The international dimensions of antimicrobial resistance: Contextual factors shape distinct ethical challenges in South Africa, Sri Lanka and the United Kingdom

Abstract Antimicrobial resistance (AMR) describes the evolution of treatment‐resistant pathogens, with potentially catastrophic consequences for human medicine. AMR is driven by the over‐prescription of antibiotics, and could be reduced through consideration of the ethical dimensions of the dilemma faced by doctors. This dilemma involves balancing apparently opposed interests of current and future patients, and unique contextual factors in different countries, which may modify the core dilemma. We describe three example countries with different economic backgrounds and cultures—South Africa, Sri Lanka and the United Kingdom. Then we discuss how country‐specific factors impact on the prominence of various ethical dimensions of the dilemma (visibility and moral equality of future generations; Rule of Rescue; prescribing autonomy and conflicts of interest; consensus on collective action). We conclude that a nuanced understanding of national prescribing dilemmas is critical to inform the design of effective stewardship approaches.

are based on clinical judgement of the underlying causes of symptoms and the likely source of infection, rather than on microbiological confirmation of infective agents, and they are therefore fraught with uncertainties. From the perspective of the individual patient with symptoms suggestive of a bacterial infection but unknown pathogens, interests are to avoid severe illness or death. In most cases, these interests would be best served by the use of antibiotics, and broad-spectrum antibiotics provide an easy and, in most cases, failsafe approach. This is because broad-spectrum antibiotics target a wide range of pathogens. Even though they may cause side effects (e.g., clindamycin and quinolones may cause serious and even life-threatening complications), many broad-spectrum antibiotics can be a comparatively safe choice even if prescribed unnecessarily. From the perspective of wider society, a more conservative approach is preferred-avoiding unnecessary antibiotic use as far as possible, and using appropriate doses and durations of narrow-spectrum antibiotics-in order to limit the drugs' contribution to AMR. 9 Decisions about individual patients have societal consequences. AMR puts all at risk: even patients who have not had prior antimicrobial treatment can be infected by resistant micro-organisms and suffer treatment failure as a consequence, and this will become increasingly problematic for patients in the future. Inequity of access to healthcare globally means that growing resistance will disproportionately affect poorer people, who will likely only have access to a more restricted range of antibiotic agents when they do receive treatment.
This social dilemma is complicated by the special role that doctors and healthcare staff play in providing access to antibiotic treatment. In most countries, antibiotic prescribing is a privilege reserved for clinicians, who act as antibiotic gatekeepers, 10 and patients need a doctor's prescription to gain legal access to antibiotics. This gatekeeping role developed in parallel with access to other drugs and was initially driven by the recognition that selecting the correct treatment, to maximize chances of recovery and minimize harm, required skilled analysis by Ethical arguments make a strong case for the moral imperative to protect the rights of future, as yet unidentified, people. 12 John Rawls' principle of 'justice between generations', 13 clearly assumes moral equality between existing populations and future offspring, and the access of the latter to common resources, such as antibiotic efficacy. Rawls' principle of justice would always stipulate a conservative and targeted prescribing approach in recognition of future patients. 14 Doctors could be argued to hold responsibility for the rights of future patients, and to have a duty to decrease the harm to future patients even if this increases the risk to present patients.
This could mean doctors having to make decisions that put current patients at slightly higher risk without their consent. It would also mean curtailing patients' liberty to obtain an antibiotic even though patients may wish to do so to have the best chance of a positive outcome. Efforts to reduce antibiotic use may put doctors in a position of acting against patients' preferences, which almost invariably lean towards the less restrictive use of broad-spectrum antibiotics and therefore threaten the rights of future patients. In practice, however, limiting the autonomy of patients is ethically challenging, and the need for paternalistic prescribing might result in conflicted doctor-patient relationships, possibly affecting trust and respect. it could be argued that most people would generally agree on making appropriate efforts to preserve antibiotic efficacy for future patients through limiting antibiotic use with current patients.
Exceptions to this would be ethically justifiable in morally exceptional cases of extreme severity and urgency, where the death of an individual patient could easily be prevented. 17 This moral reasoning is in line with Rawls' idea of 'minimising the worst outcome', 18 and could also be termed an exceptional 'Rule of Rescue'. 19 In the context of medical ethics, the Rule of Rescue has been previously considered when discussing resource allocation and deciding whether costly treatment options were justified for individual patients. 20 An example in the context of antibiotic prescribing may be a patient with symptoms of severe sepsis where the fast administration of broad-spectrum antibiotics could prevent almost certain death. The severity and immediacy of this outcome would mean that the rights of this patient would take AMR is a global problem, not respecting country boundaries.
International efforts are necessary to curb antibiotic use, but inequalities across high-and low-income countries in access to resources mean that some countries bear a larger part of the burden. 24   fact that rich, industrialized nations continue to overconsume antibiotics. This is also the case in poorer nations, some of which are characterized by legal or illegal over-the-counter sales of antibiotics but which at the same time do not have sufficient access to high-quality antibiotics or to more expensive second-line treatments. 26 Consequently, insufficient dosing is common in lower-income countries, and this can also contribute to AMR. 27 Aspects of national culture, 28 particularly uncertainty avoidance, hierarchy and masculinity, have also been found to be associated with levels of antibiotic consumption. 29 Other aspects of cultural orientation, including individual versus collectivist orientation, and long-versus short-term orientation, may also impact on how doctors weight the welfare of current and future patients, and their willingness to engage in collective endeavours to maintain antimicrobial efficacy.
The present article aims to explore how national context can shape the prominence of different dimensions of the ethical dilemmas in antibiotic prescribing decisions internationally, and receptiveness to solutions based on collective action and solidarity. This will be done by comparing three example countries, varying in their economic status, health system organization and delivery, cultural orientation, and geographical location: South Africa, Sri Lanka and the United Kingdom. We will focus on prescribing for acute medical patients in secondary care, because the hospital context is characterized by more complicated or serious cases of bacterial infections, which are associated with higher patient risks (notably fatal sepsis) and higher levels of treatment uncertainty, both of which sharpen the dilemma outlined above. The country analyses will consider national culture and the unique national environments of secondary-care prescribing, and outline the key health policies relating to antibiotic use. This analysis is informed by input from expert collaborators (national experts in infection control and AMR from each of the three countries, who were collaborating on a funded project with the authors), and by visits by the two authors to seven hospitals (one public and one private hospital in South Africa; two public and one private hospital in Sri Lanka; two public hospitals in the U.K.) involving observations and discussions with local stakeholders. After the descriptions of national context, we will map the contextual factors against dimensions of the ethical dilemma. We will conclude with reflections of the impact of cultural context on the prescribing dilemma and the implications of this for the approach to designing stewardship interventions.

| CONTE X TUAL FAC TOR S AFFEC TING ANTIB IOTIC PRE SCRIB ING INTERNATIONALLY
This section will analyse contextual factors that may be associated with antibiotic prescribing dilemmas in South Africa, Sri Lanka and the U.K., outlining the general healthcare context and relevant national policies.

| South Africa
South Africa is currently classified as a middle-income country,  many other countries worldwide. 36 Consequently, AMR is a large and increasingly visible medical problem, 37 and one that contributes to high rates of hospital-acquired infections.
Since 2012, the South African Antibiotic Stewardship Programme (SAASP), a multidisciplinary expert group, has been working to implement antibiotic stewardship programmes across primary and secondary care. 38 Their activities have been supported by South Africa's National Department of Health through the publication of a national strategy document in 2014, which defined a number of objectives, including the promotion of appropriate antibiotic use. 39 The medical use of antibiotics in South Africa legally requires prescription. Currently, the most commonly prescribed antibiotic class is the broad-spectrum penicillin oral class, which is produced nationally at comparatively low cost. 40 National guidelines for antibiotic prescribing exist in South Africa and are available electronically, but they do not apply to the private sector, where prescribing is based largely on the clinical evaluation of the practitioner in charge, 41 although there may be some carry over because most doctors working in the private sector also work in the public sector.

| Sri Lanka
Sri Lanka is a middle-income country in South Asia, with a similar gross domestic product per capita (11,639 USD, measured in 2016) to South Africa. 42 Sri Lanka has a hierarchical but collectively oriented culture with an emphasis on compromise, negotiation and self-restraint. 43 Sri Lanka provides free hospital care, but in addition to this public healthcare system, many private hospitals exist. The differences between public and private hospitals are large, 44 and the nature of public provision differs in rural and urban settings based on varying resource levels. 45 There is no public service for primary care, and the high fees of general practitioners as well as the limited opening hours of practices often result in delayed presentations of critically ill patients at hospital.
A particularly prominent problem in Sri Lanka is that some patients are reluctant to access healthcare because of the economic consequences of being hospitalized, most notably being unable to work and support their families. 46 While antibiotics cannot be purchased legally in pharmacies without prescription, many pharmacies continue to dispense antibiotics to patients over the counter, 47 as is common in many other low-and middle-income countries. 48 In fact, people frequently stock and keep antibiotics at home for self-medication; this is a problem worldwide, but more so in countries where antibiotics are more freely available off prescription.
The first national guidelines for antibiotic prescribing were issued

| IMPAC T ON E THI C AL DECIS I ON -MAKING
Following the description of contextual factors in three countries varying in culture, economic development and health systems, this section will discuss the impact of these factors on the ethical dilemma outlined at the beginning of this article. We will consider four dimensions of the ethical dilemma against the country profiles from the previous section.

| Visibility and moral equality of future generations
In Section 1, we argued that justice across generations, which rests on the assumed equality of current and future generations of identical moral status, is a key ethical imperative for antimicrobial stewardship. Out of the three countries examined, this imperative is most pronounced and visible in South Africa, where resistance levels are already very high and many patients suffer from medical complications as a result of AMR. Owing to this visibility, the temporal distance between current and future patients is blurred, potentially meaning that the recognition of the need to protect the rights to medical care for future generations of patients who may suffer the consequences of widespread AMR is more evident. Hence, even though antibiotic prescribing levels have been high in South Africa over recent years, doctors may now be forced to act on the increasingly visible consequences, which promote a 'recognition of necessity' 60 for action to preserve antibiotic efficacy.

In contrast with the South African situation, little awareness exists amongst doctors in Sri Lanka about the problem of AMR. 61
There is a lack of information about local resistance patterns, and many doctors treating acute medical patients show little concern about the health threat posed by AMR. In the public hospital sector, this lack of interest may be due to more pressing problems, in-

| Rule of Rescue
Another important dimension of the ethical dilemma is represented by the Rule of Rescue. In Section 1, we argued that extreme cases of urgency can justify extraordinary actions of rescue. For example, symptoms of severe sepsis may justify immediate prescriptions of broad-spectrum antibiotics. The prevailing importance of a doctor's concern for immediate patient needs was supported by results from a study that investigated the allocation of limited intensive care unit the treatment in order to adopt a more conservative approach.
The necessary treatment review is often delayed or does not happen at all. In this case, the focus on the Rule of Rescue means that once the initial rescue has been performed, the subsequent review and revision of the prescribing decision is given lower priority.
A problematic but different challenge to the 'Rule of Rescue' became evident in the context of Sri Lanka. Whereas severe sepsis is often over-diagnosed in the U.K., and urgency of treatment is frequently overestimated, Sri Lankan hospitals are characterized by a genuinely higher proportion of emergency cases that require more drastic action. As pointed out in the previous section, many patients in Sri Lanka present to hospital very late and only once the infection has reached a dangerous stage. 74 The lack of publicsector primary care as well as patients' worries about missing work and losing income mean that by the time patients are admitted to hospital, they may indeed require 'rescue' by administration of broad-spectrum antibiotics, limiting the ability of hospital doctors to make more conservative prescribing decisions. In addition, because of the lack of adequate onsite microbiology laboratories in many public hospitals, the clinical certainty is even lower than in more developed countries, which makes a focus on reviewing and switching from broad-spectrum to narrower-spectrum antibiotics once a patient has been 'rescued' with broad-spectrum antibiotics more difficult to achieve. The prescribing logic is similar in the public sector in South Africa.

| Prescribing autonomy and conflicts of interest
Contexts in which doctors retain full decision autonomy over antibiotic prescribing, but where significant conflicts of interest exist that incentivize antibiotic prescribing, can become problematic. A particular example appears to be Sri Lanka's private healthcare sector.
The incentive structure for hospitals in the private sector, and for the doctors who work within them, results in a privileging of current individual patient outcomes, both clinical and experience-based, over the interests of generations to follow. The sector is characterized by high levels of competition between hospitals to attract patients, a strong business orientation, and significant investment in marketing.
In Sri Lanka's private hospitals, most doctors are employees of the public sector hospitals but also work in private hospitals to augment their relatively low public sector salaries. Doctors are dependent on their extra private practice income, which in turn depends on a continuous influx of patients. As such, doctors typically aim to please their private patients. Widespread patient beliefs about antibiotics as strong and powerful drugs, and as having an almost mythical status, mean that patients often demand and expect to receive antibiotics. 75 Even if private consultants believe in the necessity to preserve antibiotic efficacy, they are aware that patients can choose to 'shop around' for other doctors until obtaining their preferred prescriptions. This practice, which has also been observed in other South Asian countries, 76 results in doctors being disempowered to act to protect the collective interest. Furthermore, in the hospitals we visited, the insurance reimbursement schemes left doctors with discretion to prescribe excessively to meet patient demand without scrutiny. With no incentive or pressure to rationalize antibiotic prescribing, doctors rarely curb or refine their treatment strategy.
Doctors working in private healthcare in South Africa face the same pressures to satisfy patient demand as those apparent in Sri Lanka, but, in contrast, we observed healthcare insurance reimbursement schemes in private hospitals that required detailed reporting of resource use, and that limited payments for antibiotic use. This incentive scheme resulted in tighter organizational monitoring and control of prescribing decisions, balancing out incentives to respond to patient demand. This is an example of a shift towards the interests of society driven by financial incentives as opposed to the moral reasoning of individual doctors; however, the same in the two cases.
As identified above, the use of collectively agreed guidelines

| Consensus on collective action
We have already established that collectively acceptable prescrib-  In Sri Lanka, a strongly coordinated, consensus-based approach to antimicrobial stewardship is led by the Sri Lankan College of Microbiologists, but only within the public sector. Guidelines are very rarely followed in private hospitals. Adherence to the guidelines is not, however, monitored or audited in either sector. 81 In public hospitals, most antibiotic prescribing is undertaken by junior doctors, who typically require microbiology sign-off to prescribe redlight antibiotics. However, owing to the limited reviews of antibiotics and the generally passive role of nurses and pharmacists, stopping or de-escalating antibiotic treatment can be a problem. Furthermore, many low-resource hospitals are forced to prioritize economic considerations over concerns regarding AMR. Often, the choice of an antibiotic is dependent on the drug's cost and affordability to patients; 82 this is particularly important if a prolonged course of antibiotic treatment is necessary.
The testing of samples in local microbiology laboratories is becoming more frequent in the public health sector, but the trust of doctors in local test results is limited as a result of a perceived lack of local expertise and poor hygiene conditions. In those cases where no laboratory facilities exist on-site, samples need to be sent to larger laboratories, which leads to delays of test results and extended periods of empirical prescribing. 83 On the whole, the existence of other pressing problems, and the higher levels of clinical uncertainty in Sri Lanka make it difficult to implement the collectively agreed antibiotic prescribing strategy in practice.
In the U.K., the national approach towards antibiotics is also much less defined than in South Africa, with antibiotic stewardship guidelines and initiatives potentially competing with other priorities, including sepsis prevention. 84 Furthermore, individual hospital trusts typically develop their own sets of local prescribing guidelines to reflect regional resistance patterns. The hospitals retain authority to design their own types of antibiotic prescribing documents, restrictions and processes as they see fit. 85 In addition, hospitals differ in their restrictive policies. While some im-

| SUMMARY AND CON CLUS I ON S
We have described how various dimensions of the ethical dilemma of prescribing antibiotics may be forefronted or attenuated in different international settings, owing to cultural and structural differences in healthcare systems and healthcare provision. The extent to which AMR is a visible threat influences the orientation of doctors towards actions that preserve the collective interests in preserving antimicrobial efficacy for the future. In South Africa, unlike in the U.K. or Sri Lanka, doctors do not have to imagine the future generations whom they have a moral duty to protect from the consequences of AMR-distinction between the rights of current individuals and future generations is blurred. Also, their engagement in working towards the collective goal of conservation of antibiotic efficacy is likely to be higher, because it has immediate consequences for themselves and their patients. In public hospitals in Sri Lanka, limitations in microbiology testing lead to a lack of information about resistance levels. The ethical principal of justice for future generations is overshadowed by the Rule of Rescue, given the severe and urgent condition of many patients. In settings where antibiotic resistance is hidden, and the risk of patient mortality is widespread and high, the ethical principles of justice for future generations are more likely to be played down.
Engaging doctors in collective efforts to preserve antimicrobial efficacy will require a 'recognition of necessity' 87 through making clear the growing scale and immediacy of the problem. This needs to be balanced, particularly in low-and middle-income countries, by supporting doctors to optimize their prescribing without significantly increasing immediate mortality risks. The approaches required will vary across settings and international contexts.
Sri Lanka has a collectively orientated culture, and this is reflected in the approach in the public sector to consensus-based guidelines, supposed to be implemented consistently across the whole country.
The national culture acts as a fertile ground for coordinated, societybased approaches to antimicrobial stewardship. Problems arise, however, from a lack of infrastructure to support monitoring and auditing of practice to maintain this in line with collective goals. Furthermore, hierarchies across professional roles (e.g., doctors, nurses and microbiologists) act as barriers to an inclusive approach to working In the U.K., levels of resistance are lower than in South Africa, and doctors lack feedback on resistance levels. Furthermore, the availability of alternative treatments (e.g., second-and third-line antibiotics) means that treatment complications as a result of AMR are rare. Like South Africa and Sri Lanka, the U.K. also has national initiatives to promote antibiotic stewardship, but a history of inter-organizational competition and a culture of local priority-setting and planning has contributed to a lack of consensus and collaboration. The U.K. context also highlights how goals to reduce drug-resistant infections can be crowded out by more immediate concerns about mortality from sepsis. Supporting U.K. doctors to make ethical decisions about antibiotic use that protect the interests of society may require efforts to make visible the problem of resistance. It may also necessitate national discussion of ethical principles to develop consensus on the prioritization of different interests under different circumstances.
AMR is a worldwide problem that can be effectively tackled only by concerted global action. In view of the gravity of this problem in the medium to long term, reforms in prescribing practices, no doubt slightly different in different countries, are required to avoid a catastrophic outcome. The problem may well be tractable, but a nuanced understanding of how the national and local context within which prescribing takes place shapes the nature of the dilemma is critical to inform the design of effective approaches.

CO N FLI C T O F I NTE R E S T
The authors declare no conflict of interest.