Point-of-care diagnostics for infection and antimicrobial resistance in sub-Saharan Africa: A narrative review.

OBJECTIVES: Sub-Saharan African (SSA) countries are severely impacted by antimicrobial resistance (AMR). Due to gaps in access to diagnostics in SSA, the true extent of AMR remains unknown. This diagnostic gap affects patient management and leads to significant antimicrobial overuse. This review explores how point-of-care (POC) testing for pathogen identification and AMR may be used to close the diagnostic gap in SSA countries. METHODS: A narrative review exploring current clinical practice and novel developments in the field of POC testing for infectious diseases and AMR. RESULTS: POC assays for identification of various pathogens have been successfully rolled out in SSA countries. While implementation studies have mostly highlighted impressive test performance of POC assays, there is limited data on the impact of implementation on clinical outcomes and cost-effectiveness. We did not encounter local studies of host-directed POC assays relevant to AMR. Novel POC assays using real-time polymerase chain reaction, isothermal amplification, microfluidics, and other technologies are in various stages of development. CONCLUSIONS: Available literature shows that POC testing for AMR applications is implementable in SSA and holds the potential to reduce the diagnostic gap. Implementation will require effective regulatory pathways, incorporation of POC testing in clinical and laboratory guidelines, and adequate value capture in existing health financing models.

Multisystemic resilience to shocks: a temporal analysis of health, fundamental rights and freedoms, and economic resilience during the first wave of the COVID-19 pandemic in 22 European countries.

OBJECTIVES: Research on resilience to the COVID-19 pandemic has primarily focused on health system resilience. The purpose of this paper is to: (1) develop a broader understanding of societal resilience to shocks by evaluating resilience in three systems: health, economic and fundamental rights and freedoms and (2) to further operationalise resilience in terms of robustness, resistance and recovery. SETTINGS: 22 European countries were selected based on the availability of data in the health, fundamental rights and freedoms, and economic systems during the first wave of the COVID-19 pandemic in early 2020. DESIGN: This study uses time series data to assess resilience in health, fundamental rights and freedoms, and economic systems. An overall resilience was estimated, as well as three of its components: robustness, resistance and recovery. RESULTS: Six countries exhibited an outlier excess mortality peak compared with the prepandemic period (2015-2019). All countries experienced economic repercussions and implemented diverse measures affecting individual rights and freedoms. Three main groups of countries were identified: (1) high health and high or moderate economic and/or fundamental rights and freedoms resilience, (2) moderate health and fundamental rights and freedoms resilience and (3) low resilience in all three systems. CONCLUSIONS: The classification of countries into three groups provides valuable insights into the multifaceted nature of multisystemic resilience during the first wave of the COVID-19 pandemic. Our study highlights the importance of considering both health and economic factors when assessing resilience to shocks, as well as the necessity of safeguarding individual rights and freedoms during times of crisis. Such insights can inform policy decisions and aid in the development of targeted strategies to enhance resilience in the face of future challenges.

Building a multisystemic understanding of societal resilience to the COVID-19 pandemic.

The current global systemic crisis reveals how globalised societies are unprepared to face a pandemic. Beyond the dramatic loss of human life, the COVID-19 pandemic has triggered widespread disturbances in health, social, economic, environmental and governance systems in many countries across the world. Resilience describes the capacities of natural and human systems to prevent, react to and recover from shocks. Societal resilience to the current COVID-19 pandemic relates to the ability of societies in maintaining their core functions while minimising the impact of the pandemic and other societal effects. Drawing on the emerging evidence about resilience in health, social, economic, environmental and governance systems, this paper delineates a multisystemic understanding of societal resilience to COVID-19. Such an understanding provides the foundation for an integrated approach to build societal resilience to current and future pandemics.

Surveillance of Resistance to New Antibiotics in an Era of Limited Treatment Options.

As with any health threat, our ability to respond to the emergence and spread of antimicrobial resistance depends on our ability to understand the scale of the problem, magnitude, geographical spread, and trends over time. This is especially true for resistance emergence to newer antibiotics coming to the market as last-resort treatments. Yet current antibiotic surveillance systems are limited to monitoring resistance to commonly prescribed drugs that have been on the market for a long time. This qualitative study determined the essential elements and requirements of antimicrobial resistance surveillance for new antibiotics based on literature review, interviews and expert consensus. After an extensive mapping exercise, 10 experts participated in a modified Delphi consultation to identify consensus on all elements required for surveillance of resistance to novel antibiotics. The main findings indicate that there is a need for a two-phase system; an early alert system transitioning to routine surveillance, led by the public sector to gather and share essential data on resistance to newer antibiotics in a transparent manner. The system should be decentralized, run largely from national level, but be coordinated by an arm of an existing international public health institution. Priority should be given to monitoring emergence of resistance among already multi-drug resistant pathogens causing infections, over a broader selection of pathogens to maximize clinical impact. In conclusion, we cannot rely on current AMR surveillance systems to monitor resistance emergence to new antibiotics. A new, public system should be set-up, starting with a focus on detecting resistance emergence, but expanding to a more comprehensive surveillance as soon as there is regional spread of resistance to the new antibiotic. This article provides a framework based on expert agreement, which could guide future initiatives.

Market concentration of new antibiotic sales.

We calculate the average sales of new antibiotics during their first 8 years on the market. The discounted net present value is only $240 m in total per antibiotic, well below costs of supplying these products. The reliance on the US for sales is striking: the US market accounts for 84% of sales during the first 8 years. These facts clarify the need for additional revenues, especially from other countries, to support incentives for the development of new antibiotics. Market entry rewards may be of particular value.

A one health framework to estimate the cost of antimicrobial resistance.

OBJECTIVES/PURPOSE: The costs attributable to antimicrobial resistance (AMR) remain theoretical and largely unspecified. Current figures fail to capture the full health and economic burden caused by AMR across human, animal, and environmental health; historically many studies have considered only direct costs associated with human infection from a hospital perspective, primarily from high-income countries. The Global Antimicrobial Resistance Platform for ONE-Burden Estimates (GAP-ON€) network has developed a framework to help guide AMR costing exercises in any part of the world as a first step towards more comprehensive analyses for comparing AMR interventions at the local level as well as more harmonized analyses for quantifying the full economic burden attributable to AMR at the global level. METHODS: GAP-ON€ (funded under the JPIAMR 8th call (Virtual Research Institute) is composed of 19 international networks and institutions active in the field of AMR. For this project, the Network operated by means of Delphi rounds, teleconferences and face-to-face meetings. The resulting costing framework takes a bottom-up approach to incorporate all relevant costs imposed by an AMR bacterial microbe in a patient, in an animal, or in the environment up through to the societal level. RESULTS: The framework itemizes the epidemiological data as well as the direct and indirect cost components needed to build a realistic cost picture for AMR. While the framework lists a large number of relevant pathogens for which this framework could be used to explore the costs, the framework is sufficiently generic to facilitate the costing of other resistant pathogens, including those of other aetiologies. CONCLUSION: In order to conduct cost-effectiveness analyses to choose amongst different AMR-related interventions at local level, the costing of AMR should be done according to local epidemiological priorities and local health service norms. Yet the use of a common framework across settings allows for the results of such studies to contribute to cumulative estimates that can serve as the basis of broader policy decisions at the international level such as how to steer R&D funding and how to prioritize AMR amongst other issues. Indeed, it is only by building a realistic cost picture that we can make informed decisions on how best to tackle major health threats.

Industry incentives and antibiotic resistance: an introduction to the antibiotic susceptibility bonus.

The scarcity of novel antibiotic compounds in a time of increasing resistance rates has begun to ring alarm bells at the highest echelons of government. Large new financial incentives to accelerate antibiotic research and development, such as market entry rewards (MERs), are being considered. However, there is little focus on how to sustain the efficacy of new, promising antibiotics reaching the market. Currently, inappropriate use of antibiotics is commonplace, which has accelerated resistance development. In an attempt to halt this trend, antibiotic stewardship policies are being implemented in many resource-rich settings. Unfortunately, this has not yet had an impact on the amount of antibiotics being prescribed globally. One important hurdle is misalignment of incentives. While governments and health services are incentivized to promote prudent use of this common good, pharmaceutical companies are incentivized to increase volume of sales to maximize profits. This problem must be addressed or else the major efforts going into developing new antibiotics will be in vain. In this paper we outline an approach to realign the incentives of pharmaceutical companies with wider antibiotic conservation efforts by making a staged bonus a component of an MER for antibiotic developers when resistance to their drug remains low over time. This bonus could address the lack of stewardship focus in any innovation-geared incentive.

Combatting Antibiotic Resistance Together: How Can We Enlist the Help of Industry?

The development of antibiotics needs to be supported through new financial stimuli, including help from the public sector. In exchange for public support, industry should be asked to do what is in their power to help curb the inappropriate use of antibiotics. This work discusses key areas through which industry has an important influence on antibiotic consumption and where agreements can be made alongside financial incentives, even those intended to stimulate very early research. As long as the traditional unit sale-based business model for antibiotics remains in place, profit-making incentives will likely undermine efforts to sell and utilize antibiotics in a sustainable manner. In the short-term, while we try to come to a consensus on how best to fix the market, we need measures to prevent major over-selling and inappropriate promotion-especially for new, badly needed antibiotics that reach the market. This paper explores ways in which the pharmaceutical industry could help buttress sustainable antibiotic use while we search for more long-term, constructive, mutually-beneficial ways to organize the market.

Conflicts of interest in infection prevention and control research: no smoke without fire. A narrative review.

Conflicts of interest (COIs) do occur in healthcare research, yet their impact on research in the field of infection prevention and control (IPC) is unknown. We conducted a narrative review aiming to identify examples of COIs in IPC research. In addition to well-known instances, we conducted PubMed and Google searches to identify and report case studies of COIs in IPC and antimicrobial resistance (AMR), which were chosen arbitrarily following consensus meetings, to illustrate different types of COIs. We also searched the Retraction Watch database and blog to systematically identify retracted IPC and/or infectious disease-related papers. Our review highlights COIs in academic research linked to ties between industry and physicians, journal editors, peer-reviewed journals' choice for publication, and guideline committees participants and authors. It explores how COIs can affect research and could be managed. We also present several selected case studies that involve (1) the chlorhexidine industry and how it has used marketing trials and key opinion leaders to promote off-label use of its products; (2) the copper industry and how reporting of its trials in IPC have furthered their agenda; (3) the influence of a company developing "closed infusion systems" for catheters and how this affects networks in low- and middle-income countries and guideline development; (4) potential perverse incentives hospitals may have in reporting healthcare-associated infection or AMR rates and how government intervention may restrict AMR research for fear of bad publicity and subsequent negative economic consequences. Finally, the analysis of reasons for the retraction of previously published papers highlights the fact that misconduct in research may have other motivations than financial gain, the most visible form of COIs. COIs occur in the field of research in general, and IPC and AMR are no exceptions. Their effects pervade all aspects of the research and publication processes. We believe that, in addition to improvements in management strategies of COIs, increased public funding should be available to decrease researchers' dependency on industry ties. Further research is needed on COIs and their management.

Encouraging Sustainable Use of Antibiotics: A Commentary on the DRIVE-AB Recommended Innovation Incentives.

The ability to sustain antibiotic efficacy is directly affected by incentive models aiming to stimulate antibiotic research and development. This paper analyzes the extent to which the models proposed by the Innovative Medicine Initiative-funded research project DRIVE-AB can be expected to support sustainable use, drawing on basic economic theory and the incentives that derive from it. It then discusses the use of minimal safeguards that will be needed to support sustainable use where industry incentives have not been re-aligned with those of public health.

Mapping global policy discourse on antimicrobial resistance.

The rising importance of antimicrobial resistance (AMR) to the global health agenda is associated with a growing number of parties voicing their concern about the issue. With more recommendations and policies appearing, understanding the policy process requires making sense of the views, values, interests and goals of each participant. Policy frame analysis provides a method to understand both the scientific view and the actions advocated by global health actors to tackle AMR. Here we review and refine policy frame analyses of AMR using a deductive approach. Among several policy frames previously defined in the field of global health, we identify 'AMR as healthcare', 'AMR as development', 'AMR as innovation' and 'AMR as security' as frequent frames used in dealing with AMR. In addition, we found that 'AMR as One Health' constitutes a recent framing of the topic that seeks to provide an integrated understanding between human and animal health. Each frame originates in distinct scientific fields, conceptualises the main causes of AMR and prioritises different interventions and measurements. Better understanding and integration of these frames into an overarching social and ecological framework will support policy progress in tackling AMR.

Delinking Investment in Antibiotic Research and Development from Sales Revenues: The Challenges of Transforming a Promising Idea into Reality.

Kevin Outterson and colleagues outline a model to address access, conservation, and innovation of antibiotics.

Exploring the Obstacles to Implementing Economic Mechanisms to Stimulate Antibiotic Research and Development: A Multi-Actor and System-Level Analysis.

This Article examines the potential stakeholder-related obstacles hindering the implementation of mechanisms to re-ignite the development of novel antibiotics. Proposed economic models and incentives to drive such development include: Public Funding of Research and Development ("R&D"), Tax Incentives, Milestone Prizes, End Payments, Intellectual Property ("IP") and Exclusivity Extensions, Pricing and Reimbursement Incentives, Product Development Partnerships ("PDPs"), and the Options Market for Antibiotics model. Drawing on personal experience and understanding of the antibiotic field, as well as stakeholder consultation and numerous expert meetings within the DRIVE-AB project and Uppsala Health Summit 2015, the Authors identify obstacles attributable to the following actors: Universities and Research Institutes, Small and Medium-sized Enterprises ("SMEs"), Large Pharmaceutical Companies, Marketing Approval Regulators, Payors, Healthcare Providers, National Healthcare Authorities, Patients, and Supranational Institutions. The analysis also proposes a characterization and ranking of the difficulty associated with implementing the reviewed mechanisms. Public Funding of R&D, Pricing and Reimbursement Incentives, and PDPs are mechanisms expected to meet highly systemic barriers (i.e., obstacles across the entire antibiotic value chain), imposing greater implementation challenges in that they require convincing and involving several motivationally diverse actors in order to have much effect.

Cost-effectiveness of long-lasting insecticide-treated hammocks in preventing malaria in South-central Vietnam.

BACKGROUND: Despite much success in reducing the burden of malaria in Vietnam, pockets of malaria persist and eliminating them remains an important development goal. In central Vietnam, insecticide-treated hammocks have recently been introduced to help counter the disease in the highly forested, mountainous areas, where other measures have so far been unsuccessful. This study assesses the cost-effectiveness of using long-lasting insecticide-treated hammocks in this area. METHODS AND FINDINGS: This cost-effectiveness study was run alongside a randomized control trial testing the efficacy of the long-lasting insecticide-treated hammocks. Data were collected through an exit survey, a household survey, expenditure records and key informant interviews. The study estimates that under normal (non-trial) conditions the total net societal cost per malaria episode averted in using long-lasting insecticide-treated hammocks in this area was 126 USD. Cost per hammock, including insecticidal netting, sewing, transport, and distribution was found to be approximately 11.76 USD per hammock. Average savings per episode averted were estimated to be $14.60 USD for the health system and 14.37 USD for households (including both direct and indirect cost savings). The study estimates that the annual financial outlay required of government to implement this type of programme to be 3.40 USD per person covered per year. CONCLUSION: The study finds that the use of a hammock intervention could represent good value for money to help prevent malaria in more remote areas, where traditional control measures such as insecticide-treated bednets and indoor residual spraying are insufficient or inappropriate to control malaria. However, the life span of the hammock-the number of years over which it effectively deters mosquitoes-has a significant impact on the cost-effectiveness of the intervention and study results should be interpreted in light of the evidence on effectiveness gathered in the years to come.

The level of income appears to have no consistent bearing on pharmaceutical prices across countries.

A generally accepted view is that it is more efficient and ethical if global pharmaceutical prices vary according to countries' relative income. To understand manufacturers' pricing strategies, we compared average pharmaceutical prices in fourteen middle-income countries to those in three high-income countries and a low-income region in western Africa from 1999 through 2008. We found that some middle-income countries pay more for pharmaceuticals than high-income countries--for example, prices in several middle-income countries exceeded those in the United Kingdom for some years of the study period. Other middle-income countries paid less than low-income countries--for example, average prices in India were consistently below prices in western Africa. These variations suggest that we need new policies on pharmaceutical pricing to improve access to pharmaceuticals around the world.

Policies and incentives for promoting innovation in antibiotic research

High levels of pathogen resistance are rendering current antibiotics obsolete. Coupled with insufficient investment in discovering new treatments, multidrug-resistant infections are an increasingly urgent public health concern. To curb the growth of antibiotic resistance and prevent major morbidity and mortality from multidrug-resistant bacterial infections, the overuse of antibiotics must be addressed and research and development for antibiotics with novel mechanisms of action actively promoted. This requires appropriately designed incentives for health and regulatory systems, in addition to economic incentives to attract academic interest and industry investment. This book, commissioned by the Swedish Government from the European Observatory on Health Systems and Policies, analyses many proposed policies and incentive mechanisms and sheds light on the key issues that will help policy-makers reach informed, concrete decisions on how to avert this potential public health crisis.

The economic burden of malaria on the household in south-central Vietnam.

BACKGROUND: Each year, several thousand cases of malaria occur in south-central Vietnam. Evidence from elsewhere suggests that malaria can have an economic impact on the household as the illness prevents households from completing their normal, physically demanding, productive duties such as tending crops and animals. The economic impact of malaria on households was explored within the Raglay ethnic minority living in the montainous and forested area of south-central Vietnam (Ninh Thuan Province). METHODS: Two-hundred fifty-one malaria patients were identified and interviewed in an exit survey at Community Health Centres. The same patient sample was then re-interviewed in a household survey two to four weeks later. Survey data were complemented by approximately 40 informal discussions with health workers, vendors, patients, and community leaders. RESULTS: Each episode of malaria was estimated to cost the patient's household an average of 11.79 USD (2005 prices), direct costs for travel and treatment representing 6% of the total while the remainder was loss in annual income. CONCLUSION: Whilst government provision of malaria treatment keeps the direct costs relatively low, the overall loss in income due to illness can still be significant given the poverty amongst this population, especially when multiple cases of malaria occur annually within the same household.