October 2021 - Part 1 in the series: Resisting Resistance - Volumes

Resisting Resistance

In biological terms, resistance can be defined as the natural ability of an organism to withstand a damaging agent or adverse condition. Animals, plants, and microbes have all demonstrated the ability to develop resistance, with either positive or negative outcomes, depending on the interaction.

On the positive side, living organisms may develop resistance or immunity to harmful pathogens or various forms of abiotic stress. These types of resistance translate into natural benefits. Unfortunately, the same adaptability exists within damaging pests, including organisms that transmit disease pathogens, and/or the pathogens themselves. The resulting potential for negative impacts on public health and/or society are a growing concern, as resistance management is a formidable problem that exists in in health care, agriculture, and the management of vector-borne disease.

Our dependency on each of these sectors for societal well-being puts the concept of resistance into clear context. Who does resistance affect? Resistance knows no geographical boundaries. Resistance impacts all levels of socioeconomic status, and is not limited by age or gender. Simply put, resistance affects everyone.

Resisting Resistance Series

In this four-part series, Public Health Landscape will examine the dynamics of resistance and its pressing impact on Public Health. Beginning with a broad overview of resistance across sectors, we will explore resistance in arthropods, resistance management strategies within Integrated Vector Management, and ultimately resistance mechanisms in vector-borne disease.

The Resistance Challenge in Healthcare

Antimicrobial resistance (AMR, or antibiotic resistance) in healthcare has been identified by the World Health Organization as one of the major public health threats of the 21st century. AMR occurs when microorganisms develop resistance to therapeutic drugs either through mutations in DNA of the target cells or through gene transfer from one resistant microbe to another. Because of AMR, important drug treatments can be rendered less, or even wholly, ineffective.

Antibiotics mitigate the risk of infection, and as such are a fundamental pillar of modern medicine. Infection is a major threat related to a wide variety of health care practices including surgery, organ transplants, dialysis, treatment of burn victims, and chemotherapy. In the short interval between 1944 and 1972, human life expectancy increased by eight years, an effect attributed largely to the advent of antibiotics.1

Penicillin, the most celebrated of these drugs, was discovered in 1928, and provides a sobering example of nature’s ability to adapt through resistance. After more than a decade of research following Alexander Fleming’s discovery, large-scale trials of penicillin were finally launched in 1940. Mass production and distribution of the drug were achieved by 1945. By that time, however, several strains of Staphylococcus aureus (staph) had already developed resistance from penicillin’s use in the clinical trials. Resistance to penicillin by four strains of staph were already documented by 1942.2

Herein lies the primary challenge behind the onset of resistance in health care and beyond. Once effective chemical interventions are developed and introduced to combat pests or pathogens, need often dictates that these solutions are used widely and used often. Consciously or unconsciously, use often leads to overuse, and in turn creates tremendous selection pressure in the population of the target organism. Naturally resistant individuals survive and carry forward gene mutations, which increase the relative proportion of resistant individuals over time. In other words, resistance is an inevitability that cannot be avoided, but can only be slowed by discerning management.

The Centers for Disease Control and Prevention (CDC) estimates that in the US, 2.8 million people per year are affected by antimicrobial infections, resulting in 35,000 deaths and a $20 billion/year impact on healthcare costs. Dynamics at the cellular level are not the only factor at play in countermanding this problem.

Economics play a critical role in the resistance problem, not only in terms of societal impact but also in product development. Between 1940 and 1962, more than 20 different classes of antimicrobials were developed. Only two new classes have been developed since, with no classes of antimicrobials developed since 1987.3,4

Why the lack of new drugs? It is estimated that the failure rate of new compounds in antibiotic development approaches 95%, with development of a single molecule costing hundreds of millions of dollars.5  Even if a new drug makes it to market, its potential for profitability is severely challenged. Despite the virulent nature of resistant microbial strains, the proportion of infections from resistant strains remains relatively low. That means that existing therapies still work well in the vast majority of cases. As a result, it proves difficult for a manufacturer to recoup the sizeable investment needed to bring a new drug to market when unit sales will be sparse, and the duration of therapy, short. Far more attractive to product developers are drugs that can be used to treat chronic conditions, creating the potential for long-term use and profits.

This played out recently when a company named Achaogen filed for bankruptcy in 2019, less than a year after the US Food and Drug Administration approved its new molecule, plazomicin. Plazomicin was targeted for treatment of urinary track infections caused by antibiotic resistant Enterobacteriaceae. Despite the fact that the company had raised nearly $500 million to develop the product, sales were insufficient to keep the company afloat.

Bacteria and Fungi Listed in the CDC 2019 Antimicrobial Resistance (AR) Threats Report

A 2019 Centers for Disease Control (CDC) study lists 18 different antibiotic-resistant bacteria and fungi, with levels of resistance ranging from urgent to concerning.

Urgent Threats Serious Threats Concerning Threats
Carbapenem-resistant Acinetobacter Drug-resistant Campylobacter Erythromycin-Resistant Group A Streptococcus
Candida auris Drug-resistant Candida Clindamycin-resistant Group B Streptococcus
Clostridioides difficile ESBL-producing Enterobacterales
Carbapenem-resistant Enterobacterales Vancomycin-resistant Enterococci (VRE)
Drug-resistant Neisseria gonorrhoeae Multidrug-resistant Pseudomonas aeruginosa
Drug-resistant nontyphoidal Salmonella
Drug-resistant Salmonella serotype Typhi
Drug-resistant i
Methicillin-resistant Staphylococcus aureus (MRSA)
Drug-resistant Streptococcus pneumoniae
Drug-resistant Tuberculosis

Public and Private Partnerships (PPP) may hold the answer. In the public sector, the Joint Programming Initiative on Antimicrobial Resistance (JPIAMR) was created in 2011 to coordinate national and transnational public investments and funds for research, with the goal of curbing antimicrobial resistance on a global scale. With the support of the European Commission, JPIAMR brings together 28 nations and provides a funding platform in a collaborative attempt to prioritize public research to combat AMR.

In the private sector, the Davos Declaration on Antibiotic Resistance was signed by more than 80 companies at the World Economic Forum in Davos, Switzerland in January, 2016. The Declaration called for focused collaboration between industry and governments, and has since spawned the AMR Alliance – an organization of more than 100 members that includes biotech, diagnostics, generics, and research-based pharmaceutical companies and associations such as Merck, Pfizer, Johnson and Johnson, Novartis, and others. The Alliance is exploring a new approach that creates a guaranteed revenue stream for manufacturers, based on a subscription model. These regional access programs would decouple the amount of revenue a manufacturer earns from the actual volume of drugs sold, giving public health entities access to new drugs while encouraging pharma companies to develop new solutions.

Resistance in Agriculture

In the agricultural sector, resistance relates not to human illness but rather its impact on our food supply. With the United Nations forecasting global population will reach nearly 10 billion by the year 2050, our ability to increase agricultural productivity is paramount.

Pests in agriculture include weeds, bacterial and fungal diseases, and insects, among others. Resistance is a challenge in all of these areas. The first case of insecticide resistance was documented in 1914, with a further 11 cases confirmed by 1946.6 The Insecticide Resistance Action Committee estimates that today, more than 600 different species of arthropods pests have developed some level of insecticide resistance.

Arthropod resistance adds another layer of variables beyond the genetics of the target and the rates and frequency of pesticide applications. The rate at which the species reproduces (number of generations per season), its ability to migrate, its habitat, and its ability for behavioral adaptation all play a role. Developed over the past several decades, integrated pest management (IPM) strategies leverage these additional factors by offering farmers alternative means to control pests within a defined production system. In addition to simply rotating insecticide classes, growers may introduce biological controls, use cultural means to modify the field environment, introduce refuge crops to lure damaging pests away, or even use plant varieties that have been bred or engineered to express resistant qualities.

Nevertheless, success of these integrated strategies comes down to proper implementation, and many would say agriculture has a track record for wearing products out. Since pests are ubiquitous and food and fiber are grown all around the world, crop protection companies have significant financial incentive to bring effective new compounds to market. But the efficacy of new tools can be quickly challenged when not managed properly.

A recent example is the diamide class of insecticides, introduced in 2006. Diamides had a novel mode of action, had strong activity against some of the most important lepidopteran and coleopteran pests, were easy to use, and exhibited a highly favorable safety profile for non-target organisms. By 2013, diamide sales had skyrocketed to $1.2 billion, which accounted for approximately 8% of global insecticide sales.7 Along with all of their favorable characteristics, however, diamides were subject to overuse. Diamide resistance appeared within a few years and now threatens the long-term viability of one of agriculture’s most important insecticide classes. According to the Arthropod Pesticide Resistance Database, today, at least 10 pest species have documented cases of diamide resistance.

Top 20 Resistant Arthropods in Agricultural and Urban Ecosystems

Of the top 20 Resistant Arthropods in the Arthropod Pesticide Resistance Database (APRD), managed by IRAC and Michigan State University, five of the insect species listed are classified as urban pests (see table). All five of these pests pose significant threats as disease vectors in the sphere of public health.

Rank Common Name Scientific Name Number* Ecosystem
1 Two-spotted spider mite Tetranychus urticae 80 Agricultural
2 Diamondback moth Plutella xylostella 76 Agricultural
3 Green peach aphid Myzus persicae 68 Agricultural
4 Colorado potato beetle Leptinotarsa decemlineata 48 Agricultural
5 House fly Musca domestica 44 Urban
6 Southern cattle tick Boophilus microplus 43 Agricultural
7 German cockroach Blatella germanica 42 Urban
8 Whitefly Bemisia tabaci 39 Agricultural
9 European red mite Panonychus ulmi 38 Agricultural
10 Cotton/Melon aphid Aphis gossypii 37 Agricultural
11 Mosquito Culex pipiens pipiens 34 Urban
12 Hop aphid Phorodon humuli 34 Agricultural
13 Corn Earworm Helicoverpa armigera 33 Agricultural
14 Tobacco budworm Heliothis virescens 33 Agricultural
15 Mosquito Culex quinquefasciatus 31 Urban
16 Cotton leafworm Spodopotera littoralis 30 Agricultural
17 Red flour beetle Tribolium castaneum 30 Agricultural
18 Sheep blowfly Lucilia cuprina 25 Agricultural
19 Bulb mite Rhizoglyphus robini 22 Agricultural
20 Malaria Mosquito Anopheles albimanus 21 Urban

*Number of active ingredients to which the pest has exhibited documented resistance.
Source: Arthropod Resistance Database

Resistance in Vector-borne Disease Management

Arthropod resistance challenges in vector-borne disease management include commonalities and differences with challenges in health care and agriculture. Economics form the basis of the most glaring dissimilarity.

In agriculture, IPM strategy is geared at maintaining pest populations below the “economic threshold.” This means farmers are encouraged to treat for pests only when populations rise such that if left unabated, the amount of damage the crop would incur would exceed the cost of treatment. This affords growers and agronomists a relatively simple equation for application decisions based on return on investment (ROI). No such leeway exists in the sphere of public health.

That is not to say economics do not play a critical role in public health – the opposite is true – but the value of a single life, or the value of maintaining health and well-being, is not so easily calculated. This abstract difference makes resistance in vector-borne disease management and health care even more complicated to contend with.

Tracking disease mortality rate, for example, is a relatively straightforward (albeit laborious) process. In terms of malaria, one might consider malaria deaths, year-on-year, when gauging the impact of cumulative interventions. Perhaps more challenging is quantifying the impact of illness that does not result in death. In the case of debilitating disease, economists focused on public health use theoretical models for this purpose. One such metric is the disability-adjusted life year, or DALY.

One DALY represents the loss of the equivalent of one year of full health, and can be considered the sum of two other important metrics: years of life lost to death (YLLs) + years of health life lost to disability (YLDs). DALYs are used as a sort of common denominator to compare the burden of diseases that cause death with diseases that cause disability, but do not cause death. DALYs, YLLs, and YLDs are all important data points used in evaluating, assessing, and projecting the assignment of resources within public health programs.

A second critical difference between the resistance challenge in public health and agriculture is the relative size of the toolbox. This challenge is predicated on the fact that, unlike agriculture, insects that vector disease cohabitate in the same environment with human beings.

Labeled insecticide applications in agriculture must include re-entry intervals (or restricted entry intervals, REIs) – the minimum amount of time, post-application, before people can return to the area without protective clothing and equipment. REIs can be hours, days, or weeks long. Conversely, insecticide applications for public health take place directly into areas where people live and work. With some exceptions, people are present and remain in the areas being treated. It follows that control agents have to be tough on insects while at the same time being safe for humans, pets, wildlife, and other non-targets. This requirement dramatically limits the range of compounds that can be used in vector management applications.

In fact, available mosquito adulticide space sprays in the US are limited to just two chemical classes: pyrethroids and organophosphates (OPs). Market estimates indicate pyrethroids account for about 65% of adulticide sales and OPs about 35% (+/- 5%). The dominant share of the former is indicative of pyrethroids’ excellent safety profile and low human toxicity – the same qualities that make them an important part of insect control programs in agriculture and home and garden use.

Public Health Statistic Acronyms

DALYDisability Adjusted Life Years. One DALY represents the loss of the equivalent of one year of full health. DALYs for a disease or health condition are the sum of the years of life lost to due to premature mortality (YLLs) and the years lived with a disability (YLDs) due to prevalent cases of the disease or health condition in a population.

YLLYears of Life Lost. YLLs are calculated from the number of deaths multiplied by a global standard life expectancy at the age at which death occurs. YLLS are expressed in per 100,000 population.

YLDYears of Health Life Lost to Disability. YLDs are calculated as the prevalence of each non-fatal condition multiplied by its disability weight.

Source: World Health Organization

The unrelenting need to manage disease vectors combined with a limited number of tools, tools which are used widely in other sectors, can only lead to one outcome: overuse and increased selection pressure. Resistance.

In our next installment, we will dive deeper into insecticide resistance in arthropods, and the broader implications for vector-borne disease management.

References:

  1. https://www.abc.net.au/science/slab/antibiotics/history.htm
  2. Lobanovska, M., & Pilla, G. (2017). Penicillin’s Discovery and Antibiotic Resistance: Lessons for the Future?. The Yale journal of biology and medicine90(1), 135–145.
  3. Coates, Anthony R M et al. “Novel classes of antibiotics or more of the same?.” British journal of pharmacologyvol. 163,1 (2011): 184-94. doi:10.1111/j.1476-5381.2011.01250.x
  4. https://www.treatsystems.com/TheChallenge/select/HistoryOfResistance
  5. Årdal, C., Balasegaram, M., Laxminarayan, R. et al.Antibiotic development — economic, regulatory and societal challenges. Nat Rev Microbiol18, 267–274 (2020). https://doi.org/10.1038/s41579-019-0293-3
  6. https://nifa.usda.gov/sites/default/files/resources/Insecticide%20resistance.pdf
  7. Nauen R., Steinbach D. (2016) Resistance to Diamide Insecticides in Lepidopteran Pests. In: Horowitz A., Ishaaya I. (eds) Advances in Insect Control and Resistance Management. Springer, Cham. https://doi.org/10.1007/978-3-319-31800-4_12