Cost-Effectiveness of Test-and-Treat Strategies to Reduce the Antibiotic Prescription Rate for Acute Febrile Illness in Primary Healthcare Clinics in Africa.

BACKGROUND: Inappropriate antibiotic use increases selective pressure, contributing to antimicrobial resistance. Point-of-care rapid diagnostic tests (RDTs) would be instrumental to better target antibiotic prescriptions, but widespread implementation of diagnostics for improved management of febrile illnesses is limited. OBJECTIVE: Our study aims to contribute to evidence-based guidance to inform policymakers on investment decisions regarding interventions that foster more appropriate antibiotic prescriptions, as well as to address the evidence gap on the potential clinical and economic impact of RDTs on antibiotic prescription. METHODS: A country-based cost-effectiveness model was developed for Burkina Faso, Ghana and Uganda. The decision tree model simulated seven test strategies for patients with febrile illness to assess the effect of different RDT combinations on antibiotic prescription rate (APR), costs and clinical outcomes. The incremental cost-effectiveness ratio (ICER) was expressed as the incremental cost per percentage point (ppt) reduction in APR. RESULTS: For Burkina Faso and Uganda, testing all patients with a malaria RDT was dominant compared to standard-of-care (SoC) (which included malaria testing). Expanding the test panel with a C-reactive protein (CRP) test resulted in an ICER of $ 0.03 and $ 0.08 per ppt reduction in APR for Burkina Faso and Uganda, respectively. For Ghana, the pairwise comparison with SoC-including malaria and complete blood count testing-indicates that both testing with malaria RDT only and malaria RDT + CRP are dominant. CONCLUSION: The use of RDTs for patients with febrile illness could effectively reduce APR at minimal additional costs, provided diagnostic algorithms are adhered to. Complementing SoC with CRP testing may increase clinicians' confidence in prescribing decisions and is a favourable strategy.

Involving patients in drug development for Neglected Tropical Diseases (NTDs): A qualitative study exploring and incorporating preferences of patients with cutaneous leishmaniasis into Target Product Profile development.

BACKGROUND: Target Product Profiles (TPPs) are instrumental to help optimise the design and development of therapeutics, vaccines, and diagnostics - these products, in order to achieve the intended impact, should be aligned with users' preferences and needs. However, patients are rarely involved as key stakeholders in building a TPP. METHODOLOGY: Thirty-three cutaneous leishmaniasis (CL) patients from Brazil, Colombia, and Austria, infected with New-World Leishmania species, were recruited using a maximum variation approach along geographic, sociodemographic and clinical criteria. Semi-structured interviews were conducted in the respective patient's mother tongue. Transcripts, translated into English, were analysed using a framework approach. We matched disease experiences, preferences, and expectations of CL patients to a TPP developed by DNDi (Drug for Neglected Diseases initiative) for CL treatment. PRINCIPAL FINDINGS: Patients' preferences regarding treatments ranged from specific efficacy and safety endpoints to direct and significant indirect costs. Respondents expressed views about trade-offs between efficacy and experienced discomfort/adverse events caused by treatment. Reasons for non-compliance, such as adverse events or geographical and availability barriers, were discussed. Considerations related to accessibility and affordability were relevant from the patients' perspective. CONCLUSIONS/SIGNIFICANCE: NTDs affect disadvantaged populations, often with little access to health systems. Engaging patients in designing adapted therapies could significantly contribute to the suitability of an intervention to a specific context and to compliance, by tailoring the product to the end-users' needs. This exploratory study identified preferences in a broad international patient spectrum. It provides methodological guidance on how patients can be meaningfully involved as stakeholders in the construction of a TPP of therapeutics for NTDs. CL is used as an exemplar, but the approach can be adapted for other NTDs.

Variability in clinical assessment of clade IIb mpox lesions.

OBJECTIVES: The ongoing global outbreak of mpox, caused by clade IIb mpox virus, poses significant challenges in accurately categorizing and assessing the diversity of lesions. With lesion resolution being a key endpoint in clinical trials and observational studies, it is essential to evaluate the inter-rater reliability and agreement of clade IIb mpox lesion assessment among clinicians. METHODS: Clinicians experienced in clade IIb mpox disease were surveyed online with 20 lesion images. They categorized lesions into active, crusted, resolved, or unclassifiable groups. Reliability was assessed with Fleiss' kappa and agreement with proportion of exact agreement. RESULTS: Fifty-three clinicians completed the survey, with a median self-reported confidence rating of 7 (on a scale of 1 to 10) in assessing mpox lesions. The inter-rater reliability was found to be moderate, with a Fleiss' kappa coefficient of 0.417 (P <0.05, 95% confidence interval: 0.409-0.425). The inter-rater agreement was 61%. CONCLUSION: This study demonstrates moderate inter-rater reliability and agreement in clade IIb mpox lesion assessment among clinicians. The findings emphasize the importance of standardizing lesion classification systems to facilitate clinical care (e.g., decision to start treatment) and public health (e.g. isolation) decisions and a need to explore alternative endpoints for clinical trials.

From private incentives to public health need: rethinking research and development for pandemic preparedness.

Pandemic preparedness and response have relied primarily on market dynamics to drive development and availability of new health products. Building on calls for transformation, we propose a new value proposition that instead prioritises equity from the research and development (R&D) stage and that strengthens capacity to control outbreaks when and where they occur. Key elements include regional R&D hubs free to adapt well established technology platforms, and independent clinical trials networks working with researchers, regulators, and health authorities to better study questions of comparative benefit and real-world efficacy. Realising these changes requires a shift in emphasis: from pandemic response to outbreak control, from one-size-fits-all economies of scale to R&D and manufacture for local need, from de novo product development to last-mile innovation through adaptation of existing technologies, and from proprietary, competitive R&D to open science and financing for the common good that supports collective management and sharing of technology and know-how.

A Qualitative Assessment of a Training and Communication Intervention on Antibiotic Prescription Practices Among Health Workers and Outpatients at Public Health Facilities in Uganda.

BACKGROUND: Antibiotic prescribing practices are 1 of the contributing causes of antimicrobial resistance (AMR). The study explored the key drivers and barriers to adherence to prescribing instructions among healthcare workers and outpatient attendees with the aim of developing a training and communication intervention to improve adherence to prescription. METHODS: Prior to randomized trials at 3 health centers in Uganda (Aduku, Kihihi, and Nagongera), a pre-intervention qualitative assessment was conducted to explore behavioral drivers for adherence to prescriptions and the communication of adherence messages. Based on the findings, a training and communication package was developed for healthcare workers and patients at Day 0 of the trial. During the trial's Day 7 patient follow-up, in-depth interviews were conducted to further investigate adherence behaviors. RESULTS: Five main themes were identified that acted as drivers or barriers to prescription adherence. Key drivers included: drug availability at health facility, health worker knowledge, and communication to patients. Barriers included: care-seeker use of treatment resorts and an inability by care-seeker to buy drugs. CONCLUSIONS: The T&C appeared to influence both health workers' and patients' behavior and improve adherence to prescription.The adapted T&C should be considered a toolkit to improve antibiotic use across health facilities accompanied with appropriate guidelines to mitigate AMR.

The Future of Epidemic and Pandemic Vaccines to Serve Global Public Health Needs.

This Review initiates a wide-ranging discussion over 2023 by selecting and exploring core themes to be investigated more deeply in papers submitted to the Vaccines Special Issue on the "Future of Epidemic and Pandemic Vaccines to Serve Global Public Health Needs". To tackle the SARS-CoV-2 pandemic, an acceleration of vaccine development across different technology platforms resulted in the emergency use authorization of multiple vaccines in less than a year. Despite this record speed, many limitations surfaced including unequal access to products and technologies, regulatory hurdles, restrictions on the flow of intellectual property needed to develop and manufacture vaccines, clinical trials challenges, development of vaccines that did not curtail or prevent transmission, unsustainable strategies for dealing with variants, and the distorted allocation of funding to favour dominant companies in affluent countries. Key to future epidemic and pandemic responses will be sustainable, global-public-health-driven vaccine development and manufacturing based on equitable access to platform technologies, decentralised and localised innovation, and multiple developers and manufacturers, especially in low- and middle-income countries (LMICs). There is talk of flexible, modular pandemic preparedness, of technology access pools based on non-exclusive global licensing agreements in exchange for fair compensation, of WHO-supported vaccine technology transfer hubs and spokes, and of the creation of vaccine prototypes ready for phase I/II trials, etc. However, all these concepts face extraordinary challenges shaped by current commercial incentives, the unwillingness of pharmaceutical companies and governments to share intellectual property and know-how, the precariousness of building capacity based solely on COVID-19 vaccines, the focus on large-scale manufacturing capacity rather than small-scale rapid-response innovation to stop outbreaks when and where they occur, and the inability of many resource-limited countries to afford next-generation vaccines for their national vaccine programmes. Once the current high subsidies are gone and interest has waned, sustaining vaccine innovation and manufacturing capability in interpandemic periods will require equitable access to vaccine innovation and manufacturing capabilities in all regions of the world based on many vaccines, not just "pandemic vaccines". Public and philanthropic investments will need to leverage enforceable commitments to share vaccines and critical technology so that countries everywhere can establish and scale up vaccine development and manufacturing capability. This will only happen if we question all prior assumptions and learn the lessons offered by the current pandemic. We invite submissions to the special issue, which we hope will help guide the world towards a global vaccine research, development, and manufacturing ecosystem that better balances and integrates scientific, clinical trial, regulatory, and commercial interests and puts global public health needs first.

Evaluations of training and education interventions for improved infectious disease management in low-income and middle-income countries: a systematic literature review.

OBJECTIVES: To identify most vital input and outcome parameters required for evaluations of training and education interventions aimed at addressing infectious diseases in low-income and middle-income countries. DESIGN: Systematic review. DATA SOURCES: PubMed/Medline, Web of Science and Scopus were searched for eligible studies between January 2000 and November 2021. STUDY SELECTION: Health economic and health-outcome studies on infectious diseases covering an education or training intervention in low-income and middle-income countries were included. RESULTS: A total of 59 eligible studies covering training or education interventions for infectious diseases were found; infectious diseases were categorised as acute febrile infections (AFI), non-AFI and other non-acute infections. With regard to input parameters, the costs (direct and indirect) were most often reported. As outcome parameters, five categories were most often reported including final health outcomes, intermediate health outcomes, cost outcomes, prescription outcomes and health economic outcomes. Studies showed a wide range of per category variables included and a general lack of uniformity across studies. CONCLUSIONS: Further standardisation is needed on the relevant input and outcome parameters in this field. A more standardised approach would improve generalisability and comparability of results and allow policy-makers to make better informed decisions on the most effective and cost-effective interventions.

C-Reactive Protein for the Early Assessment of Non-Malarial Febrile Patients: A Retrospective Diagnostic Study.

Biomarkers, especially CRP, have demonstrated their relevance to differentiate viral from bacterial infection, even though a reliable threshold is far to being found. In low- and middle-income countries, affordable and user-friendly rapid diagnostic tests based on biomarkers can be widely adopted to help health workers in the management of non-malarial fever. The primary objective of this study is to assess the best CRP cut-off to distinguish viral from bacterial infections. Other biomarkers were evaluated for the same purpose, alone or in combination with CRP. We retrospectively collected data from two referral hospital departments for infectious and tropical diseases in Italy. Areas under the ROC curve (AUC) were calculated and then compared using the DeLong test. Overall, we included 1193 febrile cases (viral 20.74% vs. bacterial 79.25%). We also collected malaria (n = 202) and intestinal parasite (n = 186) cases to establish their impact on biomarkers. CRP had the best accuracy in differentiating viral from bacterial infections. The best performance of CRP was a cut-off of 11 mg/L. All other biomarkers studied had significantly lower accuracy. Median CRP values were within the normal ranges in parasitic infections, while they were higher in malaria. None of the combinations of CRP with other biomarkers significantly increased the accuracy of CRP alone.

Impact of a package of diagnostic tools, clinical algorithm, and training and communication on outpatient acute fever case management in low- and middle-income countries: protocol for a randomized controlled trial.

BACKGROUND: The management of acute febrile illnesses places a heavy burden on clinical services in many low- and middle-income countries (LMICs). Bacterial and viral aetiologies of acute fevers are often clinically indistinguishable and, in the absence of diagnostic tests, the 'just-in-case' use of antibiotics by many health workers has become common practice, which has an impact on drug-resistant infections. Our study aims to answer the following question: in patients with undifferentiated febrile illness presenting to outpatient clinics/peripheral health centres in LMICs, can we demonstrate an improvement in clinical outcomes and reduce unnecessary antibiotic prescription over current practice by using a combination of simple, accurate diagnostic tests, clinical algorithms, and training and communication (intervention package)? METHODS: We designed a randomized, controlled clinical trial to evaluate the impact of our intervention package on clinical outcomes and antibiotic prescription rates in acute febrile illnesses. Available, point-of-care, pathogen-specific and non-pathogen specific (host markers), rapid diagnostic tests (RDTs) included in the intervention package were selected based on pre-defined criteria. Nine clinical study sites in six countries (Burkina Faso, Ghana, India, Myanmar, Nepal and Uganda), which represent heterogeneous outpatient care settings, were selected. We considered the expected seasonal variations in the incidence of acute febrile illnesses across all the sites by ensuring a recruitment period of 12 months. A master protocol was developed and adapted for country-specific ethical submissions. Diagnostic algorithms and choice of RDTs acknowledged current data on aetiologies of acute febrile illnesses in each country. We included a qualitative evaluation of drivers and/or deterrents of uptake of new diagnostics and antibiotic use for acute febrile illnesses. Sample size estimations were based on historical site data of antibiotic prescription practices for malarial and non-malarial acute fevers. Overall, 9 semi-independent studies will enrol a minimum of 21,876 patients and an aggregate data meta-analysis will be conducted on completion. DISCUSSION: This study is expected to generate vital evidence needed to inform policy decisions on the role of rapid diagnostic tests in the clinical management of acute febrile illnesses, with a view to controlling the rise of antimicrobial resistance in LMICs. TRIAL REGISTRATION: Clinicaltrials.gov NCT04081051 . Registered on 6 September 2019. Protocol version 1.4 dated 20 December 2019.

Usefulness of C-Reactive Protein and Other Host BioMarker Point-of-Care Tests in the Assessment of Non-Malarial Acute Febrile Illnesses: A Systematic Review with Meta-Analysis.

In low- and middle-income countries, in resource-limited settings, the implementation of diagnostic tools discriminating bacterial from nonbacterial fever is a matter of primary concern. The introduction of malaria rapid diagnostic tests highlighted the need for point-of-care tests (POCTs) supporting clinical decision-making for non-malarial febrile illnesses. The purpose of this work was to review the use of host biomarker POCTs for the assessment of acute non-malarial fever in resource-constraint settings. Specific objectives were as follows: 1) to estimate the accuracy of such tests in differentiating fever of bacterial from nonbacterial origin and 2) to assess the impact of host biomarkers on antibiotic prescription and clinical outcome. We conducted a systematic review searching PubMed, Embase, the Cochrane Library, and Bireme. The protocol was registered with PROSPERO (n CRD42019141735). Data on the accuracy of C-reactive protein (CRP) for the detection of bacterial infections were meta-analyzed using the hierarchical summary receiver operating characteristic model, obtaining a summary ROC (SROC). We identified 2,192 articles, eight of which were included in the review. Among the different biomarkers evaluated, CRP was the one most frequently studied. The SROC presented an area under the curve = 0.77 (CI: 0.73-0.81), which indicates good accuracy to distinguish bacterial from nonbacterial infections. However, the optimal cutoff of CRP could not be assessed, and we found insufficient evidence about its impact on antibiotic prescription and clinical outcome. The role of CRP and other host biomarker POCTs for the assessment of acute non-malarial febrile illnesses in resource-constraint settings deserves further studies.

What can National TB Control Programmes in low- and middle-income countries do to end tuberculosis by 2030?

The international community has committed to ending the tuberculosis (TB) epidemic by 2030. This will require multi-sectoral action with a focus on accelerating socio-economic development, developing and implementing new tools, and expanding health insurance coverage. Within this broad framework, National TB Programmes (NTPs) are accountable for delivering diagnostic, treatment, and preventive services. There are large gaps in the delivery of these services, and the aim of this article is to review the crucial activities and interventions that NTPs must implement in order to meet global targets and milestones that will end the TB epidemic. The key deliverables are the following: turn End TB targets and milestones into national measurable indicators to make it easier to track progress; optimize the prompt and accurate diagnosis of all types of TB; provide rapid, complete, and effective treatment to all those diagnosed with TB; implement and monitor effective infection control practices; diagnose and treat drug-resistant TB, associated HIV infection, and diabetes mellitus; design and implement active case finding strategies for high-risk groups and link them to the treatment of latent TB infection; engage with the private-for-profit sector; and empower the Central Unit of the NTP particularly in relation to data-driven supportive supervision, operational research, and sustained financing. The glaring gaps in the delivery of TB services must be remedied, and some of these gaps will require new paradigms and ways of working which include patient-centered and higher-quality services. There must also be fast-track ways of incorporating new diagnostic, treatment, and prevention tools into program activities so as to rapidly reduce TB incidence and mortality and meet the goal of ending TB by 2030.

Early warning and response system (EWARS) for dengue outbreaks: Recent advancements towards widespread applications in critical settings.

BACKGROUND: Dengue outbreaks are increasing in frequency over space and time, affecting people's health and burdening resource-constrained health systems. The ability to detect early emerging outbreaks is key to mounting an effective response. The early warning and response system (EWARS) is a toolkit that provides countries with early-warning systems for efficient and cost-effective local responses. EWARS uses outbreak and alarm indicators to derive prediction models that can be used prospectively to predict a forthcoming dengue outbreak at district level. METHODS: We report on the development of the EWARS tool, based on users' recommendations into a convenient, user-friendly and reliable software aided by a user's workbook and its field testing in 30 health districts in Brazil, Malaysia and Mexico. FINDINGS: 34 Health officers from the 30 study districts who had used the original EWARS for 7 to 10 months responded to a questionnaire with mainly open-ended questions. Qualitative content analysis showed that participants were generally satisfied with the tool but preferred open-access vs. commercial software. EWARS users also stated that the geographical unit should be the district, while access to meteorological information should be improved. These recommendations were incorporated into the second-generation EWARS-R, using the free R software, combined with recent surveillance data and resulted in higher sensitivities and positive predictive values of alarm signals compared to the first-generation EWARS. Currently the use of satellite data for meteorological information is being tested and a dashboard is being developed to increase user-friendliness of the tool. The inclusion of other Aedes borne viral diseases is under discussion. CONCLUSION: EWARS is a pragmatic and useful tool for detecting imminent dengue outbreaks to trigger early response activities.

Sustaining visceral leishmaniasis elimination in Bangladesh - Could a policy brief help?

Bangladesh has made significant progress towards elimination of visceral leishmaniasis, and is on track to achieve its target of less than one case per 10,000 inhabitants in each subdistrict in 2017. As the incidence of disease falls, it is likely that the political capital and financial resources dedicated towards the elimination of visceral leishmaniasis may decrease, raising the prospect of disease resurgence. Policy memos may play a crucial role during the transition of the elimination plan from the 'attack' to the 'consolidation' and 'maintenance' phases, highlighting key stakeholders and areas where ongoing investment is crucial. An example of a policy brief is outlined in this paper. The background to the current elimination efforts is highlighted, with emphasis on remaining uncertainties including the impact of disease reservoirs and sustainable surveillance strategies. A stakeholder map is provided outlining the current and projected future activities of key bodies. Identification of key stakeholders subsequently frames the discussion of three key policy recommendations in the Bangladeshi context for the transition to the consolidation and maintenance phases of the elimination program. Recommendations include determining optimal vector control and surveillance strategies, shifting the emphasis towards horizontal integration of disease programs, and prioritising remaining research questions with a focus on operational and technical capacity. Achieving elimination is as much a political as a scientific question. Integrating the discussion of key stakeholders with policy priorities and the research agenda provides a novel insight into potential pathways forwards in the elimination of visceral leishmaniasis in Bangladesh and in the rest of the Indian subcontinent.

An open source pharma roadmap.

In an Essay, Matthew Todd and colleagues discuss an open source approach to drug development.

Global health security: the wider lessons from the west African Ebola virus disease epidemic.

The Ebola virus disease outbreak in West Africa was unprecedented in both its scale and impact. Out of this human calamity has come renewed attention to global health security--its definition, meaning, and the practical implications for programmes and policy. For example, how does a government begin to strengthen its core public health capacities, as demanded by the International Health Regulations? What counts as a global health security concern? In the context of the governance of global health, including WHO reform, it will be important to distil lessons learned from the Ebola outbreak. The Lancet invited a group of respected global health practitioners to reflect on these lessons, to explore the idea of global health security, and to offer suggestions for next steps. Their contributions describe some of the major threats to individual and collective human health, as well as the values and recommendations that should be considered to counteract such threats in the future. Many different perspectives are proposed. Their common goal is a more sustainable and resilient society for human health and wellbeing.

Population pharmacokinetics of orally administered mefloquine in healthy volunteers and patients with uncomplicated Plasmodium falciparum malaria.

BACKGROUND: The determination of dosing regimens for the treatment of malaria is largely empirical and thus a better understanding of the pharmacokinetic/pharmacodynamic properties of antimalarial agents is required to assess the adequacy of current treatment regimens and identify sources of suboptimal dosing that could select for drug-resistant parasites. Mefloquine is a widely used antimalarial, commonly given in combination with artesunate. PATIENTS AND METHODS: Mefloquine pharmacokinetics was assessed in 24 healthy adults and 43 patients with Plasmodium falciparum malaria administered mefloquine in combination with artesunate. Population pharmacokinetic modelling was conducted using NONMEM. RESULTS: A two-compartment model with a single transit compartment and first-order elimination from the central compartment most adequately described mefloquine concentration-time data. The model incorporated population parameter variability for clearance (CL/F), central volume of distribution (VC/F) and absorption rate constant (KA) and identified, in addition to body weight, malaria infection as a covariate for VC/F (but not CL/F). Monte Carlo simulations predict that falciparum malaria infection is associated with a shorter elimination half-life (407 versus 566 h) and T>MIC (766 versus 893 h). CONCLUSIONS: This is the first known population pharmacokinetic study to show falciparum malaria to influence mefloquine disposition. Protein binding, anaemia and other factors may contribute to differences between healthy individuals and patients. As VC/F is related to the earlier portion of the concentration-time profiles, which occurs during acute malaria, and CL/F is more related to the terminal phase during convalescence after treatment, this may explain why malaria was found to be a covariate for VC/F but not CL/F.

Evaluation of initial and steady-state gatifloxacin pharmacokinetics and dose in pulmonary tuberculosis patients by using monte carlo simulations.

A 4-month regimen of gatifloxacin with rifampin, isoniazid, and pyrazinamide is being evaluated for the treatment of tuberculosis in a phase 3 randomized controlled trial (OFLOTUB). A prior single-dose study found that gatifloxacin exposure increased by 14% in the combination. The aims of the study are to evaluate the initial and steady-state pharmacokinetics of gatifloxacin when daily doses are given to patients with newly diagnosed drug-sensitive pulmonary tuberculosis as part of a combination regimen and to evaluate the gatifloxacin dose with respect to the probability of attaining a pharmacokinetic/pharmacodynamic target. We describe the population pharmacokinetics of gatifloxacin from the first dose to a median of 28 days in 169 adults enrolled in the OFLOTUB trial in Benin, Guinea, Senegal, and South Africa. The probability of achieving a ratio of ≥125 for the area under the concentration time curve to infinity (AUC0-∞) for the free fraction of gatifloxacin over the MIC (fAUC/MIC) was investigated using Monte Carlo simulations. The median AUC0-∞ of 41.2 µg · h/ml decreased on average by 14.3% (90% confidence interval [CI], -90.5% to +61.5%) following multiple 400-mg daily doses. At steady state, 90% of patients achieved an fAUC/MIC of ≥125 only when the MIC was <0.125 µg/ml. We conclude that systemic exposure to gatifloxacin declines with repeated daily 400-mg doses when used together with rifampin, isoniazid, and pyrazinamide, thus compensating for any initial increase in gatifloxacin levels due to a drug interaction. (The OFLOTUB study has been registered at ClinicalTrials.gov under registration no. NCT00216385.).