of asymptomatic P. vivax infection not captured by incidence data, and representing challenges for malaria elimination. Village-level surveillance and stratification to guide interventions to suit local context and targeting of transmission foci with evidence of drug resistance would aid elimination efforts.

The impact of malaria coinfection on Ebola virus disease outcomes: A systematic review and meta-analysis.

INTRODUCTION: Viral outbreaks present a particular challenge in countries in Africa where there is already a high incidence of other infectious diseases, including malaria which can alter immune responses to secondary infection. Ebola virus disease (EVD) is one such problem; understanding how Plasmodium spp. and Ebolavirus (EBOV) interact is important for future outbreaks. METHODS: We conducted a systematic review in PubMed and Web of Science to find peer-reviewed papers with primary data literature to determine 1) prevalence of EBOV/Plasmodium spp. coinfection, 2) effect of EBOV/Plasmodium spp. coinfection on EVD pathology and the immune response, 3) impact of EBOV/Plasmodium spp. coinfection on the outcome of EVD-related mortality. Random effects meta-analyses were conducted with the R package meta to produce overall proportion and effect estimates as well as measure between-study heterogeneity. RESULTS: From 322 peer-reviewed papers, 17 were included in the qualitative review and nine were included in a meta-analysis. Prevalence of coinfection was between 19% and 72%. One study reported significantly lower coagulatory response biomarkers in coinfected cases but no difference in inflammatory markers. Case fatality rates were similar between EBOV(+)/Pl(+) and EBOV(+)/Pl(-) cases (62.8%, 95% CI 49.3-74.6 and 56.7%, 95% CI 53.2-60.1, respectively), and there was no significant difference in risk of mortality (RR 1.09, 95% CI 0.90-1.31) although heterogeneity between studies was high. One in vivo mouse model laboratory study found no difference in mortality by infection status, but another found prior acute Plasmodium yoeli infection was protective against morbidity and mortality via the IFN-γ signalling pathway. CONCLUSION: The literature was inconclusive; studies varied widely and there was little attempt to adjust for confounding variables. Laboratory studies may present the best option to answer how pathogens interact within the body but improvement in data collection and analysis and in diagnostic methods would aid patient studies in the future.

Navigating the COVID-19 Crisis to Sustain Community-Based Malaria Interventions in Cambodia.

Cambodia has made impressive progress in reducing malaria trends and, in 2018, reported no malaria-related deaths for the first time. However, the coronavirus disease (COVID-19) pandemic presents a potential challenge to the country's goal for malaria elimination by 2025. The path toward malaria elimination depends on sustained interventions to prevent rapid resurgence, which can quickly set back any gains achieved.Malaria Consortium supported mobile malaria workers (MMWs) to engage with target communities to build acceptance, trust, and resilience. At the start of the pandemic, Malaria Consortium conducted a COVID-19 risk assessment and quickly developed and implemented a mitigation plan to ensure MMWs were able to continue providing malaria services without putting themselves or their patients at risk. Changes in malaria intervention coverage and community uptake have been monitored to gauge the indirect effects of COVID-19. Comparisons have been made between output indicators reported in 2020 and from the same month-period of the previous year.In general, malaria service intervention coverage and utilization rates did not decline in 2020. Rather, the reported figures show there was a substantial increase in service utilization. Preliminary internal reviews and community meetings show that despite a heightened public risk perception toward COVID-19, malaria testing motivation has been well sustained throughout the pandemic. This may be attributable to proactive program planning and data monitoring and active engagement with the communities and the national authorities to circumvent the indirect effect of COVID-19 on intervention coverage in Cambodia during the pandemic.

Antibiotic practices among household members and their domestic animals within rural communities in Cumilla district, Bangladesh: a cross-sectional survey.

BACKGROUND: Antibiotic resistance is a global threat to human health, and inappropriate use of antibiotics in humans and animals is widely considered to be a key driver of antibiotic resistant infections. Antibiotic use in humans and animals is growing rapidly in low- and, particularly, middle-income countries. However, there is little detailed understanding about practices related to the use of antibiotics in humans and animals within community settings in such countries. Here we aimed to understand the antibiotic practices of rural households across Cumilla district, Bangladesh, in relation to household members and their domestic animals. METHODS: In 2018 we conducted a cross-sectional survey using representative cluster sampling methods. We collected self-reported information from 682 female and 620 male household heads, with women also asked about their children's antibiotic practices. RESULTS: Only 48% (95% CI: 40, 56%) of women and men had heard of antibiotics, and among those women and men who were aware of antibiotics and the children of those women 70% (95% CI: 64, 76%) reported having previously taken antibiotics, while among these individuals who reported previously taking antibiotics 21% (95% CI: 18, 25%) said they had done so most recently within the last month. Risky/inappropriate antibiotic practices in humans and animals were often reported. For example, among women and men who were aware of antibiotics and the children of those women 52% (95% CI: 40, 63%) reported previously taking antibiotics for a "cough/cold", despite antibiotics being typically inappropriate for use against viral upper respiratory tract infections. Among poultry-owning respondents who were aware of antibiotics 11% (95% CI: 8, 15%) reported previously giving healthy poultry antibiotics, mainly for growth/prophylaxis, while among cattle-owning respondents who were aware of antibiotics and reported previously giving their cattle feed 20% (95% CI: 9, 37%) said the feed had contained antibiotics at least sometimes. CONCLUSIONS: Our results highlight the need for context-adapted interventions at both the community level and the health systems level to reduce inappropriate antibiotic use among humans and domestic animals in rural Bangladesh. Successfully reducing inappropriate use of antibiotics among humans and animals is a required and critical step in tackling antimicrobial resistance.

Eliminating Plasmodium falciparum malaria: results from tailoring active case detection approaches to remote populations in forested border areas in north-eastern Cambodia.

BACKGROUND: Remaining Plasmodium falciparum cases in Cambodia are concentrated in forested border areas and in remote populations who are hard to reach through passive case detection. A key approach to reach these populations is active case detection by mobile malaria workers (MMWs). However, this is operationally challenging because of changing movement patterns of the target population moving into less accessible areas. From January 2018 to December 2020, a tailored package of active case detection approaches was implemented in forested border areas of three provinces in north-eastern Cambodia to reach remote populations and support the elimination of falciparum malaria. METHODS: Key elements of this project were to tailor approaches to local populations, use responsive monitoring systems, maintain operational flexibility, build strong relationships with local communities, and implement close supervision practices. MMWs were recruited from local communities. Proactive case detection approaches included mobile malaria posts positioned at frequented locations around and within forests, and locally informed outreach activities targeting more remote locations. Reactive case detection was conducted among co-travellers of confirmed cases. Testing for malaria was conducted independent of fever symptoms. Routine monitoring of programmatic data informed tactical adaptations, while supervision exercises ensured service quality. RESULTS: Despite operational challenges, service delivery sites were able to maintain consistently high testing rates throughout the implementation period, with each of 45 sites testing a monthly average of 64 (SD 6) people in 2020. In 2020, project MMWs detected only 32 P. falciparum cases. Over the project period, the P. falciparum/P. vivax ratio steadily inversed. Including data from neighbouring health centres and village malaria workers, 45% (80,988/180,732) of all people tested and 39% (1280/3243) of P. falciparum cases detected in the area can be attributed to project MMWs. Remaining challenges of the last elimination phase include maintaining intensified elimination efforts, addressing the issue of detecting low parasitaemia cases and shifting focus to P. vivax malaria. CONCLUSIONS: Reaching remote populations through active case detection should remain a key strategy to eliminate P. falciparum malaria. This case study presented a successful approach combining tailored proactive and reactive strategies that could be transferred to similar settings in other areas of the Greater Mekong Subregion.

Health systems readiness and quality of inpatient malaria case-management in Kano State, Nigeria.

BACKGROUND: Nigeria was among the first African countries to adopt and implement change of treatment policy for severe malaria from quinine to artesunate. Seven years after the policy change health systems readiness and quality of inpatient malaria case-management practices were evaluated in Kano State of Nigeria. METHODS: A cross-sectional survey was undertaken in May 2019 at all public hospitals. Data collection comprised hospital assessments, interviews with inpatient health workers and data extraction from medical files for all suspected malaria patients admitted to the paediatric and medical wards in April 2019. Descriptive analyses included 22 hospitals, 154 health workers and 1,807 suspected malaria admissions analysed from malaria test and treat case-management perspective. RESULTS: 73% of hospitals provided malaria microscopy, 27% had rapid diagnostic tests and 23% were unable to perform any parasitological malaria diagnosis. Artemisinin-based combination therapy (ACT) was available at 96% of hospitals, artemether vials at 68% while injectable quinine and artesunate were equally stocked at 59% of hospitals. 32%, 21% and 15% of health workers had been exposed to relevant trainings, guidelines and supervision respectively. 47% of suspected malaria patients were tested while repeat testing was rare (7%). 60% of confirmed severe malaria patients were prescribed artesunate. Only 4% of admitted non-severe test positive cases were treated with ACT, while 76% of test negative patients were prescribed an anti-malarial. Artemether was the most common anti-malarial treatment for non-severe test positive (55%), test negative (43%) and patients not tested for malaria (45%). In all categories of the patients, except for confirmed severe cases, artemether was more commonly prescribed for adults compared to children. 44% of artesunate-treated patients were prescribed ACT follow-on treatment. Overall compliance with test and treat policy for malaria was 13%. CONCLUSIONS: Translation of new treatment policy for severe malaria into inpatient practice is compromised by lack of malaria diagnostics, stock-outs of artesunate and suboptimal health workers' practices. Establishment of the effective supply chain and on-going supportive interventions for health workers accompanied with regular monitoring of the systems readiness and clinical practices are urgently needed.

A process for developing a sustainable and scalable approach to community engagement: community dialogue approach for addressing the drivers of antibiotic resistance in Bangladesh.

BACKGROUND: Community engagement approaches that have impacted on health outcomes are often time intensive, small-scale and require high levels of financial and human resources. They can be difficult to sustain and scale-up in low resource settings. Given the reach of health services into communities in low income countries, the health system provides a valuable and potentially sustainable entry point that would allow for scale-up of community engagement interventions. This study explores the process of developing an embedded approach to community engagement taking the global challenge of antibiotic resistance as an example. METHODS: The intervention was developed using a sequential mixed methods study design. This consisted of: exploring the evidence base through an umbrella review, and identifying key international standards on the appropriate use of antibiotics; undertaking detailed formative research through a) a qualitative study to explore the most appropriate mechanisms through which to embed the intervention within the existing health system and community infrastructure, and to understand patterns of knowledge, attitudes and practice regarding antibiotics and antibiotic resistance; and b) a household survey - which drew on the qualitative findings - to quantify knowledge, and reported attitudes and practice regarding antibiotics and antibiotic resistance within the target population; and c) drawing on appropriate theories regarding change mechanisms and experience of implementing community engagement interventions to co-produce the intervention processes and materials with key stakeholders at policy, health system and community level. RESULTS: A community engagement intervention was co-produced and was explicitly designed to link into existing health system and community structures and be appropriate for the cultural context, and therefore have the potential to be implemented at scale. We anticipate that taking this approach increases local ownership, as well as the likelihood that the intervention will be sustainable and scalable. CONCLUSIONS: This study demonstrates the value of ensuring that a range of stakeholders co-produce the intervention, and ensuring that the intervention is designed to be appropriate for the health system, community and cultural context.

Evaluation of a capacity building intervention on malaria treatment for under-fives in rural health facilities in Niger State, Nigeria.

BACKGROUND: Despite the uptake of parasitological testing into policy and practice, appropriate prescription of anti-malarials and artemisinin-based combination therapy (ACT) in accordance with test results is variable. This study describes a National Malaria Control Programme-led capacity building intervention which was implemented in 10 States of Nigeria. Using the experience of Niger State, this study assessed the effect on malaria diagnosis and prescription practices among febrile under-fives in rural health facilities. METHODS: The multicomponent capacity building intervention consisted of revised case management manuals; cascade training from national to state level carried out at the local government area (LGA) level; and on the job capacity development through supportive supervision. The evaluation was conducted in 28, principally government-owned, health facilities in two rural LGAs of Niger State, one in which the intervention case management of malaria was implemented and the other acted as a comparison area with no implementation of the intervention. Three outcomes were considered in the context of rapid diagnostic testing (RDT) for malaria which were: the prevalence of RDT testing in febrile children; appropriate treatment of RDT-positive children; and appropriate treatment of RDT-negative children. Outcomes were compared post-intervention between intervention and comparison areas using multivariate logistic regression. RESULTS: The intervention did not improve appropriate management of under-fives in intervention facilities above that seen for under-fives in comparison facilities. Appropriate treatment with artemisinin-based combinations of RDT-positive and RDT-negative under-fives was equally high in both areas. However, appropriate treatment of RDT-negative children, when defined as receipt of no ACT or any other anti-malarials, was better in comparison areas. In both areas, a small number of RDT-positives were not given ACT, but prescribed an alternative anti-malarial, including artesunate monotherapy. Among RDT-negatives, no under-fives were prescribed artesunate as monotherapy. CONCLUSION: In a context of significant stock-outs of both ACT medicines and RDTs, under-fives were not more appropriately managed in intervention than comparison areas. The malaria case management intervention implemented through cascade training reached only approximately half of health workers managing febrile under-fives in this setting. Implementation studies on models of cascade training are needed to define what works in what context.

Gender-related factors affecting health seeking for neglected tropical diseases: findings from a qualitative study in Ethiopia.

BACKGROUND: Despite known gender-specific differences in terms of prevalence, transmission and exposure to neglected tropical diseases (NTDs), there is limited discussion of the influence of gender in NTD programmes and interventions. There is a paucity of research on how gender interacts with NTD service provision and uptake. This study, part of broader implementation research in Ethiopia, applied a gender lens to health seeking for five NTDs: lymphatic filariasis, podoconiosis, schistosomiasis, soil-transmitted helminth infection and trachoma. METHODOLOGY/PRINCIPAL FINDINGS: The study was conducted in a district of the Southern Nations, Nationalities, and Peoples' Region of Ethiopia where the five NTDs are prevalent. A qualitative methodology was adopted to explore participants' perspectives and experiences. Data generation methods included 20 interviews and four focus group discussions. Community members, volunteer Health Development Army leaders, Health Extension Workers and a range of health workers at the health post, health centre and hospital level (n = 59) were purposively sampled. Interviews and focus group discussions were audio recorded, transcribed verbatim into English then analysed through open coding, drawing on constant comparative methods. Gender related factors affected care seeking for NTDs and were described as reasons for not seeking care, delayed care seeking and treating NTDs with natural remedies. Women faced additional challenges in seeking health care due to gender inequalities and power dynamics in their domestic partnerships. Participants recommended raising community awareness about NTDs, however this remains problematic due to gender and social norms around appropriate discourse with members of the opposite gender. CONCLUSIONS/SIGNIFICANCE: The findings from this study provide crucial insights into how gender interacts with accessing health services, at different levels of the health system. If we are committed to leaving no one behind and achieving universal health coverage, it is essential to address gender disparities to access and utilisation of interventions delivered by national NTD programmes.

Consequences of restricting antimalarial drugs to rapid diagnostic test-positive febrile children in south-west Nigeria.

OBJECTIVES: To investigate the consequence of restricting antimalarial treatment to febrile children that test positive to a malaria rapid diagnostic test (MRDT) only in an area of intense malaria transmission. METHODS: Febrile children aged 3-59 months were screened with an MRDT at health facilities in south-west Nigeria. MRDT-positive children received artesunate-amodiaquine (ASAQ), while MRDT-negative children were treated based on the clinical diagnosis of non-malaria febrile illness. The primary endpoint was the risk of developing microscopy-positive malaria within 28 days post-treatment. RESULTS: 309 (60.5%) of 511 children were MRDT-positive while 202 (39.5%) were MRDT-negative at enrolment. 18.5% (50/275) of MRDT-positive children and 7.6% (14/184) of MRDT-negative children developed microscopy-positive malaria by day 28 post-treatment (ρ = 0.001). The risk of developing clinical malaria by day 28 post-treatment was higher among the MRDT-positive group than the MRDT-negative group (adjusted OR 2.74; 95% CI, 1.4, 5.4). A higher proportion of children who were MRDT-positive at enrolment were anaemic on day 28 compared with the MRDT-negative group (12.6% vs. 3.1%; ρ = 0.001). Children in the MRDT-negative group made more unscheduled visits because of febrile illness than those in MRDT-positive group (23.2% vs. 12.0%; ρ = 0.001). CONCLUSION: Restricting ACT treatment to MRDT-positive febrile children only did not result in significant adverse outcomes. However, the risk of re-infection within 28 days was significantly higher among MRDT-positive children despite ASAQ treatment. A longer-acting ACT may be needed as the first-line drug of choice for treating uncomplicated malaria in high-transmission settings to prevent frequent re-infections.

CONSÉQUENCES DE LA RESTRICTION DES ANTIPALUDIQUES AUX ENFANTS FÉBRILES POSITIFS AU TEST DE DIAGNOSTIC RAPIDE DANS LE SUD-OUEST DU NIGÉRIA: OBJECTIFS: Investiguer la conséquence de restreindre le traitement antipaludéen uniquement à des enfants fébriles avec un résultat positif à un test de diagnostic rapide (TDR) du paludisme dans une zone de forte transmission du paludisme. MÉTHODES: Les enfants fébriles âgés de 3 à 59 mois ont été dépistés avec un TDR du paludisme dans des établissements de santé du sud-ouest du Nigéria. Les enfants avec un TDR positif ont reçu de l'artésunate-amodiaquine (ASAQ), tandis que ceux avec un TDR négatif ont été traités sur la base du diagnostic clinique de maladie fébrile non liée au paludisme. Le critère d'évaluation principal était le risque de développer un paludisme positif au microscope dans les 28 jours suivant le traitement. RÉSULTATS: 309 (60,5%) des 511 enfants étaient positifs au TDR du paludisme tandis que 202 (39,5%) étaient négatifs au moment de leur inscription. 18,5% (50/275) des enfants TDR-positifs et 7,6% (14/184) des enfants TDR-négatifs ont développé un paludisme positif au microscope endéans le jour 28 après le traitement (ρ = 0,001). Le risque de développer un paludisme clinique endéans le 28è jour après le traitement était plus élevé dans le groupe TDR-positif que dans le groupe TDR-négatif (OR ajusté = 2,74; IC95%: 1,4 - 5,4). Une proportion plus élevée d'enfants TDR-positifs au moment de l'inscription étaient anémiques au 28è jour par rapport au groupe TDR-négatif (12,6% contre 3,1%; ρ = 0,001). Les enfants du groupe TDR-négatif ont effectué plus de visites non planifiées en raison d'une maladie fébrile que ceux du groupe TDR-positif (23,2% contre 12,0%; ρ = 0,001). CONCLUSION: Le fait de limiter le traitement de combinaison à l'artémisinine (TCA) aux seuls enfants fébriles présentant un résultat positif au TDR n'a pas eu d'effet indésirable significatif. Cependant, le risque de réinfection dans les 28 jours était significativement plus élevé chez les enfants TDR-positifs malgré le traitement par ASAQ. Un TCA à action prolongée pourrait être nécessaire en tant que médicament de choix en première ligne pour traiter le paludisme sans complications dans les régions à forte transmission afin de prévenir les réinfections fréquentes.

Molecular determinants of sulfadoxine-pyrimethamine resistance in Plasmodium falciparum in Nigeria and the regional emergence of dhps 431V.

There are few published reports of mutations in dihydropteroate synthetase (dhps) and dihydrofolate reductase (dhfr) genes in P. falciparum populations in Nigeria, but one previous study has recorded a novel dhps mutation at codon 431 among infections imported to the United Kingdom from Nigeria. To assess how widespread this mutation is among parasites in different parts of the country and consequently fill the gap in sulfadoxine-pyrimethamine (SP) resistance data in Nigeria, we retrospectively analysed 1000 filter paper blood spots collected in surveys of pregnant women and children with uncomplicated falciparum malaria between 2003 and 2015 from four sites in the south and north. Genomic DNA was extracted from filter paper blood spots and placental impressions. Point mutations at codons 16, 50, 51, 59, 108, 140 and 164 of the dhfr gene and codons 431, 436, 437, 540, 581 and 613 of the dhps gene were evaluated by nested PCR amplification followed by direct sequencing. The distribution of the dhps-431V mutation was widespread throughout Nigeria with the highest prevalence in Enugu (46%). In Ibadan where we had sequential sampling, its prevalence increased from 0% to 6.5% between 2003 and 2008. Although there were various combinations of dhps mutations with 431V, the combination 431V + 436A + 437G+581G+613S was the most common. All these observations support the view that dhps-431V is on the increase. In addition, P. falciparum DHPS crystal structure modelling shows that the change from Isoleucine to Valine (dhps-431V) could alter the effects of both S436A/F and A437G, which closely follow the 2nd ß-strand. Consequently, it is now a research priority to assess the implications of dhps-VAGKGS mutant haplotype on continuing use of SP in seasonal malaria chemoprevention (SMC) and intermittent preventive treatment in pregnancy (IPTp). Our data also provides surveillance data for SP resistance markers in Nigeria between 2003 and 2015.

Health worker and policy-maker perspectives on use of intramuscular artesunate for pre-referral and definitive treatment of severe malaria at health posts in Ethiopia.

BACKGROUND: The World Health Organization (WHO) recommends injectable artesunate given either intravenously or by the intramuscular route for definitive treatment for severe malaria and recommends a single intramuscular dose of intramuscular artesunate or intramuscular artemether or intramuscular quinine, in that order of preference as pre-referral treatment when definitive treatment is not possible. Where intramuscular injections are not available, children under 6 years may be administered a single dose of rectal artesunate. Although the current malaria treatment guidelines in Ethiopia recommend intra-rectal artesunate or alternatively intramuscular artemether or intramuscular quinine as pre-referral treatment for severe malaria at the health posts, there are currently no WHO prequalified suppliers of intra-rectal artesunate and when available, its use is limited to children under 6 years of age leaving a gap for the older age groups. Intramuscular artesunate is not part of the drugs recommended for pre-referral treatment in Ethiopia. This study assessed the perspectives of health workers, and policy-makers on the use of intramuscular artesunate as a pre-referral and definitive treatment for severe malaria at the health post level. METHODS: In-depth interviews were held with 101 individuals including health workers, malaria focal persons, and Regional Health Bureaus from Oromia and southern nations, nationalities, and peoples' region, as well as participants from the Federal Ministry of Health and development partners. An interview guide was used in the data collection and thematic content analysis was employed for analysis. RESULTS: Key findings from this study are: (1) provision of intramuscular artesunate as pre-referral and definitive treatment for severe malaria at health posts could be lifesaving; (2) with adequate training, and provision of facilities including beds, health posts can provide definitive treatment for severe malaria using intramuscular artesunate where referral is delayed or not possible; (3) health workers at health centres and hospitals frequently use the intravenous route because it allows for co-administration of other drugs, but they find the intramuscular route easier to use at the health post level; (4) the reasons commonly cited against the management of severe malaria using intramuscular artesunate at health post level were: lack of capacity to manage complications and fear of irrational drug use; (5) use of intramuscular artesunate at health post level will require evidence on safety and feasibility before policy shift. CONCLUSION: From the perspective of health workers, use of intramuscular artesunate as pre-referral treatment of severe malaria cases at the health post is possible but dependent on training and availability of skilled workers. Use of intramuscular artesunate as definitive treatment at health posts was not supported, however, operational research to establish its feasibility, safety and efficacy was recommended to guide any implementation of such an intervention.

Health worker perspectives on the possible use of intramuscular artesunate for the treatment of severe malaria at lower-level health facilities in settings with poor access to referral facilities in Nigeria: a qualitative study.

BACKGROUND: Innovative strategies are needed to reduce malaria mortality in high burden countries like Nigeria. Given that one of the important reasons for this high malaria mortality is delay in receiving effective treatment, improved access to such treatment is critical. Intramuscular artesunate could be used at lower-level facilities given its proven efficacy, ease of use and excellent safety profile. The objective of this study was therefore to explore health workers' perspectives on the possible use of intramuscular artesunate as definitive treatment for severe malaria at lower-level facilities, especially when access to referral facilities is challenging. The study was to provide insight as a formative step into the conduct of future experimental studies to ascertain the feasibility of the use of intramuscular artesunate for definitive treatment of severe malaria in lower level facilities where access to referral care is limited. METHODS: This qualitative study was done across three southern States in Nigeria (Oyo, Cross River and Enugu). Key informant interviews were conducted over a period of three months between October and December 2014 among 90 purposively selected health workers with different roles in malaria case management from primary care to policy level. A thematic content analysis was used to analyse data. RESULTS: Overall, most of health workers and other key informant groups thought that the use of intramuscular artesunate for definitive treatment of severe malaria at lower-level facilities was possible. They however reported human resource and infrastructure constraints as factors affecting the feasibility of intramuscular artesunate use as definitive treatment for severe malaria in lower-level facilities.. Specifically identified barriers included limited numbers of skilled health workers available to manage potential complications of severe malaria and poorly equipped facilities for supportive treatment. Intramuscular artesunate was considered easy to administer and the proximity of lower-level facilities to communities was deemed important in considering the possibility of its use at lower-level facilities. Health workers also emphasised the important role of operational research to provide additional evidence to guide the implementation of existing policy recommendations and inform future policy revisions. CONCLUSIONS: From the perspective of health workers, use of intramuscular artesunate for definitive treatment of severe malaria at lower-level health facilities in Nigeria is possible but dependent on availability of skilled workers, well-equipped lower-level facilities to provide supportive treatment There is need for further operational research to establish feasibility and guide the implementation of such an intervention.

The use of formative research to inform the design of a seasonal malaria chemoprevention intervention in northern Nigeria.

BACKGROUND: Experience of seasonal malaria chemoprevention (SMC) is growing in the Sahel sub-region of Africa, though there remains insufficient evidence to recommend a standard deployment strategy. In 2012, a project was initiated in Katsina state, northern Nigeria, to design an appropriate and effective community-based delivery approach for SMC, in consultation with local stakeholders. Formative research (FR) was conducted locally to explore the potential feasibility and acceptability of SMC and to highlight information gaps and practical considerations to inform the intervention design. METHODS: The FR adopted qualitative methods; 36 in-depth interviews and 18 focus group discussions were conducted across 13 target groups active across the health system and within the community. Analysis followed the 'framework' approach. The process for incorporating the FR results into the project design was iterative which was initiated by a week-long 'intervention design' workshop with relevant stakeholders. RESULTS: The FR highlighted both supportive and hindering factors to be considered in the intervention design. Malaria control was identified as a community priority, the community health workers were a trusted resource and the local leadership exerted strong influence over household decisions. However, there were perceived challenges with quality of care at both community and health facility levels, referral linkage and supportive supervision were weak, literacy levels lower than anticipated and there was the potential for suspicion of 'outside' interventions. There was broad consensus across target groups that community-based SMC drug delivery would better enable a high coverage of beneficiaries and potentially garner wider community support. A mixed approach was recommended, including both community fixed-point and household-to-household SMC delivery. The FR findings were used to inform the overall distribution strategy, mechanisms for integration into the health system, capacity building and training approaches, supportive interventions to strengthen the health system, and the social mobilization strategy. CONCLUSIONS: Formative research played a valuable role in exploring local socio-cultural contexts and health system realities. Both opportunities and challenges for the introduction of SMC delivery were highlighted, which were appropriately considered in the design of the project.