This anonymous essay was submitted to Open Philanthropy's Cause Exploration Prizes contest and posted to the Forum with the authors' permission.

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Introduction

Antimicrobial resistance is a growing worldwide public health problem and deserves much more consideration than is currently given. If left unchecked, AMR could allow bacterial infections to be substantially more lethal. Antimicrobials are greatly used in both human and animal medicine, which can subsequently wash into the environment. Therefore, the perspective to take when analyzing the problem of antimicrobial resistance is through the lens of One Health. This is the concept of interconnectedness among human, animal, and environmental health. Both human and animal patients with bacterial infections rely on the susceptibility of bacteria to available antibiotics. The development of genetic resistance of microorganisms such as members of the Enterobacteriaceae family (e.g. E. coli or Salmonella) is particularly worrisome since they are commonly found in the environment and human and animal gut flora. Also worrying is that these microbes are developing resistance to antibiotics such as the extended-spectrum beta-lactams (ESBLs) and carbapenems, which are key antimicrobials in treating bacterial infections in humans. In addition, they can be especially pathogenic and are particularly dangerous for immunocompromised individuals. 

For such a growing problem, there has been a lack of research and development by large pharmaceutical companies to develop novel antimicrobials and tackle antimicrobial shortages. In addition, far more effort into active surveillance and microbiological testing is needed to understand the extent of the problem and which antimicrobials are safe to use for certain pathogens.

Problem

Antimicrobial resistance (AMR) is a global problem; and while it can occur naturally, the improper overuse of pharmaceutical antimicrobials has drastically increased the rate at which pathogens are developing resistance. In 2019, the global burden associated with drug-resistant infections was 4.95 million deaths, with 1.27 million being directly attributable to drug resistance¹. AMR is a leading global health issue, contributing more to the global cause of death than HIV or malaria in 2019.^[1][2] 

 Since a large part of AMR is caused by medications prescribed by medical doctors and veterinarians, AMR requires a multi-disciplinary approach involving both human and veterinary medical professionals. Large quantities of antibiotics are used within the agricultural and veterinary industries, affecting the food we eat and our environment. AMR infections last longer and are more expensive to treat.^[3] They cause longer hospital stays, longer time off work, lower quality of life, increased likelihood of death from inadequate or delayed treatment, increased insurance costs, and/or additional hospital costs from nosocomial infections.^[4] These infections also disproportionally affect young, elderly, and immunocompromised human and animal patients.^[5] Veterinarians, physicians, public health professionals, lab technicians, and other medical/veterinary workers require continuous training to help them understand AMR developmental patterns and appropriate drug usage. Human and veterinary patients are affected by AMR, and thus appropriate usage and a correct understanding of antimicrobial drugs is vital for protecting the effectiveness of antimicrobial drugs and thus the health of patients.

Importance

The Centers for Disease Control (CDC) considers extended spectrum cephalosporin resistant (ESC^T) Enterobacteriaceae (a type of resistant bacteria) as a serious health threat.^[6] One of the reasons for this is that ESCs are considered critically important antimicrobials for both human and animal medicine.^[7][8] ESC resistance is primarily caused by bacterial expression of AmpC beta-lactamases, extended spectrum beta-lactamases (ESBL), and carbapenemases.^[9] ESBL producing Enterobacteriaceae are associated with 26,000 infections, 1,700 deaths, and more than $40,000 in excess hospital charges for bloodstream infections per occurrence.^[6] Human contact with pets increases the chance of being colonized with ESBL producing E. coli by sevenfold.^[10] Due to the continual movement of people from hospitals to the community (and vice versa) and international travel, ESBL Enterobacteriaceae is a growing public health issue. Extended-spectrum beta-lactamases (ESBL) are prevalent in hospital settings, but they are also increasingly being found in the community.^[11] There is a worldwide increase in dissemination of carbapenem resistance which is a problem due to the fact that they are a last line of defense against non-Enterobacteriaceae pathogens.^[11] Adverse outcomes include animal health problems, economic concern to the owner (longer treatment times or hospital stays), economic burden to the veterinarian (hospital biosecurity), and human health problems (zoonotic transmission).^[11]

Another Enterobacteriaceae that can produce ESBLs is Salmonella - a zoonotic pathogen that can cause illness in animals and humans. Annually, nontyphoidal Salmonella is associated with 1.2 million infections, 100,000 antimicrobial resistant infections, and 300 million dollars in medical costs.⁶ Animals that are hospitalized are at a greater risk of salmonellosis due to comorbidities, stress from transport to the hospital, change in housing, and treatment (such as surgery or immunosuppressant drugs).^[12] Animals with a compromised immune system are more susceptible to getting an infection although subclinical carriers also exist. This is especially problematic for identifying Salmonella-infected animals for isolation to prevent further spread throughout a hospital. Outbreaks of salmonellosis have occurred in veterinary teaching hospitals.^[13] These outbreaks can result in zoonotic transmission (increasing the risk of morbidity among people), morbidity and mortality in patients, and increased costs from biosecurity efforts.^[14] 

Environmental burden 

Bacteria and/or genetic resistance elements can enter healthcare settings in a number of ways, including people bringing pathogens in (intestinal flora), water, air, soil that is tracked in, and food.^[15] Resistance can develop in healthcare settings where immunocompromised patients can harbor bacteria that may not survive in healthy individuals. When antibiotics are used, there are some bacteria that are resistant and fail to be affected by the drug. Over time these resistant bacteria become more common because they are less susceptible to antibiotics. 

Antibiotics degrade differently depending on the type. For example, penicillins degrade relatively quickly whereas fluoroquinolones and tetracyclines are more persistent and can accumulate in high concentrations in the environment which contributes to the natural acquisition of resistance.^[16] Therefore, understanding resistance profiles in the environment is key to understanding the best areas to focus infection control efforts. 

Surveillance for antibiotic resistant bacteria in veterinary teaching hospitals is important for understanding the risk for bacterial infections to animal care workers, veterinary staff and students, pet owners, and pets. The predominant transmission routes for resistant bacteria include person to person especially in healthcare settings, between people and animals, between environmental systems (e.g. soil, water), and between organisms and the environment (e.g. food).^[17] Bacteria present in the environment may gain resistance genes (via transformation by horizontal gene transfer) from antibiotic residues and metabolites from industry, agricultural runoff, improper antibiotic disposal, excreta from humans and animals, and household use.^[17]

The soil bacteria in the order Actinomycetales synthesize over half of most clinically important antimicrobials (including tetracycline, gentamicin, and streptomycin). The presence of these in the natural environment has promoted the evolution of specific resistance on mobile genetic elements.^[11] This provides evidence that the environment is an important reservoir of resistance. The rate of antimicrobial degradation in the environment depends on temperature, available oxygen, pH, and presence of organic and inorganic discharges.^[11] While antimicrobials are found naturally in the environment, their use in veterinary and human hospitals contributes to the development of resistant bacteria and can pose a health risk to immunocompromised patients found in a hospital setting. Animals or humans taking immunosuppressive drugs are less able to fight off a bacterial infection and rely on antibiotics to bolster their defenses. AMR is a threat to human and animal health. 

AMR in East and South Africa

AMR is a global issue due to its worldwide health, economic, and societal consequences. Infections from drug resistant microbes result in longer recovery times, higher mortality rates, and increased costs due to the need for multi-drug regimens and/or alternative treatments. Many less affluent countries, especially those in the tropics, demonstrate proportionately higher rates of illness and death from communicable diseases. The inability of some governments to provide basic services such as clean water, sewage treatment, and health care along with the presence of disease vectors carrying an assortment of infectious microbes often lead to widespread infectious outbreaks. The poorly supervised and overuse of antibiotics can then contribute to the development of AMR strains. 

In agropastoral households in Eastern Africa, people depend on livestock for their livelihood and food source, but AMR can limit the types of treatment available for livestock and humans (zoonotic diseases). Additionally, AMR often increases the cost of treatment for the herd owners in the long term. Communal grazing and prior illness are positively associated with an increased probability of having antimicrobials available for livestock possibly increasing the chance of misuse or overuse.^[18] Antimicrobial use that reduces the intensity and duration of pathogen shedding can lower pathogen transmission to other herds, but also leads to a larger proportion of pathogen populations being resistant to antimicrobials.^[18] It is important to balance antimicrobial use in livestock with other methods to protect people’s livelihoods by limiting the spread of antimicrobial resistance. 

In African countries, AMR in gram-positive isolates or isolates implicated in respiratory tract infections, meningitis, urinary tract infections, or nosocomial infections showed a high prevalence of chloramphenicol, trimethoprim/sulphamethoxazole, and tetracycline resistance.^[19] These data show that, in spite of limited surveillance information, restricted laboratory capacity for monitoring, limited quality-assured information, biases from hospital-based and urban settings compared to community-based settings, and more isolates from febrile patients, the African region has a large AMR burden.^[19] Clearly, more research should be done to elucidate the nature and extent of AMR in Eastern and Southern Africa. Only two countries (4.3%) out of the WHO African region were found to have national AMR plans in place and seven (14.9%) had national infection prevention control policies in place.^[20] While over 90% of these African countries had essential medicines lists and national medicines policies and treatment guidelines, no countries were found to have a national surveillance system that routinely generates representative data on antimicrobial use and resistance.^[20] However, South Africa has a national laboratory-based surveillance program for some bacterial and fungal pathogens. In addition, Africa does have an international network designed to compare pulse-field gel electrophoresis (PFGE) profiles across countries, although the presence of mobile elements do not necessarily indicate genetic relatedness.^[20][21]

Neglectedness

AMR within the human and veterinary medicine professions remains a growing problem despite some efforts to initiate surveillance and educational programs. Data collection on AMR in the U.S. is not harmonized, and this presents challenges in understanding resistance dissemination methods and trends between humans, animals, and the environment. Currently, passive surveillance is used for tracking and reporting of AMR on a national level.^[22] We know that resistant bacteria can be transferred from animals to humans through the food chain, through direct or indirect contact (livestock workers, animal health workers, or contact with wildlife), and through contaminated environments from the spread of agriculture or aquaculture manure. However, there is lack of active surveillance to understand the full extent of the problem and the emergence of resistance elements or interactions among microorganisms.

AMR remains a large problem globally and can lead to adverse health outcomes especially within East and South Africa with proportionately higher rates of illness and death from communicable diseases. One recent study found that within the global burden of bacterial resistance, the all-age death rate attributed to AMR was highest in western sub-Saharan Africa¹. Current data gaps remain among low-income settings partially due to a need for more data collection and laboratory capacity. 

There is a lack of development of new antimicrobial drugs in part because of the time -consuming path to drug approval, high cost, and low success rate²³. According to Dr. Haileyesus Getahun, WHO Director of AMR Global Coordination, “time is running out to get ahead of [AMR], the pace and success of innovation is far below what we need to secure the gains of modern medicine against age-old but devastating conditions like neonatal sepsis.”^[23] 

Current initiatives into the development of vastly different antimicrobials are mostly present at research or educational institutions, where progress can be slower and at a much smaller scale than larger well-funded private companies. In addition to the need for developing new antimicrobials to fight resistance, there are shortages of existing antimicrobials locally and globally, particularly in low-income and middle-income countries (LMICs). Several reasons for this include fragmented supply chain issues, issues of policy and regulatory processes, and more specifically, unavailable or inefficient forecasting systems.^[24] Poorly functioning forecasting systems contribute to disrupted supply chain issues, which also affect strategic partnerships and alliances that depend on the availability of raw materials to make the drugs.^[24] Exiting organizations like the WHO’s Global Antimicrobial Resistance Surveillance System (GLASS) and the World Organization for Animal Health (OIE) AMR surveillance network are important for providing frameworks and examples to increase the capacity of surveillance among private organizations.^[24] There is a real need to build more robust forecasting systems where antimicrobials are used.  

Solutions

Since both the pathogens and the drugs used to combat them are the same or similar for humans and animals, a comprehensive plan to monitor AMR in veterinarian clinics and hospitals is of great importance. Failure to properly monitor AMR and to develop procedures to mitigate the loss of antibiotic effectiveness can have dire consequences for public health and safety. Bacterial pathogens have been shown to survive long periods of time on contact surfaces in healthcare environments.^[25] In addition, the level of contamination on surfaces has been shown to exceed the number of bacteria required for transmission.²⁶ Subsequent occupants of a room previously occupied by an infected individual have an increased risk for acquiring an infection by the same pathogen which indicates that cross contamination is increasing the risk for infection.^[26] 

An antimicrobial stewardship program is an example of a mitigation strategy for antimicrobial resistance. Antimicrobial stewardship may be defined as “a coherent set of actions which promote using antimicrobials responsibly.”^[27] An alternate definition could be “a coherent set of actions which promote using antimicrobials in ways that ensure sustainable access to effective therapy for all who need them.”^[27] Antimicrobial stewardship is recognized as an important component in hospitals to prevent the overuse of resources and contribute to the control of increasing antimicrobial resistance.^[28] Antimicrobial stewardship programs increasingly include concepts of responsibility in addition to technical definitions (drug, dose, duration) that focus on good clinical practice.^[27]

Antimicrobial stewardship promotes appropriate antimicrobial (e.g. antibiotic) use in a coordinated manner to improve patient outcomes and reduce pathogen resistance. While there are antimicrobial stewardship programs in many human hospitals, there are no comprehensive programs in place in large veterinary hospitals. That having been said, there is evidence that antibiotics are still being overprescribed in human medicine and continual surveillance is needed even in hospitals with established stewardship programs.^[29] It is interesting that there is little infrastructure to support antimicrobial stewardship programs in veterinary practices even though surveys show that small animal veterinarians are increasingly concerned about AMR.^[30] 

The U.S. does not have a system to track antibiotics prescribed for companion animals. While some veterinary teaching hospitals utilize an antimicrobial policy and oversight group, there is no system to communicate general knowledge or lessons learned to community veterinarians. Antimicrobial stewardship programs can also be a part of infection control strategies through monitoring resistance trends and outbreaks in the facility, promoting hand hygiene compliance, establishing contact and transmission precautions, and promoting educational efforts.^[31] Since extended-spectrum beta-lactamases (ESBL) resistance is primarily spread through community-based and long-term care facilities, more efforts may need to be taken to control resistance outside of large healthcare facilities.^[32]

New and improved monitoring tools have become available in the last few years that have allowed for more efficient surveillance. New technologies include: Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) which can be used in stewardship programs as a cost-effective way to characterize bacterial isolates and has been associated with reduced length of stay and hospital costs.^[31][33] Multiplex polymerase chain reaction (MPCR) can also be used to detect multiple organisms and resistance markers.^[31] The use of MALDI-TOF MS, MPCR, and other sampling technologies can provide inexpensive and rapid evaluations of the presence of AMR infectious agents. 

To address these solutions, I would propose funding through grants to be directed at local organizations to use publicly available resources and frameworks from the WHO and OIE AMR programs to set up surveillance and monitoring of resistant pathogens in various health care and agricultural settings globally, but most importantly in lower income areas such as East or South Africa. Effort should be taken to work with local governments to set up sustainable surveillance programs. Microbiology labs could be set up in rural locations to do simple testing for environmental and agricultural samples. Data could then be shared across the nation and published globally to track AMR spread and development. Data collection and sharing is essential for budgetary planning and tracking infectious disease epidemiology and AMR. In addition, enhancing forecasting and preparedness systems for antimicrobials and investing in surveillance is critical.^[24] My proposed solution to start reducing AMR by setting up surveillance programs within human and veterinary healthcare is feasible and cost-effective because it is a public health approach that emphasizes prevention over downstream treatment of disease. Antimicrobials are used in both humans and animals, so any approach to AMR must include the consideration of these two groups. Developing collaborations and commitments of local governments may take time, but providing resources and training and encouraging sustainable programs that involve the community will last a longer time than transient medical care that does not address the problem. Knowledge of how AMR is spreading, which drugs are available and used, and the epidemiology of infections are all insights gained from active surveillance. This kind of knowledge is invaluable for determining responsible and safe use of antimicrobials to limit resistance and deserves much more investment than is currently given. 

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