Stemming the Superbug Tide

Just A Few Dollars More

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OECD Health Policy Studies

7 November 2018

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Chapter 5. Policies to combat antimicrobial resistance

Michele Cecchini

Stella Danek

Jennifer Deberardinis

Abstract

During the last few years, there has been a growing interest in developing and implementing policies to combat the spread of antimicrobial resistance (AMR). This chapter provides an overview of the current status of OECD, Group of Twenty (G20) and European countries’ action plans for tackling AMR and highlights the critical need for extensive international collaboration among all stakeholders. It looks at varied policy options to promote the prudent use of antimicrobials, stop the spread of infections, and prevent infections all together. Actions such as antimicrobial stewardship programmes, improved environmental hygiene, and vaccination use are examined and their effectiveness illustrated in a variety of contexts. The chapter describes some of the implementation decisions and challenges associated with these interventions, and where possible, addresses the degree to which these policies have been adopted globally.

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Key findings

There is widespread international recognition of the need to develop and implement policies to combat the spread of antimicrobial resistance (AMR), and most countries have now established action plans that address antimicrobial resistance in the health sector.
In designing and implementing national action plans to combat AMR, countries have a broad arsenal of policy options from which to choose: key among them are policies related to promoting prudent use of antimicrobials, improving infection prevention and control, and increasing vaccinations.
A growing body of evidence supports many of these interventions, especially those that reduce and/or rationalise the use of antimicrobials.
Although some policies require major investments and involve complex implementation, a number of policies – such as hygiene interventions – can be effectively implemented in resource-constrained settings.
The need for international coordination and the wide variety of stakeholders involved in AMR reduction renders policy making particularly challenging. In order to be effective, many policies will need to be coordinated among countries and address multiple types of stakeholders.
Countries that have successfully addressed AMR tend to use a multi-pronged approach, with interventions targeting a variety of stakeholders and with different goals.

5.1. Introduction

There is widespread international recognition of the need to develop and implement policies to combat the spread of AMR. All OECD member countries have approved the World Health Organization’s (WHO) 2015 global action plan, whose goal is to ensure the continuity of successful treatment and prevention of infectious diseases with effective and safe medicines that are quality-assured, used in a responsible way, and accessible to all who need them (WHO, 2015[1]). The plan hinges on five strategic objectives:

improve awareness and understanding of AMR
strengthen knowledge through surveillance and research
reduce the incidence of infection
optimise the use of antimicrobial agents
develop the economic case for sustainable investment that takes account of the needs of all countries and increase investment in new medicines, diagnostic tools, vaccines and other interventions.

The Sixty-eighth World Health Assembly also urged all member states to develop and put in place, by 2017, national action plans on AMR that are aligned with the objectives of the global plan. The G20 health ministers reiterated this commitment in 2017, highlighting their focus on improving surveillance of AMR, raising awareness, improving infection prevention and control, promoting vaccination, and facilitating the prudent use of antimicrobials (G20, 2017[2]). In addition, the Food and Agriculture Organization of the United Nations (FAO) recently published its action plan on AMR in the food and the agricultural sector, which identified four key pillars: awareness, surveillance and monitoring, governance, and the promotion of good practices (FAO, 2016[3]).

As of 2011, fewer than half of all countries had implemented many of the basic policies needed to ensure appropriate use of antimicrobials, such as regular monitoring of use, regular updating of clinical guidelines, maintaining a medicine information centre for prescribers, and having therapeutics committees in most hospitals or regions (Holloway and van Dijk, 2011[4]). While there has been some progress in developing and implementing global action plans, only half of the 194 WHO Member States reported that they had a national action plan on AMR in place as of 2017 (WHO, FAO and OIE, 2018[5]). Another quarter reported to have such a plan under development. According to the same survey, 84% of OECD, G20, and remaining European Union (EU) countries had developed a national action plan, with the remaining countries undertaking the development of a plan at the time of the survey (Figure 5.1).

In designing and implementing national action plans to combat antimicrobial resistance, countries have a broad arsenal of policy options from which to choose and the opportunity to tailor each of these policies to their unique needs. Fortunately, a growing body of evidence supports many of these interventions, and a number of international success stories can help to guide their design and implementation. This chapter will provide an overview of a broad set of interventions aimed at decreasing AMR, describe some of the implementation decisions and challenges associated with these interventions, and where possible, address the degree to which these policies have been adopted globally.

While the information that follows focuses on policies in the human health sector, it is important to note that these represent just a portion of broader antimicrobial policies that governments are developing. As the agricultural sector accounts for a significant portion of resistance development, agricultural policy is also a critical part of the multi-sectoral one-health approach (Box 5.1).

Figure 5.1. National AMR action plans among OECD, G20, and other EU countries

Box 5.1. One Health approach and agricultural policies

The magnitude of antimicrobials in livestock production underscores the critical role of the agricultural sector in combatting AMR. In the United States, antimicrobial use in food animals has been estimated to account for approximately 80% of antimicrobial consumption in the country and is expected to increase by two-thirds by 2030 (Van Boeckel et al., 2015[7]). This widespread use of antimicrobials in agriculture is a major driver of the emergence and spread of antimicrobial resistant microbes in humans and the environment, and interventions reducing antimicrobial use in animals have been shown to affect resistance development in humans. A meta-analysis of nearly 200 studies evaluating the impact of interventions to reduce antimicrobial use in food-producing animals found not only a difference in resistance among animals but also a 24% lower incidence of resistance in human populations, particularly those with direct animal contact (Tang et al., 2017[8]).

Through the multisectoral One Health approach, WHO, the World Organisation for Animal Health (OIE), and the Food and Agriculture Organization of the United Nations (FAO) are tackling all causes of antimicrobial resistance and addressing its public health implications. Such a holistic view of resistance is critical given that resistant bacteria spread between humans, animals, and the environment, meaning that success in one sector requires success in others. The broad aims of the One Health approach are to (WHO, 2017[9]):

ensure that antimicrobial agents continue to be effective and useful for curing diseases in humans and animals
promote prudent and responsible use of antimicrobial agents
ensure global access to medicines of good quality.

Specific policy measures that have been implemented in the agricultural sector include regulatory measures that limit the use of over-the-counter antimicrobials, wholesale bans of specific antimicrobials and growth promoters, manufacturing requirements and quality control, and surveillance and monitoring of agricultural use (Cogliani, Goossens and Greko, 2011[10]; Goutard, 2017[11]). Because of the use of antimicrobials to prevent and manage disease outbreaks among livestock populations, effective antimicrobial resistance policy within the agricultural sector will also need to involve interventions that improve animal health.

5.2. Effective antimicrobial policy requires global coordination

The ability of microbes and antimicrobial resistance to cross geographical borders presents a unique challenge for policy makers and underscores the importance of international collaboration to curb its spread. Even in the absence of direct collaboration, ensuring impact of many policies requires international harmonisation, such as intellectual property and regulatory policies that universally encourage companies to pursue innovation in vaccines, medicines and diagnostics.

WHO specifically calls for international collaboration to establish networks that can undertake surveillance, develop international inspection teams to monitor drug quality, encourage innovation within the pharmaceutical industry, and support research to contain AMR. Conducting surveillance in particular requires close international collaboration, given that consistent data collection is critical to understand national and international trends (Shah et al., 2017[12]). To that end, European countries have developed the ESAC-Net and the EARS-Net networks while, at the global level, WHO has launched a Global Antimicrobial Resistance Surveillance System (GLASS), which collects and reports resistance rates aggregated at a national level, to standardise surveillance of AMR.

Despite the critical role of international collaboration, national and local strategies need to be tailored to the specific area’s culture, existing practices, and antimicrobial resistance profile in order to be most effective. Evaluations of several policy interventions aimed at curbing antimicrobial use suggest that certain policies are more effective in countries with higher or lower antimicrobial use. Across a sample of OECD countries, the frequency of non-prescription antimicrobial use varied between 3% and 44% (Morgan et al., 2011[13]), with countries in Northern and Western Europe, particularly Scandinavia, presenting lower frequency compared to countries in Southern and Eastern Europe as well as Mexico. The appropriateness of different interventions is also shaped by the legal environment of specific countries, such as whether antimicrobials are available over the counter, and typical health care practices, including in which settings antimicrobials are most often prescribed.

Box 5.2. Complex coordination of many stakeholders creates additional challenges for policy makers

Beyond the need for international collaboration, the required coordination of many different types of stakeholders, even at the local and regional levels, makes antimicrobial policy making particularly challenging. AMR is a clear case in which cooperation between national governments and agencies, professional societies, non-governmental organisations, and international agencies is needed to develop and implement successful strategies. Also key to successful implementation are local level stakeholders, such as hospitals, pharmacies, and other care facilities. For example, effective resistance surveillance requires individual physicians to collect cultures, hospitals to build laboratory capacity, and national health authorities to aggregate and disseminate data (DiazGranados, Cardo and McGowan, 2008[14]).

The WHO’s global strategy specifically lays out policy recommendations for the general public, physicians, pharmacists, hospitals, national governments and health systems, and pharmaceutical companies (WHO, 2001[15]):

Patient interventions include education about both the appropriate use of antimicrobials and infection transmission prevention, with the aim of aligning expectations with appropriate practice and avoiding self-medication
Prescriber and dispenser interventions include education and training on appropriate antimicrobial use and infection control, prescription management such as auditing and guideline development, and regulatory requirements for professional registration. These strategies aim to combat lack of training and access to information as well as other factors that lead to poor antimicrobial and infection control practices, such as peer pressure, patient pressure, and perverse economic incentives
Hospital interventions include establishing infection control programmes, antimicrobial use committees, and monitoring systems as well as bolstering diagnostic laboratory services. Hospitals are also key in implementing infection control measures (e.g., through cleaning practices) and promoting prudent antimicrobial use through audit feedback, formularies, and guidelines
National governments and health system interventions may include creating task forces, allocating appropriate resources, establishing dispensation regulations, marketing authorisation and manufacturing, and safety/quality standards. Governments may also be responsible for developing guidelines for appropriate treatment practices, national drug lists, and immunisation as well as conducting national education programmes and maintaining surveillance systems

Studies have shown that those policy interventions that are most effective at addressing AMR tend to target multiple stakeholders simultaneously. For example, campaigns raising awareness about resistance seem to be more effective when they address both the general public and health care professionals, including physicians and nurses, than when focused on only one group (McNulty et al., 2010[16]). Despite historically focusing on physicians, many interventions are increasingly recognising the importance of other health care professionals (WHO-Europe, 2014[17]). In particular, pharmacists play a critical role as the interface between physicians and patients, with the potential to dramatically influence their behaviour by creating greater patient awareness on the importance of appropriate antimicrobial consumption while simultaneously guiding physician decision making. Achieving the buy-in of a wide variety of health care workers will be critical to implementing policies promoting better hygiene in the health care sector.

5.3. Strategies to reduce antimicrobial resistance address varied goals

Policies aimed at addressing AMR can be broadly categorised based on the goal of the intervention. The three major goals of policies concern avoiding the development of resistant infections (largely through controlling the use of antimicrobials), stopping the spread of resistant infections (typically involving improved hygiene practices), and promoting vaccination.

Other key differences among antimicrobial policies are whether such interventions are prescriptive (restrictive methods/requirements) or persuasive (suggestive). Prescriptive policies require or prevent a behaviour, such as hospital prescription controls that limit antimicrobial prescribing to particular specialists or patients (Pulcini, 2015[18]). Persuasive policies, on the other hand, tend to involve education, advice, and feedback in an attempt to change behaviour but not mandate it. A Cochrane review of over 50 studies assessing the impact of various interventions showed that restrictive methods tend to have a larger impact on reducing antimicrobial resistance than persuasive methods. However, this differential effect appeared to be short-lived; there were no signiﬁcant differences at 12 or 24 months between restrictive and persuasive policies in terms of prescribing outcomes (Davey et al., 2013[19]).

In this chapter, we will characterise policies based on their goal: reducing the development of AMR, preventing its spread, and promoting immunisation, given that a comprehensive approach to antimicrobial policy involves all three types of interventions. The policies described herein were selected based on several key criteria involving their scope, goal, and current deployment. Selected policies that concern the human sector, rather than agricultural or environmental sectors, are consistent with the WHO Global Action Plan objectives of improving awareness and understanding of AMR, reducing incidence of infection, and optimising the use of antimicrobial products. To the extent possible, we focused on interventions whose effectiveness at reducing resistance has been evaluated in multiple studies.

5.4. Policies may target specific stakeholders, care settings, and microbes

Given the widespread potential for pathogen transmission and the development of resistance, policies targeting antimicrobial resistance are often broad in scope, rather than focused on particular sub-groups. However, accounting for the scale of the problem and limited resources, it may be effective to employ more targeted polices. Policies can be tailored to specific health care stakeholders, health care setting, and microbial targets.

Policies targeting specific stakeholders are most common. Policies may target specific patient populations at higher risk for developing microbial resistance, including pregnant women, children, people with chronic illnesses, and the elderly. Emigrants and travellers hospitalised in another country also tend to have high rates of antimicrobial resistance (Van der Bij and Pitout, 2012[20]). The most obvious target involves health care workers, who have the greatest exposure to microbes and may transmit resistant bacteria from patient to patient.

Polices may also target specific settings of care (e.g., community care vs. hospitals), where there is often significant disparity in terms of the severity of antimicrobial resistance and likelihood of pathogen transmission. Many interventions are targeted to the primary care setting, where antimicrobial prescribing tends to be the highest, accounting for about three-quarters of all human prescriptions globally, but where up to half of respiratory infections cannot be effectively treated with antimicrobials (Scott and Del Mar, 2017[21]). In addition, infections presenting in this setting tend to be self-limiting and less severe, which makes the setting particularly amenable to policies limiting antimicrobials or delaying the prescription of antimicrobials. Certain interventions may also work better in certain hospital settings than others, such as the intensive care unit vs. medical wards, based on the patient profiles, prescribing behaviour and nature of interactions that could potentially spread bacteria, among other differences.

Finally, specific microbial targets, such as those that are most susceptible to developing resistance and cause the most severe infections, may serve as policy targets. For example, overuse of several antimicrobials has been associated with increased risk of methicillin-resistant Staphylococcus aureus (MRSA) infections (Kinoshita et al., 2017[22]). Because of its high prevalence in both hospital and community settings, some policies have targeted MRSA specifically; the United Kingdom established an MRSA screening policy in 2010, mandating all patients in all health care facilities to be screened for MRSA when first admitted (Otter et al., 2013[23]). France, Germany, Belgium, and Italy have also implemented surveillance policies and national guidelines specifically targeted at MRSA infections (Kinoshita et al., 2017[22]).

Box 5.3. Policy design: Moving from an understanding of what to why

Traditionally, evaluations of policies have involved determining the impact of those policies on processes, outputs, and outcomes, such as prescribing, administration, patient outcomes, and resistance development. However, researchers have increasingly criticised these evaluations for failing to address why specific interventions are successful, thereby informing future policy development and implementation.

Increasingly, researchers are focusing on determinants of behaviours that influence the development of AMR in order to inform effective policy design. Behavioural science may also be used to explain large differences in the impact of similar policies implemented in different settings, such as the fact that effect of dissemination of educational materials has varied between 3.1% and 50.1% improvement (Hulscher and Prins, 2017[24]). Other prescribing interventions such as audit and feedback, educational outreach, specialist approval, and others have seen similar disparities in effect size.

A recent study demonstrated the time-dependent nature of antimicrobial prescribing, as physicians tend to prescribe more antimicrobials as they fatigue later in the day (Linder et al., 2014[25]). Another study found that physicians’ senior colleagues tend to wield significant influence over their antimicrobial prescribing (Charani et al., 2011[26]). By identifying the types of interventions most likely to influence physician prescribing, these types of insights can help to guide the development of stewardship programmes, such as those involving engagement with senior colleagues who can influence more junior physicians and teams that oversee physician prescribing.

5.5. Specific interventions in toolkit: Prevent or reduce emergence of resistance

5.5.1. Stewardship programmes

Among the most widely deployed types of interventions, stewardship programmes involve the simultaneous implementation of regulations, guidelines, monitoring, and education and campaigns around the prescribing of antimicrobials, optimising the selection, dose, and duration. As such, these programmes help to determine whether a patient should be prescribed an antimicrobial, which antimicrobial should be prescribed, and for how long it should be taken. The Infectious Disease Society of America and Society for Healthcare Epidemiology of America describe the complexity of these types of interventions as “a multidisciplinary approach by a team consisting of infectious disease clinicians, pharmacists, microbiologists, hospital epidemiologists, and infection preventionists” (Goff et al., 2016[27]). Stewardship programmes can be either persuasive or prescriptive and often involve both types of interventions.

Stewardship programmes have been shown to be widely effective as a means to reduce antimicrobial prescribing and resistance, particularly when implemented together with infection control measures such as hand-hygiene interventions (Baur et al., 2017[28]). However, their impact tends to differ among clinical settings and existing prescribing landscapes. A large body of evidence supports the effectiveness of stewardship programmes in both hospital and community care settings. A Cochrane review showed that implementation of a stewardship programme in a hospital setting decreases both antimicrobial prescription rates (median change up to -40%) and AMR prevalence rates (median change between -24% to -68%, depending on the type of infective bacteria) (Davey et al., 2013[19]). Specifically evaluating the inpatient setting, a more recent meta-analysis of stewardship programmes yielded similar results, showing that these programmes reduced the incidence of infections and colonisation with multidrug-resistant Gram-negative bacteria, extended-spectrum β-lactamase-producing Gram-negative bacteria, and methicillin-resistant Staphylococcus aureus (S. aureus), and Clostridium difficile (C. difficile) infections by approx. 30-50% (Baur et al., 2017[28]).

The effects of stewardship programmes tend to be less dramatic in both areas and specific hospital settings that already have lower rates of antimicrobial prescribing. For example, programmes involving audit and feedback report insignificant effects in Scandinavian countries, where use of antimicrobials tends to be low (Ellegård, Dietrichson and Anell, 2017[29]). Another study showed a much higher effect in the critical care setting —deemed the “epicentre of resistance development”—than in medical wards (Brusselaers, Vogelaers and Blot, 2011[30]). However, there is limited evidence on effectiveness in long-term care settings, where inappropriate microbial prescribing can be particularly high (up to 50% of residents colonised with resistant organisms) (Morrill et al., 2016[31]).

While there is limited evidence on the impact of stewardship programmes at different types of hospitals, certain hospitals tend to more readily adopt antimicrobial stewardship programmes than others. In the United States, over half of hospitals with more than 50 beds were compliant with the Centre for Disease Control’s (CDC) Hospital Antibiotic Stewardship Program, while only 26% of hospitals with 25 beds or less were compliant (Nebraska Medicine, 2017[32]). These findings suggest that successful antimicrobial stewardship policies may need to provide additional support, such as financial and educational support to particular types of institutions.

Despite significant evidence on the effectiveness of stewardship programmes in general, there is limited evidence on the specific types of interventions within such programmes that are most effective. Programmes evaluated have included pre-approval strategies for antimicrobials, audit and feedback, guidelines and formulary restrictions, and educational components—often employed simultaneously, making it challenging to assess the effect of particular interventions. However, there is some evidence that antimicrobial stewardship programmes in the hospital setting were more effective when implemented with infection control measures, particularly hand hygiene initiatives (Baur et al., 2017[28]).

While there is not a universal set of initiatives included as part of a stewardship programme, the CDC has outlined several core elements of stewardship programmes (CDC, 2017[33]):

Leadership Commitment: Dedicating necessary human, financial and information technology resources
Accountability: Appointing a single leader responsible for programme outcomes. Experience with successful programmes shows that a physician leader is effective
Drug Expertise: Appointing a single pharmacist leader responsible for working to improve antimicrobial use
Action: Implementing at least one recommended action, such as systemic evaluation of ongoing treatment need after a set period of initial treatment (i.e. “antimicrobial time out” after 48 hours)
Tracking: Monitoring antimicrobial prescribing and resistance patterns
Reporting: Regular reporting information on antimicrobial use and resistance to doctors, nurses and relevant staff
Education: Educating clinicians about resistance and optimal prescribing.

Many countries have been successful in implementing stewardship programmes at both national and sub-national levels (Huttner, Harbarth and Nathwani, 2014[34]). Over 92% of OECD, G20, and other European countries had at least some national policy and/or regulations related to antimicrobial stewardship as of 2017 (Figure 5.2). While many stewardship programmes require significant financial investments, they have also been successful in resource-limited settings. A group of private hospitals in South Africa reported a 20% drop in antimicrobial consumption through implementation of a pharmacist-driven, prospective audit and feedback strategy for antimicrobial stewardship (Brink et al., 2016[35]). A review of 27 studies carried out in low and middle-income countries suggests that stewardship interventions have a positive effect on antimicrobial resistance reduction (Van Dijck, Vliegheb and Coxc, 2018[36]). However, successful implementation of interventions in these countries — as opposed to higher income countries — will need to take into account high levels of heterogeneity among health care centres in terms of resources, organisation, and prescribing practices (e.g., differences between urban and rural areas). It is also critical to identify easily measurable elements that can be used to track outcomes (e.g., infection with particular organisms), which may be different from those in countries with more substantial resources.

Given the highly variable nature of the interventions included in stewardship programmes, it is challenging to evaluate their economics. However, several studies have demonstrated significant cost savings associated with these programmes, both in terms of direct, antimicrobial costs themselves, and indirect costs, such as length of hospital stay and additional care required. Implementation of stewardship programmes was associated with a significant drop in antimicrobial costs by over a third, without including other potential decreases in health care expenditure such as reduced side effects and hospital length of stay (Karanika et al., 2016[37]).

Figure 5.2. Stewardship programmes among OECD, G20, and other EU countries

Box 5.4. National stewardship programme in China

With the ability to purchase antimicrobials over the counter, high reliance on antimicrobials for treatment by both patients and physicians, and financial incentives associated with drug sales, China faces a relatively high prevalence of antimicrobial resistance compared with other countries (Xiao et al., 2013[38]). Over a 10-year period, Chinese health administration authorities established a suite of largely persuasive interventions, including issuing guidance on rational antimicrobial use, creating a national surveillance system, requiring hospitals to establish drug and therapeutics committees, creating continuing education programmes, and emphasising hand hygiene and cleaning measures. However, these policies did not appear to affect the resistance rate, largely due to poor implementation and insufficient enforcement (Xiao et al., 2013[38]).

In 2011, the Chinese Ministry of Health initiated a new strategy: a stewardship programme featuring mandatory management strategies with targets, taskforce organisation, and audit and inspection systems. The strategy required hospitals to have antimicrobial administrative groups, strict formulary restrictions, and prescribing rights given to different physicians. The strategy employed specific targets, including antimicrobials serving as less than specific portions of all drugs prescribed (60% for hospitalised patients and 20% for outpatients) and reducing prophylactic antimicrobial use and duration, among others. These targets would be linked to evaluations of hospitals and “allocation of medical resources”. Hospitals that failed to meet targets would be downgraded to lower classifications by the Chinese Ministry of Health.

While these policies seemed to have early success, longer-term studies have shown a continuation of the increase in antimicrobial resistance. A 2013 study using IMS Research data found the percentage of drug sales for antimicrobials decreased from 25% in 2011 to 17% in 2012, corresponding to a reduction in the volume of antimicrobials sold (Xiao et al., 2013[38]). However, a study of 468 tertiary hospitals found that total antimicrobial consumption increased by 26% between 2011 and 2015, despite some success in isolated areas such as Shanghai, whose antimicrobial consumption decreased by 25% (Wushouer et al., 2017[39]).

These mixed results highlight the importance of multi-faceted policies that target a variety of factors influencing the use of antimicrobials. The stewardship programme did not address significant economic incentives for physicians to prescribe drugs that exist in China (mark-up policies) or patient education to reduce prescribing pressure on physicians (Wang et al., 2016[40]). Prescriptive policies aimed at physicians also need to be complimented by thorough educational programmes as part of formal and informal training (Xiao et al., 2013[38]).

Box 5.5. Regional antimicrobial stewardship programmes in Canada

Two western Canadian provinces, Alberta and British Columbia (BC), implemented regional education-based antimicrobial stewardship programmes (“Do Bugs Need Drugs?”) in 2005 with the aim of promoting both improved hygiene and more prudent use of antimicrobials. Through a variety of programme components including multimedia tools, classroom materials, and social media, the effort focused on the importance of hand washing, the need to limit antimicrobial use, and the inability of antimicrobials to work against viruses (Carson and Patrick, 2015[41]). The programme targeted both clinicians (physicians, nurses, pharmacists) and the public (children, parents, teachers, employers, long-term care facilities).

As an example of key partnerships, the programme forms part of primary school Grade 2 curricula, delivered by medical and nursing students. By aligning the interests to both train future health care workers and educate young children about disease prevention and prudent antimicrobial use, the partnership contributes to the relatively low cost of the overall campaign (Carson and Patrick, 2015[41]).

A 2011 assessment of the programme confirmed significant improvement in health care professionals’ clinical knowledge of appropriate treatment against upper respiratory tract infections (McKay et al., 2011[42]). Overall consumption of antimicrobials in BC, including fluoroquinolones and macrolides, decreased by 7.5% between programme implementation and 2013, with an even larger decrease in children aged under 14 (25%). In addition, the proportion of overall inappropriate use of antimicrobials in the treatment of respiratory tract infections, except acute bronchitis, also declined (BCCDC, 2014[43]).

Importantly, antimicrobial resistance against various clinically important antimicrobials declined or at least remained stable in a majority of pathogens after 2005. For example, resistance of MRSA to erythromycin declined from approximately 95% in 2007 to 82% in 2013 in BC (BCCDC, 2014[43]).

5.5.2. Delayed prescribing

The majority of respiratory infections are viral and self-limiting, meaning that symptoms are likely to resolve without any prescription treatment (Peters et al., 2011[44]). However, antimicrobials are often prescribed for these conditions, which account for much of the 30% of antimicrobials that are estimated to be prescribed inappropriately (Fleming-Dutra et al., 2016[45]). Delayed prescribing involves asking patients to wait up to 3 days or the worsening of their health status before filling a prescription for antimicrobials, with the aim of reducing antimicrobial use in those cases that will resolve themselves. Unlike not prescribing at all, delayed prescribing offers a perceived “safety net” for those few patients who may develop complications and is more amenable for patients than receiving no prescription at all. Delayed prescribing is mostly used in the community care (rather than hospital) setting, where patients’ infections are likely to be less severe.

There is substantial evidence that delayed prescribing reduces antimicrobial prescription rates. A Cochrane review of patients with respiratory infections, including sore throat, middle ear infection, cough (bronchitis), and the common cold found that antimicrobial use was greatest in a group prescribed antimicrobials immediately (93%), followed by delayed antimicrobials (31%), and no antimicrobials (14%) (Spurling et al., 2017[46]). Studies have also consistently demonstrated that delayed prescribing is not associated with any negative impact on patient safety, including symptoms like fever, pain, feeling unwell, cough and runny nose (Little et al., 2017[47]). In addition, primary care practices that prescribe fewer antimicrobials for self‑limiting respiratory tract infections encounter only a slightly higher incidence of a variety of infections. A study in the United Kingdom concluded that if an average-size general practice reduced the proportion of respiratory tract consultations with antibiotics prescribed by 10%, it would face only one additional case of pneumonia a year (Gulliford et al., 2016[48]).

Delayed prescribing can be implemented in a number of ways:

with a post-dated prescription, the patient may obtain an antimicrobial treatment only at a later point in time, by the date indicated within the prescription
re-contact a patient after an initial clinical visit for re-assessment or to instruct the patient to retrieve the prescription at a later appointment
verbally instruct the patient to delay filling the prescription.

Physicians can also choose not to provide a prescription at the time of the initial consultation but wait for the patient to return if case symptoms do not resolve (Ryves et al., 2016[49]). While data comparing the effectiveness of these methods are limited, a clinical trial showed no differences in terms of severity or duration of symptoms, antimicrobial prescribing and patient satisfaction between different means of implementation (Little et al., 2014[50]).

Delayed prescribing may be implemented at the local, national, or international levels. In the United Kingdom, the National Institute for Health and Clinical Excellence (NICE) guidelines recommend delayed prescribing for patients with a number of conditions (NICE, 2008[51]). NICE guidelines also require physicians to provide patients with advice about the nature of their conditions (e.g. timing of symptom resolution). Like other interventions that target physician prescribing behaviour, delayed prescribing interventions may benefit from audit and feedback components, wherein prescribing is monitored and communicated back to physicians. Studies have shown that audit and feedback can help to improve physician adherence to prescribing guidelines (Høgli et al., 2016[52]) and may help to assuage physician concerns that less antimicrobial prescribing is associated with poorer patient outcomes. Physicians may also require guidance on addressing patient concerns and answering questions without prescribing antimicrobials in order to maintain positive relationships with patients (Ryves et al., 2016[49]).

5.5.3. Limiting use of antimicrobials without prescription and counterfeit and substandard antimicrobials

Limiting counterfeit and substandard antimicrobials and antimicrobial consumption without a prescription are another set of interventions aimed at reducing inappropriate antimicrobial use. Counterfeit drugs are a major issue in much of the world, potentially accounting for over 30% of all drugs in Africa, Asia, and the Middle East (though a likely less than 1% in the United States and Western Europe) (El-Jardali et al., 2015[53]). Containing a wrong active ingredient or no active ingredient at all, counterfeit drugs can result in improper concentrations of antimicrobials in the body and the unnecessary escalation to later line antimicrobials, ultimately promoting antimicrobial resistance (Blackstone, Fuhr and Pociask, 2014[54]). Efforts to limit counterfeit and substandard antimicrobials are extremely varied and can include drug regulatory measures and establishment of drug regulatory authorities, onsite inspection and surveillance systems, drug laws, legislation and decrees, product authentication technology, pharmacovigilance systems, public awareness and education, and recursive trust labelling (Fadlallah et al., 2016[55]).

While there are limited data on the scale of use of antimicrobials without a prescription, it has emerged as a challenge not only in countries lacking regulations on over-the-counter sales but also for regulated markets because of access to internet sales. A study in India found that antimicrobial drugs were obtained without a prescription from 174 of 261 (66.7%) pharmacies visited (Shet, Sundaresan and Forsberg, 2015[56]). A 2009 study found 138 unique online vendors selling and shipping antimicrobials without a prescription in the United States (Mainous et al., 2009[57]).

Though the sale of antibiotics without prescriptions is illegal in many markets, online pharmacies are often able to circumvent such regulations by allowing customers to purchase antimicrobial products and other drugs in other countries with poor regulation or enforcement (O'Neill, 2015[58]). The global nature of antimicrobial e-commerce underscores the need for international collaboration to address the availability of antimicrobials without a prescription: for example, the recent Operation Pangea X: a global cooperative effort led by INTERPOL meant to address the sale and distribution of illegal drugs on the internet (FDA, 2017[59]). From ten participating countries at its launch, the operation has now attracted 123 countries to participate in its week of action each year (INTERPOL, 2018[60]), and the 2017 effort saw the seizure of more than USD 51 million worth of medicines (INTERPOL, 2017[61]).

There is very limited evidence on the impact of interventions specifically targeted at counterfeit or substandard antimicrobials, but some data suggest that certain policies are effective at limiting counterfeit drugs more generally. A review of studies evaluating methods to control counterfeit drugs identified regulatory measures such as drug registration and WHO prequalification of drugs to effectively reduce the prevalence of counterfeit drugs (El-Jardali et al., 2015[53]). Despite more limited evidence, additional interventions such as deployment of handheld spectrometry technologies at various inspection points, an international cross-disciplinary model of collaboration, and public awareness campaigns on the danger of counterfeit medicine from illegal drug outlets may also be effective (El-Jardali et al., 2015[53]).

A review of studies examining various types of system-level interventions to combat counterfeit drugs identified a number of features of successfully implemented systems (Fadlallah et al., 2016[55]). Particularly critical are regulatory interventions, which involve the control of drug use by international agreement or national regulatory authorities (e.g., European Medicines Agency or US Food and Drug Administration). These interventions can address the online purchase of drugs, inclusion of public education campaigns, effective pharmacovigilance systems, and onsite surveillance and inspection systems. All policies need to promote communication among stakeholders across the supply chain, including manufacturers, wholesalers, providers, and regulatory bodies.

Policies that limit access to antimicrobials need to take into account the potential consequences of policies on the treatment landscape at large. For example, an unintended effect of over-the-counter antimicrobial sales restrictions in Mexico and Brazil occurred when users substituted antimicrobials with non-steroidal anti-inflammatory drugs and analgesics in both countries as well as cough and cold medicines in Mexico (Santa-Ana-Tellez et al., 2016[62]).

5.5.4. Mass media campaigns

As their name suggests, mass media campaigns are aimed at raising awareness about inappropriate antimicrobial prescribing and consumption. Campaigns are commonly used across OECD countries as a way to promote rational prescribing (Earnshaw et al., 2009[63]). As of 2017, over half of OECD, G20, and other European countries had national-level awareness campaigns in place to influence antimicrobial prescribing (Figure 5.3). Efforts can be targeted at a variety of stakeholders involved in pharmaceutical consumption but typically address patients and physicians. By illustrating the impact of rational or inappropriate antimicrobial use, campaigns aim to improve physician practice and better align patient expectations with good prescribing practice. Many campaigns have focused on antimicrobial prescribing for children, given that they comprise a very high percentage of antimicrobial prescriptions (Huttner, Harbarth and Nathwani, 2014[34]).

While the exact nature of campaigns varies widely, the basic form involves the development and dissemination of campaign materials through channels such as print, television, radio, internet, and social media. While campaigns are often broad in scope (i.e., do not focus on specific illnesses), some campaigns specifically highlight respiratory tract infections and the flu, for which antimicrobials are typically inappropriate.

Few studies have been able to draw conclusions on the effectiveness of mass media campaigns, but the available evidence suggests that campaigns affect patient attitudes toward antimicrobials and result in a modest decrease in antimicrobial prescriptions. A meta-analysis concluded that mass media campaigns have a small but statistically significant effect on the general population’s satisfaction and knowledge toward appropriate antimicrobial use (Thoolen, de Ridder and van Lensvelt-Mulders, 2011[64]). Three studies assessing the effectiveness of mass media campaigns in England (Lambert, Masters and Brent, 2007[65]), Italy (Formoso et al., 2013[66]) and the United States (Gonzales et al., 2008[67]) concluded that implementation of a mass media campaign is responsible for a 4% to 9% decrease in antimicrobial prescriptions.

According to an international survey by WHO, less than half of campaigns involved any evaluation component, making it challenging to evaluate these programmes in practice (WHO, 2016[68]).

Box 5.6. Mass media campaigns in Belgium

The Belgian Antimicrobial Policy Coordination Committee (BAPCOC), a national committee established by the Ministry of Health to promote rational antimicrobial use and improved hygiene in both the health and agricultural sectors, undertook a multi-year public awareness campaign targeting improper antimicrobial use (Goossens et al., 2008[69]). While no specific targets were set, the public awareness campaign maintained general goals to improve the public’s understanding of self-limiting infections, explain when antimicrobials are needed, and communicate the importance of antimicrobial resistance. The Belgian campaign ran over three consecutive winter seasons – when antibiotic consumption increases – and was broadcast through booklets, handouts, posters, prime-time television, radio spots, and websites.

The campaign involved fairly simple messaging and a multi-stakeholder approach. Messages included: “Use antimicrobials less frequently, but better”, “Save antimicrobials, they may save your life”, and “Talk to your doctor, talk to your pharmacist”. During one winter season, the campaign focused on communicating that antimicrobials are ineffective for common viral diseases such as cold and flu. Beyond directly targeting the general public, physicians were sent personalised letters with campaign materials that they were asked to present to patients.

The fact that the broader BAPCOC suite of interventions, including publication of clinical practice guidelines, surveillance programmes, and campaigns to promote better hygiene, were implemented concurrently makes it challenging to isolate the specific impact of the prudent use public awareness campaign. However, studies of antimicrobial prescriptions and antimicrobial resistance suggest that the campaign at least contributed to major improvements. Outpatient antimicrobial use decreased by 36% from 1997 to 2007 in Belgium, including several broad-spectrum antimicrobials known to cause resistance. In an evaluation of actual outcomes, macrolide resistance in Streptococcus pyogenes decreased dramatically from 17% of strains in 2001 to 2% in 2007. The Belgian campaign also demonstrated that mass media campaigns can be executed with relatively modest investments. The Belgian campaign cost approximately EUR 400 000 per year (Zowawi et al., 2015[70]). On the other hand, a French antimicrobial awareness campaign from 2002 to 2007 was estimated to cost EUR 500 million over a six-year period1 (Huttner and Harbarth, 2009[71]).

Figure 5.3. Awareness campaigns among OECD, G20, and other EU countries

5.5.5. Prescriber education

Prescriber education entails a wide range of informative activities to enhance physicians’ knowledge of evidence-based medicine or to improve physicians’ communication skills as they relate to antimicrobial prescribing. Like mass media campaigns, education can be delivered through a number of channels, including formal coursework, workshops, dissemination of educational material, and one-on-one coaching/feedback. They can also target various personnel involved in prescribing and dispensing antimicrobials, including physicians and nurses in community care, hospital, and long-term care settings. The scale on which educational programmes are implemented also varies considerably from country to country, as programmes may be offered locally through universities or employers or nationally through national health authorities. While most OECD, G20, and other European countries report that regular training is offered as part of professional curricula or continuing education, only 14% of countries had an integrated programme that systematically incorporates antimicrobial resistance into pre-medical service training for all relevant healthcare stakeholders as of 2017 (Figure 5.4).

Many studies have evaluated the impact of educational programmes on various outcomes related to prescribing, including adherence to guidelines, antimicrobials prescribed, attitude toward antimicrobial prescribing, and development of resistance. However, evidence on the degree to which prescriber education affects antimicrobial resistance is not as compelling as that associated with some other interventions, particularly in terms of overall antimicrobials prescribed. A recent Cochrane review determined that the quality of evidence associated with studies focused on physician education interventions was very low, preventing any conclusions about the impact of education in primary care (Tonkin-Crine et al., 2017[72]). Another review found that only 41% of studies evaluating the intervention found a decrease in total antimicrobials prescribed (Roque et al., 2014[73]).

Some evidence suggests that prescriber education can be most helpful at promoting more rational prescribing of particular antimicrobials, rather than reducing antimicrobial use overall. A study in Greece that included both prescriber and public education found no decrease in the overall volume of antimicrobials prescribed but that choice of antimicrobials changed to be more aligned with clinical guidelines, including decrease in broad-spectrum antimicrobials (Plachouras et al., 2014[74]). Similarly, a US study of paediatric prescribing found that prescriber education, along with audit and feedback, resulted in a 6.7% decrease in the portion of broad spectrum antimicrobials prescribed (Gerber, Prasad and Fiks, 2013[75]).

Interactive types of educational programmes tend to be the most effective. A review of evidence on these programmes found that interventions such as education outreach, workshops, small group-discussions, and other practice-based interventions were more effective than the dissemination of leaflets or other written materials (Roque et al., 2014[73]).

A well-known physician education programme, Choosing Wisely, combines physician education with guidelines as well as tools to help physicians communicate with patients. Started in 2012 by the American Board of Internal Medicine Foundation, the campaign has now expanded to over 20 countries and includes not only antimicrobials but also a host of treatments and procedures that are believed to be “overused” across specialities (Born and Levinson, 2017[76]). Two of the top ten international recommendations concern avoiding the use of antimicrobials for particular types of infections.

Figure 5.4. Education and training in human health among OECD, G20, and other EU countries

5.5.6. Use of existing and new medical technologies such as rapid diagnostic tests

In determining whether to prescribe antimicrobials and which antimicrobials to prescribe, physicians have a number of diagnostic tools at their disposal. However, traditional diagnostic testing methods used to identify bacteria and evaluate antimicrobial susceptibility often require 48-72 hours, which limits their usefulness in guiding antimicrobial prescribing. New technology is allowing clinicians to rapidly acquire information that can guide treatment decisions, such as whether an infection is viral or bacterial, the specific type of bacterial infection, and whether the infection is susceptible to specific antimicrobials. As such, use of existing and new medical technologies such as rapid diagnostic tests (RDTs) can determine whether antimicrobials will be useful in treating an infection and in some cases, which specific antimicrobial will be most useful. By reducing the time to results to hours or minutes, these medical technologies have the potential to reduce unnecessary antimicrobial use, particularly the use of broad-spectrum antimicrobials, and improve patient outcomes. They can be used directly at all sites of care, including community care, outpatient, and emergency setting.

Among the most widely used RDTs are C-reactive protein (CRP) tests and rapid viral diagnostics. CRP testing, which measures inflammation, is used to rapidly detect the presence of bacteria. Rapid viral diagnostics can be conducted in 15-60 min and can detect the presence of certain viruses, such as influenza A and B and other common respiratory viruses, effectively ruling out the need for antimicrobials.

The use of a variety of medical technologies such as rapid diagnostic tests is growing globally. For example, an assay that can detect a bacterium that causes tuberculosis (TB) and resistance to an important antimicrobial (rifampicin) is now used in 122 of 145 developing countries with high TB burden (Sachdeva et al., 2015[77]), increasing the detection of multi-drug resistant TB by three to eight-fold (Albert et al., 2016[78]). Recent treatment guidelines have also supported the uptake of testing. In the United Kingdom, NICE recommends that physicians should consider carrying out rapid diagnostic tests that detect bacterial infection, CRP tests, for people presenting in primary care with symptoms of lower respiratory tract infection, if it is not clear whether antimicrobials should be prescribed (NICE, 2018[79]). The guidance goes on to recommend no antimicrobials or delayed antimicrobial prescribing for some patients based on the result.

The effectiveness of rapid diagnostic testing at reducing antimicrobial prescribing appears to vary among different technologies, and there have been limited comprehensive studies evaluating the impact of many types of rapid diagnostic tests. Because effectiveness has been widely demonstrated for CRP testing and the test can be widely used to distinguish bacterial from viral infections, the remainder of this section will focus on this particular test as a case study. However, it is important to acknowledge the heterogeneity among RDTs.

As reported in a Cochrane review, multiple trials have shown that CRP tests reduce antimicrobial prescribing, typically by approximately 25% in both primary and emergency care (Tonkin-Crine et al., 2017[72]). This effect appears to be sustained one month up to consultation (Aabenhus et al., 2014[80]; Huang et al., 2013[81]). While it reduces antibiotic prescribing, CRP testing does not affect symptom duration, patient satisfaction, or consultation. Importantly, studies have demonstrated the impact of CRP testing in both developed and developing countries. For example, CRP point-of-care testing reduced antimicrobial use for non-severe acute respiratory tract infection without compromising patients’ recovery in primary health care in Vietnam (Do et al., 2016[82]).

Evidence supporting the impact of other types of RDT is sparser. A review of the impact of a number of RDTs identifying specific pathogens found a few studies suggesting they reduce antimicrobial prescribing, time to appropriate antimicrobial therapy, and hospital length of stay (Bauer et al., 2014[83]). The utilisation of rapid antigen-detection tests for Strep A has been associated with a lower prescribing of antimicrobials for patients with sore throat but showed no clear benefits over clinical scoring (Little et al., 2013[84]). An evaluation of several clinical trials showed no statistically significant evidence that rapid viral diagnostics have an impact on antimicrobial prescribing in emergency departments for paediatric patients (Doan et al., 2012[85]).

As tests vary considerably in their methodology, implementation of RDTs varies significantly depending on the test, including the need for investment in capital equipment and personnel needed to conduct testing (Frickmann, Masanta and Zautner, 2014[86]). CRP testing is generally simple to implement in routine practice given both the ease of conducting and interpreting the blood test. In clinical practice, large-scale implementation of RDTs could involve the need to refine workflow between the laboratory, physician, and other clinical staff (for example, discussion between laboratory technician and physician to ensure results are acted upon).

However, it can be more challenging to implement guidance for how to use the test results: i.e., which patients receive antimicrobials and for which patients delayed prescribing or no prescribing is more appropriate. Beyond building the testing infrastructure, successful implementation often requires an education and training component. Several studies involving the impact of RDTs have included training programmes that helped physicians explain the test results to patients and an additive effect was observed when CRP tests and training sessions in communication skills were combined (Aabenhus et al., 2014[80]).

Despite their promise, a combination of technical, social, regulatory, economic, and infrastructural barriers have hindered the more widespread uptake of RDTs (Miller and Sikes, 2015[87]). Clear regulatory pathways are necessary to ensure that tests used are sufficiently accurate and specific to yield confidence in their results. Integration of testing within standard clinical practice is also challenging. In low-resource countries, the widespread use of diagnostics is limited by low ability to pay for the diagnostics themselves and limited resources for training. Successful adoption across countries will also hinge upon sufficient quality assurance to ensure accurate results that can appropriately guide treatment decisions (Peeling and Boeras, 2016[88]).

Facilitating the development of new RDTs at the national and international level will be critical to drive their impact in reducing antimicrobial resistance. A report by the National Academies of Sciences advises health care systems to create financial incentives for test development. Specifically, the report recommends developing specific target product profiles to ensure companies develop the most appropriate test, create a rapid and inexpensive regulatory pathway to bring tests to market quickly, and establish pre-purchase agreements or sales guarantees with companies to offset a portion of the development cost (Mundaca-shah et al., 2017[89]). Future development of multiplex tests—those able to detect susceptibility among a wide variety of organisms—should decrease the implementation burden of rapid diagnostic testing that must currently be done as separate tests.

RDTs have the potential to save significant health care costs via reduced antimicrobial prescribing, need for follow-up visits, and length of stay (Doan et al., 2012[85]). When conducted by nurses, CRP testing has been shown to be cost effective (Hunter, 2015[90]). In its cost-effectiveness analysis, NICE estimated that a CRP test would cost GBP 12–15 in the United Kingdom, including the cost of reagents, equipment depreciation and staff time (Chaplin, 2015[91]; Hunter, 2015[90]). However, one-time and recurring costs vary significantly depending on the specific test conducted (Frickmann, Masanta and Zautner, 2014[86]).

C-reactive testing for patients with lower respiratory tract infections has been implemented in a number of EU countries, including Sweden, Norway, the Netherlands, Germany, Switzerland, the Czech Republic and Estonia (Huddy et al., 2016[92]). In 2014, the UK’s NICE included CRP thresholds, which specify the CRP levels at which antimicrobials should be prescribed, in antibiotic prescribing guidelines. A qualitative assessment of the success factors of CRP implementation within the EU identified the inclusion of testing in guidelines and treatment algorithms, central laboratory capacity, effective quality control, and management of potential work flow impacts as key success factors (Huddy et al., 2016[92]). However, because of the significant efforts required, the process from initial adoption to large-scale national implementation of new testing technologies can vary from 2-7 years.

Box 5.7. Policies to increase use of RDTs in Slovenia

Measures restricting the use of antimicrobials and strongly incentivising the use of RDTs significantly decreased antimicrobial consumption in Slovenia. Implemented in 2000, these efforts were part of a broader antimicrobial stewardship policy to tackle the substantial increase in antimicrobial consumption and resistance within the country. The policy includes restrictive prescription criteria for amoxicillin and clavulanic acid (co-amoxiclav), fluoroquinolones, third-generation cephalosporins, and macrolides in community care and hospital settings (Cizman et al., 2015[93]). For example, fluoroquinolones can only be prescribed for urinary tract infections as a second-line treatment (i.e. when the first-line treatment does not produce any positive clinical effect) or when microbial susceptibility is demonstrated by diagnostic test results. Similar measures were implemented for antimicrobials at high risk of inappropriate use.

While introduction of this policy did not make use of RDTs compulsory, it strongly incentivised their increased use. The concurrent introduction of educational interventions for professionals also supports higher use of RDTs in clinical practice.

The policy resulted in a significant increase in the use of RDTs and positive effects on antimicrobial use and AMR. Between 1999 (the year before the new policy was introduced) and 2003, the use of two common RDTs (C-reactive protein testing and streptococcal antigen detection test) in primary care settings increased by 220% (Cizman et al., 2005[94]). Following more widespread use of RDTs, overall antimicrobial consumption decreased by 20.3%, and consumption of restricted antimicrobials also decreased by 27.7% between 2000 and 2007. Penicillin resistance among invasive pneumococci also decreased (Cizman, 2008[95]).

5.5.7. Economic incentives

Economic incentives refer to a host of policies that encourage appropriate antimicrobial behaviour via financial bonuses and/or penalties. Such incentives are widely applied in the health sector to foster specific behaviours—such as reduced consumption of various health care resources—and have more recently been applied specifically to antimicrobial prescribing and consumption to promote more rational use (Schaffer, Sussex and Feng, 2015[96]). While policies are most often targeted at physicians, they may also be used to promote specific behaviours among patients.

Studies that have evaluated specific pay-for-performance programmes have shown that these incentives do influence physician prescribing, but the magnitude of their impact is variable. A large-scale antimicrobial prescription pay-for-performance scheme targeting general practitioners was established in Sweden between 2006 and 2013 with the goal of converting some antimicrobial prescribing from broad to narrow spectrum antimicrobials for respiratory infections. The financial incentives, which accounted for between 0.05% and 1.2% of physicians’ total reimbursement, depending on geographical area, were tied to the share of narrow spectrum penicillin prescriptions of total respiratory tract antimicrobials. The programme led to a 3% reduction in narrow-spectrum penicillin V share (Ellegård, Dietrichson and Anell, 2017[29]). A study in the United Kingdom found similar outcomes in the hospital setting (McDonald et al., 2015[97]), and a study of the primary care setting in China also showed a reduction in antimicrobial prescribing associated with a change from fee-for-service to capitated payments (Yip et al., 2014[98]). However, all of these studies have key methodological weaknesses, limiting the ability to draw definitive conclusions on the impact of economic incentives.

The impact of employing financial incentives to alter antimicrobial prescribing for physicians is consistent with the impact of such incentives on changing physician behaviour in general. A Cochrane review including 32 studies found that financial incentives are effective at changing a variety of health care professionals’ practice, including prescribing, referrals and admissions, and guideline compliance. While the review does not distinguish between bonuses and penalties (Flodgren et al., 2011[99]), whether incentive payments involve incentives or penalties creates major consequences for the difficulty of achieving the buy-in of providers. Because penalties typically require significantly more negotiation between payers and providers, administrative cost considerations tend to favour the establishment of bonus payments to influence antimicrobial prescribing (Cashin et al., 2014[100]).

Economic incentives targeting patients are less widespread and their impact less studied than physician-targeted economic incentives. Patient incentives most often take the form of higher cost-sharing on antimicrobials, with the aim of limiting use in situations where they are unnecessary. A classic study of the impact of cost-sharing on medical care in general, conducted in six US cities across 2 000 households, demonstrated that an increase in co-payment was associated with a significant reduction in antimicrobial use (Newhouse and the insurance experiment group, 1993[101]). However, more recent studies have demonstrated that higher patient cost-sharing is linked to antimicrobial resistance. By incentivising patients to seek medical care from less well-regulated private providers, a 10% increase in the expenditures that were out-of-pocket was associated with a 3.2% increase in resistant isolates across 47 low and middle-income countries (Alsan et al., 2015[102]). Higher cost-sharing in the public sector led patients to seek medical care in the private sector, wherein antimicrobial prescribing was less tightly controlled (Alsan et al., 2015[102]).

While economic incentives have proven to be successful in the past, their design can be challenging, requiring the determination of appropriate outcomes and size of the financial incentive. Importantly, however, evidence suggests that incentives do not need to involve significant financial stakes for physicians to be effective. Physicians have been consistently responsive to very nominal bonuses, suggesting that the mechanism behind successful pay-for-performance schemes is “lowering physicians’ psychological barriers to changing prescription routines” (Celhay et al., 2015[103]).

While there is no universal formula for the development of successful economic incentive programmes, incentive design needs to consider a number of factors (Kondo et al., 2016[104]):

focus on measures targeting process-of-care or clinical outcomes that are transparently evidence-based and viewed as clinically important
incentive structure needs to consider several factors, including incentive size, frequency, and target group.
programmes need to be able to change over time based on measurement and physician input
target areas of poor performance and consider de-emphasising areas that have achieved high performance.

In designing effective economic incentive policies, it is also key to keep in mind unintended economic consequences that can create perverse incentives for physicians and patients. For example, after the reduction of China’s 15% mark-up policy, which incentivised physicians to overprescribe because drug administration made up a significant portion of their revenue, some hospitals provided additional inpatient care services as well as increased use of intravenous prescriptions (Wang et al., 2016[40]). In health care systems with both public and private channels, changes in patient cost-sharing likely only have the potential to be effective if implemented across both.

Box 5.8. Reimbursement of antimicrobials in Japan

Since 1996, Japan’s health care system has employed a reimbursement-based fee schedule for medical services and prescription medicine. The schedule contains embedded economic incentives in the form of bonuses to promote prudent use of medical resources, including the use of antimicrobials, in hospitals (Federal Ministry of Health, 2015[105]). The most recent national action plan on AMR includes a set of policies to enhance capacity building and training on adaptation of diagnostic and treatment technologies, clinical and public health expertise on infectious diseases, and rapid response to AMR emergence. In fulfilling the level of activities dedicated to reducing inappropriate antimicrobial consumption, the programme sets out specific performance indicators, such as the number of antimicrobial stewardship seminars carried out each year and the number of cases of antimicrobial-resistant infections at each medical institution. Upon meeting specific targets, hospitals are rewarded reimbursement credits that can eventually be recovered as hospital revenues (AMR Special Group, 2016[106]).

Conversely, health care providers can only be fully reimbursed by the insurer for the costs of prescribed antimicrobials when required stewardship precautions are demonstrated and the treatment of choice is judged prudent. Under the Health Insurance Act and the Act on Assurance of Medical Care for Elderly People, physicians are required to not prescribe medicines beyond necessity (Japan Ministry of Health, 2016[107]).

At the community level, additional economic incentives are in place to facilitate regional co-operation of hospitals regarding infection control through mutual audit and feedback. A support network of specialists in the community aims to increase awareness and provide adequate expertise and consultation to facilitate aspects of AMR prevention.

Box 5.9. Role of business stakeholders in promoting prudent use of antimicrobials

While many interventions are targeted at physicians and the patients taking antimicrobials, stakeholders who benefit commercially from the sale and dispensation of antimicrobials, such as pharmaceutical manufacturers and private pharmacies, also have a significant role to play in promoting rational use of antimicrobials.

Numerous pharmaceutical companies, which can be involved in interventions from reducing counterfeit products to ensuring sales and marketing practices are transparent, have publicly committed to tackling AMR, with many signing the Davos Declaration in 2016 (IFPMA, 2016[108]). This Declaration was followed by the publication, by a core group of manufacturers, of an “Industry Roadmap for Progress on Combating Antimicrobial Resistance” (IFPMA, 2016[109]). The Access to Medicines Foundation developed an evaluation metric for pharmaceutical companies to assess their impact on AMR, with a focus on:

ensuring affordability and limiting shortages
registering products
ensuring manufacturing quality
supporting/engaging in antimicrobial stewardship
supporting/engaging in surveillance systems
adapting packaging to enable rational use
supporting efforts to limit uncontrolled use
employing ethical sales and marketing practices

The Foundation found that a number of pharmaceutical manufacturers have made progress in promoting the prudent use of antibiotics, such as AMR surveillance and promotional activities (Foundation, 2018[110]). Almost half of companies that market antimicrobials have undertaken surveillance across 147 countries. Only four companies, however, are working to reduce overuse of antimicrobials by modifying sales incentives to be separate from the volume of antibiotics sold, thereby disincentivising the sale of unnecessarily high volumes.

Private pharmacies not only influence antimicrobial use by educating patients on appropriate antimicrobial use but also in how they dispense antimicrobials. Even in markets where antimicrobials are prescription-only, some pharmacy outlets—both online and more traditional brick-and-mortar facilities—dispense them without a prescription. In a 2017 World Bank study, antimicrobials were dispensed without a prescription derived from appropriate clinical diagnosis in more than 60% of pharmacy visits in Botswana, Georgia, Ghana, Nicaragua, and Peru (World Bank, 2016[111]). A recent survey of 20 online pharmacies that deliver to the United Kingdom found that 45% of them did not require a prescription prior to purchase. Even among those requiring a prescription, nearly all of the pharmacies allowed customers to select the specific antimicrobial they wanted, along with the dose and treatment duration (Boyd et al., 2017[112]). Importantly, it was unclear whether most of the pharmacies surveyed were actually operating in the United Kingdom, highlighting the critical importance of international collaboration in pharmacy regulatory policy.

Some private pharmacies are actively working to promote rational prescribing. For example, one pharmacy chain conducted an antimicrobial resistance audit across the home care facilities it supported to ultimately improve antimicrobial dispensation (PharmacyMagazine, 2017[113]). However, significantly more work is needed in order for pharmacies to curtail the inappropriate acquisition of antimicrobials by patients.

5.6. Specific interventions in toolkit: Prevent spread or transmission of resistance in health care settings

5.6.1. Improved environmental hygiene in health care settings

Environmental hygiene in health care settings encompasses the decontamination, disinfection, cleaning and sterilisation of the environment and equipment as well as proper disposal of items that have potentially come into contact with infected individuals. Because many organisms are able to live in the health care environment for days, proper hygiene is critical to preventing the spread of resistant bacteria. Studies have shown that only 50% of surfaces in hospital rooms are sufficiently cleaned between patient stays, meaning rooms previously occupied by patients with multidrug-resistant organisms are at an increased risk of subsequent infection or colonisation with these organisms (Anderson et al., 2017[114]).

Cleaning practices are extremely variable in terms of frequency, method, equipment, benchmarks, monitoring, and standards (Dancer, 2014[115]). While the types of interventions applied to improve these cleaning practices differ widely, they can be clustered into three broad categories (Donskey, 2013[116]).

Disinfectant substitution involves a change from detergent to disinfectant, or to a different disinfectant assumed to have higher effectiveness against certain pathogens.
No-touch cleaning involves the use of an automated cleaning device, emitting hydrogen peroxide vapour or ultraviolet (UV) radiation, to disinfect rooms after routine cleaning. UV and hydrogen peroxide attack the molecular bonds in DNA and other essential cell components, thereby destroying the microorganisms (Weber, Kanamori and Rutala, 2016[117]).
Interventions to improve effectiveness of cleaning may include additional cleaning time through the employment of new staff; audit, monitoring and feedback regarding cleaning practices and thoroughness (Curtis, 2008[118]); staff education as well as novel techniques of applying products, such as using disposable wipes or colour-coded cloths.

Several studies have found that improved cleaning practices have decreased contamination with antimicrobial resistant bacteria, both on humans and within the health care environment. A recent clinical trial investigated the effect of three enhanced strategies for terminal room cleaning on the acquisition of several types of antimicrobial-resistant organisms at eight hospitals in the United States. The three strategies tested comprised the use of bleach and ultraviolet-C decontamination as well as a combination of both compared to standard cleaning with quaternary ammonium. On all target organisms, UV-C cleaning alone was the most effective and resulted in a significant 30% decrease in pathogen transmission (Anderson et al., 2017[114]).

A number of studies have also demonstrated the impact of improved hygiene practices on contamination and infections more generally. A study of four US hospitals found that a change in gown and glove donning and removal technique resulted in a significant reduction in skin and clothing contamination that was sustained for up to three months (Tomas et al., 2015[119]). Other studies have identified various cleaning methods that reduce contamination of hospital rooms. For example, one study identified that a solution used to disinfect pieces of equipment in intensive care units significantly reduced catheter-related infections (Chopra and Saint, 2015[120]).

Though it may seem straightforward, implementation of improved cleaning practices involves both process improvements (e.g., skin disinfection or use of UV lights) as well as education and training, with an eye to key “socioadaptive” considerations (Chopra and Saint, 2015[120]). Medical personnel need to be not only trained but also effectively encouraged and incentivised to adhere to hygiene practices (Chopra and Saint, 2015[120]). Most hygiene programmes evaluated include both educational and evaluative components, with training, proficiency monitoring, and feedback (Doll and Bearman, 2015[121]; Tomas et al., 2015[119]). Particularly effective programmes have included immediate visual feedback on contaminated surfaces to allow health care workers to improve their practices.

However, interventions also need to address some of the broader challenges surrounding medical facility cleaning in general, such as poor compensation of staff, which can undermine proper hygiene. In community settings, proper sanitation infrastructure and education of the public on the importance of environmental hygiene are essential to prevent contamination with resistant pathogens (Cecchini, Langer and Slawomirski, 2015[122]). In 2015 in India, the National Health Mission launched the Kayakalp (clean hospital initiative) Award Scheme, which aims to promote infection control practices in health care facilities (Swaminathan et al., 2017[123]). Under the scheme, health facilities are incentivised to achieve certain cleanliness, hygiene, waste management, and infection control practices with monetary rewards (MoHFW, 2016[124]). Funds provided through the scheme may be used for cleaning equipment, improved cleaning practices, and staff training. Introduced to district hospitals in 2016 and 2017, the programme is now being rolled out to community health centres and other health care facilities.

Studies in the United Kingdom and Canada have shown that enhanced environmental hygiene can lead to substantial cost-savings ranging from GBP 31 600 to CAD 500 000 per year (Conlon-Bingham et al., 2016[125]; Dancer et al., 2009[126]; Semret et al., 2016[127]). If resources are limited, targeted approaches could be considered such as enhanced cleaning for patients deemed to be at higher risk of infection (e.g., those in exposed rooms or those undergoing critical care) (Siegel et al., 2017[128]).

5.6.2. Improved hand hygiene

Transmission via hand contact, in particular through health care workers’ hands, is deemed the most important vector for spreading healthcare-associated pathogens. Since microorganisms can survive on the skin for several minutes, pathogens can be readily spread from patient to patient (Allegranzi and Pittet, 2009[129]; Sroka, Gastmeier and Meyer, 2010[130]). The ease with which infections can spread on the hands highlights the critical importance of hand hygiene as a mechanism to control infections. Often, however, hand hygiene is extremely inadequate: a global review of hand hygiene compliance found that compliance with hand hygiene guidelines was just 40% on average (Erasmus et al., 2010[131]).

The WHO World Alliance for Patient Safety campaign, launched in 2005, initiated a series of international and national efforts to improve hand hygiene. The campaign strategy featured five key components: system change, training and education, observation and feedback, reminders in the hospital, and a hospital safety climate. Since then, a number of countries have established hand hygiene guidelines and national policies. Many of the most recent guideline updates recommend hand cleaning after removal of gloves (Wilson et al., 2016[132]), such as the UK’s NICE guidelines (NICE, 2012[133]).

There is some evidence suggesting that specific hand hygiene measures can reduce the spread of infections; however, many of these studies have significant limitations, including inadequate sample sizes, inappropriate analyses and failure to compare the efficacy of different types of interventions (Fätkenheuer, Hirschel and Harbarth, 2015[134]). Despite these drawbacks, a European study demonstrated that increased use of alcohol‑based handrubs was associated with reduced MRSA rates (Fätkenheuer, Hirschel and Harbarth, 2015[134]). In a study focused on rural hospitals in New Hampshire, a hospital-wide hygiene initiative targeting both nurses and physicians was associated with a reduction in the incidence of hospital-associated infections (Kirkland et al., 2012[135]).

The most successful hand hygiene interventions tend to be the most comprehensive, such as those that include accountability, feedback, education and training, marketing and communication, in addition to simply making cleaning products available (Bauer-Savage et al., 2013[136]; Kirkland et al., 2012[135]). The multi-faceted WHO-5 intervention, which includes goal setting, reward incentives, and accountability also appears to improve health care worker compliance (Luangasanatip et al., 2015[137]). While such comprehensive solutions are useful in specific settings, simple changes can also drive improvements in resource-limited settings. More straightforward solutions such as WHO-recommended locally-produced handrubs have been rolled out in many countries, eliminating the need for resource-constrained health care facilities to purchase cleaning products (Bauer-Savage et al., 2013[136]).

Key regulatory actions are also important in improving hand hygiene, particularly in ensuring that products used for cleaning are appropriate and effective. In light of no evidence supporting the effectiveness of 19 chemicals used in soap products, the US Food and Drug Administration (FDA) banned the use of 19 different chemicals in consumer hand soap in 2016 (Food and Drug Adminnistration, HHS, 2016[138]). Before the ban, about 40% of soaps – including liquid hand soap and bar soap – contained the chemicals.

Box 5.10. National Hand Hygiene Initiative in Australia

Introduced in 2006, Australia’s National Hand Hygiene Initiative, commissioned by the Australian Commission on Quality and Safety in Health Care, has achieved significant reductions in infection rates of resistant bacteria. The programme aims to improve both surveillance and hand hygiene practice, including improvements in hand hygiene compliance rates, reducing rates of healthcare-associated infections, as well as accurately measure rates of staphylococcal disease and an effective education and credentialing system to improve knowledge about hand hygiene (Hand Hygiene Australia, 2018[139]). The hand hygiene strategy hinges upon the “5 Moments” when hand hygiene should be performed: before touching a patient, before a procedure, after a procedure or body fluid exposure, after touching a patient, and after touching a patient’s surroundings.

While the initiative initially focused on acute care public hospitals, it now includes a variety of both public and private health care facilities, and it tracks compliance rates across the country, with breakdowns by specific moment in patient journey, health care worker type, hospital wards, and types of hospitals. As of 2017, the national compliance rate (84.8%) has exceeded the 80% benchmark established by the Australian Health Ministers’ Advisory Council (Hand Hygiene Australia, 2017[140]).

Two evaluations of the Initiative found it yielded both improved health outcomes and cost savings. A study of 38 hospitals across eight states and territories found that the initiative was associated with infection rate reductions from 8% per year in South Australia to 28% in the Australian Capital Territory (Barnett et al., 2014[141]). A cost-effectiveness analysis including 50 hospitals determined the cost effectiveness ratio of AUD 29 700 per life year gained, with total implementation costs of the programme amounting to AUD 2.85 million (Graves et al., 2016[142]).

5.6.3. Screening and isolation of infected patients

Aimed at reducing the transmission of infections from patient to patient, screening and isolation involves the quarantining of specific patients to separate areas of a health care facility (most typically a hospital). The intervention can be broad or targeted, involving patients colonised with epidemiologically important bacteria (such as MRSA and vancomycin-resistant Enterococci) after screening or pre-emptive isolation of high-risk patients. Isolation itself can range from contact precautions (e.g., gloves and gowns for contact with patients) to patient cohorting (groups of patients in one area) or single-room isolation (Worby et al., 2013[143]).

Evidence evaluating the effectiveness of policies to screen and isolate infected patients in reducing antimicrobial resistance is limited. A number of observational studies have suggested that isolation of patients, when included as part of a bundle of interventions, can reduce the spread of MRSA (Fätkenheuer, Hirschel and Harbarth, 2015[134]). However, these studies tend to be low quality and often couple isolation with other actions such as decolonisation, thus making it challenging to disentangle the impact of one intervention from the another (Worby et al., 2013[143]). For example, a screening and isolation policy in the Netherlands was successful at controlling a large MRSA outbreak (Vos, Ott and Verbrugh, 2005[144]). Following an outbreak of MRSA, in a university hospital, the proportion of a particular strain of MRSA rose from 3% to 33%. An intensive “search-and-destroy” policy on patients and health care workers lowered the portion of that strain to 5% over several years. National guidelines for the more sensitive detection of strains with low-level resistance were also implemented across laboratories nationally.

While isolation of infected patients may seem straightforward, there are major open questions related to the implementation of screening and isolation policies. A first issue concerns where and under what circumstances patients should be isolated (Tacconelli, 2009[145]). Because screening tests can often require 24-72 hours to yield results, a period during which patients could spread infections, there is a significant trade-off between isolating patients pre-emptively as opposed to isolating them after receiving screening results. There is also a lack of consensus surrounding which patients should be screened; some evidence suggests that screening and isolation may be most effective and best implemented in intensive care units rather than other wards of the hospital. Finally, some investigators have expressed concern that isolation may decrease overall quality of care for isolated patients because of the more limited time health care professionals spend with them (Fätkenheuer, Hirschel and Harbarth, 2015[134]).

Despite very limited evidence on the impact of screening and isolation on infection control, at least on a theoretical basis, the intervention could be both clinically sound and cost effective. As screening would reduce expensive nosocomial infections, such as MRSA, the intervention might result in significant cost savings. A few studies have shown savings from USD 100-150 000 annually in individual hospitals: the result of both fewer infections and reduced use of antimicrobials (Tacconelli, 2009[145]). However, the need for single rooms in many cases makes this intervention particularly resource-intensive. Most guidelines recommend the use of a single room along with contact precautions for patients infected with multi-drug resistant bacteria, which can be virtually impossible to provide in countries with a limited supply of rooms (Otter et al., 2015[146]).

Box 5.11. Hospital screening to combat rising resistance in Hong Kong

In Hong Kong, the authority managing the city’s public hospitals and other health care facilities has recently established more stringent screening guidelines for hospitalised patients in an attempt to address rising rates of antimicrobial resistance. High resistance rates and spread largely result from historically high antimicrobial use and a significant population of international visitors (Tsang et al., 2012[147]). A recent study showed that antimicrobials cephalexin, amoxicillin, ofloxacin and erythromycin were ubiquitous in seawater throughout Victoria Harbour as a result of continuous discharge into the environment (Cheng et al., 2015[148]). Hong Kong faces particular concerns about the spread of carbapenem-resistant Enterobacteriaceae (CRE): a so-called “super bug” because it is resistant to nearly all antimicrobial products.

In recent years, Hong Kong established a hospital surveillance system that involves routine screening of high risk patients, including those who were hospitalised overseas within six months or had received a surgical operation outside Hong Kong within 12 months of admission (Cheng et al., 2015[148]). In many cases, patients hospitalised for 14 days or more are also screened.

If screened patients are found to harbour certain types of resistant bacteria, an infection control team carries out a bedside assessment and establishes strict contact precautions, including isolation of the patient to a single room. In addition, all of their hospital contacts are tracked for potential secondary cases and immediately screened. If those patients have been discharged from the hospital into secondary care facilities, they are screened at those facilities. For patients who have been discharged to home, the hospital computer system records their status, and they are screened upon readmission (Cheng et al., 2015[148]).

However, with a major increase in CRE cases between 2016 and 2017 (340 cases to 473), Hong Kong has announced multiple changes to the screening programme. Public hospitals will now conduct screening on site within hospitals, and criteria for screening may also be expanded to include more patients, given an increasing number of cases of CRE reported in patients who were not hospitalised outside of Hong Kong (van Dongen, 2018[149]).

Screening is just one component of Hong Kong’s comprehensive national action plan, which includes efforts to optimise the use of antimicrobials in both humans and animals, reduce the incidence of infection, improve surveillance, grow awareness about resistance, and promote relevant research and development (The Government of the Hong Kong Special Administrative Region, 2017[150]).

5.6.4. Decolonisation

Colonisation of body surfaces with drug-resistant pathogens, in particular patient skin, serves as a key vector for transmission and is linked to an increased risk of infection. Approaches to decolonisation can be highly variable. Decolonisation may target individuals with a specific infection or a broad set of infections; it can occur pre-emptively (before admission) or following screening, and may target health care workers or specific patients, such as those undergoing surgery or treatment in the intensive care unit. Decolonisation can also be carried out using one of several methods:

nasal decolonisation involving topical antimicrobials and usually targeting a specific pathogen
selective decontamination involving prophylactic application of antimicrobials in the stomach
skin decolonisation with topical antiseptics involving use of an antiseptic and can thus be used for a variety of drug-resistant bacteria.

Because decolonisation may involve the use of antimicrobials, there is a risk not only of additional resistance development but also other adverse events such as allergic skin reactions. Resistance to a topical antimicrobial product has been reported in some studies of MRSA decolonisation (Edgeworth, 2011[151]; Robicsek et al., 2009[152]), making decolonisation relatively controversial among hygiene interventions (Edgeworth, 2011[151]; Worby et al., 2013[143]).

Despite its risks, however, decolonisation has been proven to be effective in reducing infections in high-risk patient groups, such as those with surgical site infections and wound complications. The pooled effects of 17 studies showed that decolonisation had a significantly protective effect against surgical site infection associated with S. aureus both when all patients and only S. aureus patients underwent decolonisation (Schweizer et al., 2013[153]). A review of 19 studies showed a reduction in surgical site infections (effect ranging from 13% to 200%) by instituting an S. aureus screening and decolonisation protocol in elective orthopaedic (total joints, spine, and sports) and trauma patients. The screening and decolonisation protocol also saved costs in orthopaedic patients (Chen, Wessel and Rao, 2013[154]).

Because decolonisation runs the risk of actually increasing antimicrobial resistance, effective implementation typically involves specific patient populations that are likely to yield the most benefit. For example, decolonisation may be used for patients increased risk of developing an MRSA infection during a specific period, such as patients admitted to inpatient care units and those undergoing cardiothoracic surgery (Clarke, 2014[155]). UK guidance suggests screening only patients at high risk for organisms such as MRSA and carbapenemase-producing Enterobacteriaceae and decolonising only select MRSA patients (Public Health England, 2017[156]).

Box 5.12. Role of business stakeholders in promoting hygiene in the natural environment

While hygiene within health care facilities falls to the facilities themselves, business stakeholders have a profound responsibility in promoting broader environmental hygiene in order to combat antimicrobial resistance. Antimicrobial manufacturing, which is largely concentrated in India and China, releases antimicrobials into the environment and has been cited as a major source of antimicrobial resistance. A 2009 study showed antimicrobial concentrations in rivers around Hyderabad higher than in the bloodstream of a patient undergoing antimicrobial treatment (Rotthier and Gharabaghi, 2015[157]). A 2016 study recommended that regulators not only set targets on maximum levels of antimicrobial discharge but also that pharmaceutical companies improve monitoring of their manufacturing and that of their suppliers (Milmo, 2017[158]). The lack of environmental regulation and enforcement in some countries underscores the need for pharmaceutical manufacturers to adhere to the most rigorous environmental hygiene practices.

Beyond prudent antimicrobial use, the Access to Medicines Foundation also evaluates pharmaceutical manufacturers on their environmental risk management efforts. Currently, only 8 of 19 companies are reducing antimicrobial release into the environment through limits on antimicrobial wastewater discharge and none of them publishes discharge levels (Foundation, 2018[110]). In 2016, a group of companies within the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) published a roadmap that includes specifying steps they would undertake to control the release of antimicrobials from pharmaceutical plants (IFPMA, 2016[159]). The companies agreed to review their manufacturing and supply chains, build a common framework for assessing and mitigating antimicrobial discharge, and begin to apply the framework to their own practices in 2018. They have also worked with external experts and have developed targets for antimicrobial discharge concentrations (AMR Industry Alliance, 2018[160]).

5.7. Specific interventions in toolkit: Vaccination

Vaccination is a key intervention that can reduce antimicrobial resistance by lowering the incidence of diseases that are treated with antimicrobials, particularly those bacteria that tend to develop resistant strains. Vaccines essentially train the immune system to recognise pathogens and mount an immune response, thereby reducing the severity of infection or preventing its establishment all together (Jansen, Knirsch and Anderson, 2018[161]). Vaccines also protect unvaccinated individuals through herd immunity by reducing the likelihood of transmission. While vaccination is one of a suite of infection prevention measures, such as better nutrition, clean water, and hygiene, vaccination can be easier to implement and produces significant results (Ginsburg and Klugman, 2017[162]).

Vaccination, particularly for Streptococcus pneumoniae (S. pneumoniae) and Haemophilus influenzae type b (Hib), can help to combat antimicrobial resistance by both reducing the incidence of resistant strains of bacteria as well as allowing for differential diagnoses that allow narrower spectrum antimicrobials to be used when vaccinated patients become ill. For the most part, vaccines do not specifically target resistant strains of bacteria but address all strains of a particular type of bacteria. One notable exception is pneumococcal conjugate vaccines (PCVs), which address specific serotypes of pneumoniae that have a high resistance frequency. Highlighting the potential impact of vaccination in curbing antimicrobial use, universal coverage by a PCV could yield a 47% reduction in the amount of antimicrobials used for pneumonia cases caused by S. pneumoniae (Laxminarayan et al., 2016[163]).

Vaccination has been shown to be extremely effective in reducing the incidence of many clinical diseases, including those pathogens with high rates of resistance. In the United States, after the introduction of the PCV into the routine childhood immunisation programme, incidence of penicillin non-susceptible invasive pneumococcal disease decreased by 81% in children under the age of two (Kyaw, 2006[164]). Within four years of the introduction of the PCV in children under two years of age in South Africa, reductions of greater than 80% were recorded in the incidence of invasive pneumococcal disease caused by penicillin, ceftriaxone, and multidrug non-susceptible serotypes (von Gottberg et al., 2014[165]).

Although they do not target bacterial pathogens, influenza vaccines also help to reduce AMR by both preventing secondary bacterial infections, which occur as a result of viral infections, and preventing inappropriate antibiotic use for patients with viral infections (Jansen, Knirsch and Anderson, 2018[161]). The impact of influenza vaccination on inappropriate antimicrobial use is particularly profound in light of the fact that in the United States, approximately one-third of antimicrobial prescriptions are unnecessary, with the majority of these prescriptions written for respiratory illnesses caused by viruses (CDC, 2016[166]). A study in Canada showed that following the introduction of a universal influenza vaccination in Ontario, influenza-associated antibiotics were prescribed 64% less often than prior to the implementation of the vaccination policy (Kwong et al., 2009[167]).

Despite its demonstrated effectiveness at not only reducing disease burden but also decreased antimicrobial resistance, implementation of more widespread vaccination faces ideological, logistical, and financial hurdles. Global vaccination rates—the portion of children who receive vaccinations—have recently levelled out at approximately 86%, with certain diseases such as pneumococcal diseases achieving much lower rates (42%) (WHO, 2018[168]). Though developed countries tend to have high vaccination rates, global coverage rates for the Hib and PCVs are, respectively, only 45% and 19% (Greenwood, 2014[169]).

Several key factors need to be addressed to bolster vaccination coverage in low and middle-income countries, including simultaneous licensure in developed and developing countries, faster rollout of vaccines, logistics improvements to grow vaccination rates in remote areas, increasing funding, and reducing public resistance. In 2017, the Ministers of Health from 194 countries endorsed a resolution to improve efforts to achieve the goals of the Global Vaccine Action Plan, which aims to achieve more equitable access to vaccines by 2020. The resolution includes efforts to bolster national immunisation programmes as well as monitoring systems, mobilise financing, and expand immunisations to adolescents and adults (WHO, 2018[168]).

Although vaccination rates are fairly high across OECD and G20 countries (Figure 5.5), coverage falls short of the WHO’s 95% target for each vaccine in the routine vaccination schedule by the age of two (Williams et al., 2011[170]). It is therefore critical to not only focus on the need to promote vaccine uptake in low-income countries but also on continuing to improve vaccination rates in higher income countries. A review of strategies to improve vaccination rates in preschool children identified successful interventions targeting both parents and providers (Williams et al., 2011[170]). Parental reminders increased immunisation rates by 34%, while physician-targeted reminders, educational programmes, and feedback programmes increased rates by 7%, 8%, and 19% respectively.

While these efforts can improve utilisation of current vaccines, realising the full potential impact of vaccination on AMR will also require the development of novel vaccines. There are no licensed vaccines for any bacterial species that address bacteria considered “critical” or “high” on the WHO Priority Pathogens List (WHO, 2017[171]). In addition, only 4% of research and development spending on products to prevent infections specifically related to AMR is spent on diagnostics, vaccines, or other technologies, with 95% on antimicrobials (OECD et al., 2017[172]). This suggests that sustaining viable markets and supporting new vaccine research, in addition to supporting uptake of current vaccines, will be critical to combatting the spread of AMR. Pipeline vaccines such as those to prevent C. difficile or S. aureus infection, PCVs with extended serotype coverage, and vaccines to prevent infections with Gram-negative bacteria offer the promise of significantly reduced infection and antimicrobial prescribing (Jansen, Knirsch and Anderson, 2018[161]).

Figure 5.5. Vaccination rates among OECD, G20, and other EU countries

Conclusions

In developing policies to combat antimicrobial resistance, policy makers have a lengthy menu of interventions from which to choose. Interventions aimed at promoting more rational use of antimicrobials, improving environmental hygiene in the health care setting, and bolstering vaccination rates have all been shown to lower the burden of antimicrobial resistance. Additionally, many of these policies have been effectively used in a variety of health care settings and across geographies, demonstrating the potential of policies to be successfully tailored to meet local needs. The fact that many of these efforts have been studied and work in consort, rather than separately, underscores the need to implement a wide variety of policies rather than attempt to identify and select the most effective one. In addition, given the global nature of microbes and antimicrobial resistance, successfully reducing resistance development will also require global surveillance, co-operation, and coordination for the impact of antimicrobial policies to be fully realised.

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Note

← 1. While this cost seems much higher than the cost of the mass media campaign in Belgium, it is noteworthy that the authors report that the reduction in antibiotic costs was higher than the cost to implement the mass media campaign. A significant share of the total budget was devoted to buying television broadcast time.

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