key: cord-0897320-jr3rcl87
authors: Pierce, Jacob; Apisarnthanarak, Anucha; Schellack, Natalie; Cornistein, Wanda; Maani, Amal Al; Adnan, Syamhanin; Stevens, Michael P.
title: Global Antimicrobial Stewardship with a Focus on Low- and Middle-Income Countries
date: 2020-06-04
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2020.05.126
sha: 3756db772e09d8ce1e99f8ffad0353ef0983727f
doc_id: 897320
cord_uid: jr3rcl87

Abstract Antimicrobial resistance is a global public health crisis. Antimicrobial Stewardship involves adopting systematic measures to optimize antimicrobial use, decrease unnecessary antimicrobial exposure and to decrease the emergence and spread of resistance. Low- and middle-income countries (LMICs) face a disproportionate burden of antimicrobial resistance and also face challenges related to resource availability. Although challenges exist, the World Health Organization has created a practical toolkit for developing Antimicrobial Stewardship Programs (ASPs) that will be summarized in this article.

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In 2016 the United Kingdom commissioned a report to define the problem of antimicrobial resistance (AMR). According to the report coordinated by economist Jim O'Neill, AMR is projected to cause 10 million deaths per year by 2050. Additionally, governments of all countries are projected to have escalating healthcare costs attributed to AMR. There is a projected 100 trillion USD global economic impact. The report stresses that resources dedicated to preventing AMR now will prevent far larger costs in the future (O'Neill 2016) . According to the Centers for Disease Control and Prevention (CDC) 2019 threat report, in the United States alone there are over 2.8 million AMR infections and 35,900 deaths from AMR per year (CDC 2019). ASPs have been shown to decrease rates of AMR (Rahal et al. 1998; Raymond et al. 2001; Bantar et al. 2003; Cook et al. 2006; Buising et al. 2008 (Hsu et al. 2017 ).

Carbapenem-Resistant Enterobacteriaceae rates exceeding 10% in South Asia and lower but increasing rates in Southeast Asia were also reported (Hsu et al. 2017 (Watson et al. 2019) . A review from the International Society of Infectious Diseases is available that discusses hand hygiene in LMICs. (Loftus et al. 2019) .

Agriculture provides an additional target for ASP activities at the national level. In the United States up to 70% of antimicrobials are utilized in agriculture (O'Neill 2016) . There is some evidence correlating antimicrobial resistant infections in humans to use in agriculture (Chang et al. 2015) . There are limited data on agricultural antimicrobial use in LMICs. The European Union has banned use of antimicrobials for growth promotion in animals and studies from Denmark demonstrate no adverse effects on livestock (Aarestrup et al. 2010) . By extension, the utilization 5 of antimicrobials in aquaculture may put humans at risk for antimicrobial resistant pathogens. A study published in EcoHealth examined 94 aquaculture farms in Vietnam and reported an average of 3.3 kg of antibiotics for every ton of aquatic product, most of which were on the World Health Organizations (WHO) highly or critically important antimicrobials list. 26.9% of fish bought from local markets tested positive for antimicrobial residues (Pham et al. 2015) .

Additional data are needed to contextualize agricultural use of antimicrobials in LMICs and their role in AMR.

Consumption data for animals are scarce, come from variable sources, and are often measured in per kilogram consumption due to the high proportion of in-feed utilization. National programs to monitor antimicrobial distribution in animals should be essential, but such programs have not universally been adopted (Schellack, 2017) . Some LMIC are already acting, however. China 

Part of the role of ASPs is to ensure guideline-directed empiric therapy (Geneva: World Health consumption with cost savings ranging from 12-73%. A non-significant reduction in mortality was observed; a subgroup examining therapeutic drug monitoring (6 studies) did demonstrate significant reductions in mortality with a relative risk of 0.77, although this was largely driven by 7 a single study. There was also a significant reduction in hospital-acquired infections, although this may have been confounded by infection prevention and control initiatives (Lee et al. 2018) .

In 2015, at the 68 th World Health Assembly, a global action plan to address AMR was adopted focusing on 5 major objectives ( Figure 1 ). Members of the assembly stressed the importance of developing a national action plan focusing on these objectives while adapting to local situations If the resources or government support is unavailable for the creation of a national action plan, there are alternative resources available to assist in creating country-specific antibiotic use and resistance data. The United States Center for Disease Dynamics, Economics and Policy (CDDEP) supports a program called the Global Antimicrobial Resistance Partnership (GARP) 8 (https://cddep.org/wp-content/uploads/2017/06/garp_factsheet-1.pdf), which provides tools for LMIC to collect data on nation-wide trends in antibiotic use and AMR along with supporting stewardship activities (Cox et al. 2017 Country-level support and data are highly valuable in creating hospital-level efforts. If resources are available, a gap analysis can be performed to help determine regional needs. This involves surveying local institutions for current practices related to antimicrobial stewardship. As an example, this has successfully been performed in Thailand (Apisarnthanarak et al. 2019) .

Currently, lack of access to antimicrobials may cause more deaths than antimicrobial resistant pathogens in LMICs. A 2016 report in the Lancet extrapolated data from 101 LMICs and estimated 445,000 deaths per year from pneumonia in children under 5 compared to 214,500

deaths per year from neonatal sepsis related to antibiotic resistant organisms (Laxminarayan et al. 2016) .

Essential to ASP activity is having access to appropriate antimicrobial therapy as defined in WHO essential medicines (Geneva: World Health Organization 2019). Broad spectrum antimicrobials designed to treat drug resistant organisms are not as widely available in LMICs (Laxminarayan et al. 2016) . The WHO AWaRE classifications provide a framework for categorizing key antimicrobials (Figure 2 ). Within this framework, RESERVE category antimicrobials are a key target for ASPs. Although antimicrobial access is a major issue in LMICs, AMR is also significant. Point prevalence surveys (PPS) for collecting data on AMR or use from a few sites can provide a relatively quick assessment that is less resource intensive than more broad, continuous surveillance of use and resistance. Such surveys can be used to supplement existing surveillance in high-income countries but are particularly useful for providing a "snapshot" of resistance in LMICs without the infrastructure for continuous surveillance (IACG 2018).

Methodology can be found from the WHO at: https://apps.who.int/iris/handle/10665/280063.

Reducing suboptimal global antimicrobial consumption is critical for reducing the threat of antibiotic resistance, but reduction efforts must balance access limitations in LMICs and take into account both local and global resistance patterns (Klein et al. 2018) .

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The committee will ideally include an Infectious disease physician, clinical-pharmacist, clinical microbiologist or technologist (if a microbiology lab is present) and nurses (with infection control training if possible) (Geneva: World Health Organization 2019). An expert panel from Asia also recommended the addition of an Information Technology expert (Apisarnthanarak et al. 2018 ). If some of these staff are not readily available, institutions may need to rely on antimicrobial stewardship champions. These can be physicians, pharmacists, or nurses with a special interest in antimicrobial stewardship. However, if a physician and/or pharmacist are not available to join the team, individuals should be identified from whom to seek advice when needed (Geneva:

World Health Organization 2019). The committee may also be established as a subcommittee of a pre-existing committee such as an Infection Prevention committee. In the latter instance, it is important that Antimicrobial Stewardship be a standing agenda item for reporting and discussion 

The role of the ASP committee is to optimize antimicrobial use along with promoting behavioral change in antimicrobial prescribing and dispensing. The aims of the committee should be to improve quality of care, reduce unnecessary antimicrobial exposure (with the goal of reducing the emergence of AMR) while also decreasing unnecessary health-care costs. A useful tool designed to focus priorities for the ASP team is a SWOT (Strengths, Weaknesses, Opportunities, and Threats) analysis. ASP committees can implement a SWOT analysis to help focus priorities (Figure 3 ). One role of the ASP committee should be developing a plan for data collection. Electronic collection is optimal but paper-based collection can also be utilized based on local resources.

Data collection infrastructure is also essential to infection prevention and control programs In the South African context, especially in the public sector, it is difficult to replicate resource abundant stewardship models that are mostly driven by medical microbiology teams, infectious disease (ID) specialists and epidemiologists. Consequently, it is critical in the South African context to utilize the existing resources of pharmacists, registered nurses (RNs) and other 12 members of the health care team, who are well placed to coordinate anti-infective management and improve patient outcomes.

After data are collected basic ASP interventions can be employed. The ASP committee can identify targets for interventions. Examples provided In the WHO toolkit include ensuring written indications for antimicrobial prescribing, reviewing treatments for patients prescribed three or more broad-spectrum antibiotics or surgical prophylaxis prescribed beyond 24 hours (Geneva:

World Health Organization 2019). Appropriate surgical prophylaxis has been proven to be an effective measure to prevent hospital acquired infections in LMICs and could serve as a joint goal for both ASP and infection prevention and control programs (Bardossy et al. 2016) .

Once targets are identified, guidelines can be established and providers can be educated, which are both proven effective measures to decrease inappropriate antimicrobial prescribing in LMICs (Cox et al. 2017 ).

Guidelines should be developed by the local institution to facilitate optimal antimicrobial use.

Depending on available resources these can be enhanced and expanded over time. An example would be producing a guideline on appropriate empiric antimicrobials for a condition such as urinary tract infection or pneumonia or suggested regimens for surgical prophylaxis. 

In order to measure outcomes specific goals should be set. The SMART (specific, measurable, achievable, relevant, time-bound) framework is a good method to help in setting goals (Geneva:

World Health Organization 2019). A specific timeframe should be set in order to achieve goals (e.g. before the next ASP meeting, et cetera) (Geneva: World Health Organization 2019). Goals can also be department specific. The Plan-Do-Study-Act (PDSA) framework is a useful tool for tracking progress and measuring outcomes of specific interventions (http://www.ihi.org/resources/Pages/Tools/PlanDoStudyActWorksheet.aspx). Basic measures such as antimicrobial consumption should be tracked as mentioned previously. More advanced measures can include length of stay, readmission rates, rates of AMR, mortality, et cetera (Apisarnthanarak et al. 2018) .

Although outcome measures are easily identifiable, access to data is a major barrier, particularly in LMICs. As an example, a study of 45 hospitals in Thailand reported 49% had access to antimicrobial consumption data and 64% regularly published an antibiogram (Apisarnthanarak et al. 2019 ). 

LMICs, including sub-Saharan Africa, have higher infectious disease rates than other developed countries. Additionally, there is extensive self-purchasing of antibiotics in LMICs and much of the global increase in antibiotic consumption in recent years has been in LMICs. The general public may come to expect the availability of non-prescription antibiotics, but these can pose a barrier to antimicrobial stewardship. AMR has been associated with non-prescription availability 15 of antimicrobials (Bartoloni et al. 1998; Larsson et al. 2000; Dromigny et al. 2005; Apisarnthanarak and Mundy 2008) . Poor knowledge on the optimal use of antibiotics among the public could be one of the contributing factors of misuse of antibiotics by the community in LMICs (Che Roos, Nur Aishah , Abu Bakar, Muhamad, Haque 2019).

Cost-effective measures LMICs can employ to combat AMR include public health campaigns designed to inform of the dangers of AMR and decrease unnecessary over the counter (OTC) antimicrobial use. Improved labeling for OTC medications may lead to decreased antimicrobial utilization, especially for countries in Africa where nearly all antimicrobials are obtained over the counter (O'Neill 2016) .

Prescribers in LMICs agree that AMR is a growing problem, although few acknowledge that their own practice contributes to this issue (García et al. 2011; Thriemer et al. 2013 ). Among 78 medical doctors and 106 medical students in Kisangani, Democratic Republic of Congo, more than 70% answered on a questionnaire they would prescribe antibiotics for an upper respiratory tract infection, for instance (Thriemer et al. 2013 ). Donkor and colleagues found that just under half of the students at tertiary level facilities in Ghana had poor knowledge about the suboptimal use of antibiotics (Donkor et al. 2012) . Similarly, there were concerns about the level of knowledge of antibiotics and AMR among medical students in South Africa as well as appreciable differences in the knowledge and perception of ASPs among final year pharmacy students in South Africa (Wasserman et al. 2017) . Many physicians and nurses in Ethiopia also lack knowledge about antimicrobials and AMR (Abera et al. 2014) .

A key target for closing knowledge gaps is in medical school education. There is evidence that medical students would prefer additional education on appropriate antimicrobial prescribing 16 while in medical school (Pulcini and Gyssens 2013) . The WHO Department of Health Workforce has produced a report on e-Learning that could be utilized for this purpose (World Health Organization 2015) . Direct education in the context of active patient interventions from ASPs to providers have proven to be some of the most effective education strategies (these include prospective audit and feedback along with antimicrobial restriction) (Pulcini and Gyssens 2013) .

Lack of microbiological laboratory support is a significant barrier in LMICs, and lack of laboratory diagnostic ability has been associated with increased mortality (Petti et al. 2006) . A study of 251 children in Ghana demonstrated that approximately 40% of patients presumed to have severe malaria by symptoms actually had bacteremia (Evans et al. 2004 ). LMICs often have limited access to microbiology services and testing is often deferred to avoid associated costs (Petti et al. 2006 ).

Short term solutions may include partnering with larger institutions with microbiology laboratory capabilities, while long term solutions include prioritizing expanding microbiology laboratory infrastructure via a national action plan with dedicated funding. Global programs such as Strengthening Laboratory Medicine Toward Accreditation (SLMTA) and Stepwise Laboratory Improvement Process Towards Accreditation are working to increase access to microbiology laboratories in LMICs (Nkengasong et al. 2018) . Other resources are available to aid in developing microbiology labs in LMICs (Barbé et al. 2016 (Barbé et al. , 2017 .

Encouraging optimal use of antimicrobials through antimicrobial stewardship can help best utilize these limited resources. However, a disproportionate availability of WATCH or RESERVE antimicrobials compared to ACCESS antimicrobials may pose a barrier to effective stewardship 17 in many countries (Frost et al. 2019) . One goal of the WHO is to increase utilization of ACCESS group antibiotics from the AWaRE classification to greater than 60% of all antimicrobials (Geneva: World Health Organization 2019). Essential to this goal is ensuring these ACCESS group antibiotics are available.

According to the 2011 WHO World Medicines Situation Report, 17.6% of the world's population live in low-income countries, but they account for only 1% of total pharmaceutical spending. In the same report, a seven-day course of ciprofloxacin among 20 LMICs was projected to cost more than 2 days wages in greater than 50% of the countries sampled. A cost greater than 1 day of wages is considered to be unaffordable (World Health Organization 2011). This report suggests critical antimicrobials are financially inaccessible for a large proportion of the population in LMICs. However, there is evidence that access to antimicrobials in LMICs may be increasing. Between 2000 to 2015 cephalosporin use increased by 399% in LMICs compared to an 18% decrease in high income countries (Frost et al. 2019) . Increasing optimal access to antimicrobials should be part of a country's national action plan (Geneva: World Health Organization 2019). However, key antimicrobial stewardship principles should be adopted with newly accessible antimicrobial agents in order to limit the emergence of AMR.

The optimal personnel profile of an ASP has been described above; however, major barriers to optimal personnel access exist, especially in LMICs. A 2012 global survey of 660 hospitals across 67 countries conducted by the European Society of Clinical Microbiology and Infectious Diseases revealed that only 12% of hospitals in Africa reporting the existence of an antimicrobial stewardship committee. Staff on these committees were primarily drawn from infection control personnel in Africa. Respondents from Africa and South and Central America noted the least average resource hours per week from an infectious disease-trained pharmacist 18 or infectious disease physician. Lack of personnel or funding was the most commonly cited barrier to ASP activities among all surveyed institutions at 29% (Howard et al. 2014) . In limited resource settings non-clinical pharmacists or nurses may need to play a larger role in ASPs (Brink et al. 2016) . Other countries such as Oman have had success pooling limited resources into a single national antimicrobial stewardship team (Directorate General for Disease Surveillance and Control 2018).

On January 30 th 2020 the WHO declared Coronavirus Disease 2019 (COVID-19) a public health emergency of international concern (World Health Organization 2020). As of May 16 2020, COVID-19 has affected over 4.6 million people worldwide and has caused over 310,000 deaths (The Center for Systems Science and Engineering (CSSE) at JHU 2020).

Although infection prevention programs have a defined role in outbreak management, to date ASPs have not been involved in outbreak response efforts. There is emerging literature on the role of ASPs in pandemic response efforts, specifically in the context of COVID-19 (Stevens et al. 2020 ). ASPs can help identify patients with COVID-19, develop treatment protocols utilizing novel or repurposed medications and help manage limited medication supplies through existing structures such as prospective audit and feedback or antimicrobial restriction. ASPs are likely to have a key role in future outbreak response efforts.

Antimicrobial resistance is an established and growing threat and LMICs share a disproportionate burden related to limited resources. It is vital that governments and health organizations identify action to limit antimicrobial resistance as a top priority. Antimicrobial 

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