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Review

Antimicrobial Resistance: Implications and Costs

Pages 3903-3910 | Published online: 20 Dec 2019

Abstract

Antimicrobial resistance (AMR) has developed as one of the major urgent threats to public health causing serious issues to successful prevention and treatment of persistent diseases. In spite of different actions taken in recent decades to tackle this issue, the trends of global AMR demonstrate no signs of slowing down. Misusing and overusing different antibacterial agents in the health care setting as well as in the agricultural industry are considered the major reasons behind the emergence of antimicrobial resistance. In addition, the spontaneous evolution, mutation of bacteria, and passing the resistant genes through horizontal gene transfer are significant contributors to antimicrobial resistance. Many studies have demonstrated the disastrous financial consequences of AMR including extremely high healthcare costs due to an increase in hospital admissions and drug usage. The literature review, which included articles published after the year 2012, was performed using Scopus, PubMed and Google Scholar with the utilization of keyword searches. Results indicated that the multifactorial threat of antimicrobial resistance has resulted in different complex issues affecting countries across the globe. These impacts found in the sources are categorized into three different levels: patient, healthcare, and economic. Although gaps in knowledge about AMR and areas for improvement are obvious, there is not any clearly understood progress to put an end to the persistent trends of antimicrobial resistance.

Background

Antimicrobial Resistance (AMR) occurs when microorganisms including bacteria, viruses, fungi, and parasites become able to adapt and grow in the presence of medications that once impacted them.Citation1,Citation2 AMR is considered a significant threat to the public health systems not just in developing countries but throughout the world.Citation1,Citation3 The fact that infectious diseases can no longer be treated with antibiotics depicts an unknown future in health care.Citation4 Infection with AMR leads to serious illnesses and prolonged hospital admissions, increases in healthcare costs, higher costs in second-line drugs, and treatment failures.Citation3,Citation5,Citation6 For instance, just in Europe, it has been estimated that antimicrobial resistance has been correlated with more than nine billion euros per year.Citation3,Citation7 Furthermore, according to the Centers for Disease Control and Prevention (CDC), antimicrobial resistance adds a 20 billion dollar surplus in direct healthcare costs in the United States, which is exclusive of about 35 billion dollars in loss of productivity annually.Citation8

The daunting threat of antimicrobial resistance is of particular importance in the category of antibiotic resistance in bacteria.Citation3 According to the CDC, more than two million people in the United States become ill with antibiotic-resistant diseases every year, resulting in a minimum of 23,000 deaths.Citation8 Antibiotic resistance compromises a human immune system’s capacity to fight infectious diseases and also contributes to different complications in vulnerable patients undergoing chemotherapy, dialysis, surgery, and joint replacement.Citation8 Furthermore, people with chronic conditions like diabetes, asthma, and rheumatoid arthritis will be heavily impacted by antibiotic resistance.Citation2 Since the effectiveness of antibiotics will be reduced due to persistence in trends of AMR, physicians should use last-resort classes of medicine such as carbapenems and polymyxins, which are not necessarily readily available in developing countries, have a high cost, and have many different side-effects.Citation9

One of the most well-known cases of AMR, Methicillin resistance in Staphylococcus aureus (MRSA), has been associated with high mortality rates every year across the globe.Citation1 In addition, multi-drug resistant gram-negative bacteria (MDR-GNB) has made the treatment of different infections like pneumonia and urinary tract infections more challenging.Citation10Citation12 Furthermore, drug resistance to tuberculosis, gonorrhea, and typhoid fever are increasing every year and substantially contribute to the high costs of individuals’ health as well as the health care systems around the world, particularly in developing countries.Citation7 Currently, 4.1% of new tuberculosis cases are considered to be multi-drug resistant.Citation13 In countries like India, the Philippines, Russia, and South Africa, which have always had a high number of TB cases compared to other parts of the world, multi-drug resistant TB is anticipated to escalate significantly by 2040.Citation14

Factors Accelerating the Rate of AMR

Misuse and Overuse of Antibiotics

From early days of discovery of antibiotics in the 1940s, Sir Alexander Fleming warned the public about the high demand for antibiotics in the future which could lead to their overuse.Citation15Citation17 Different surveys across the globe indicate that many patients firmly believe antibacterial agents would help with viral diseases like the common cold or flu.Citation9 Furthermore, in many developing countries where there are deficiencies in proper diagnostic tools, patient management is predominantly contingent upon the prescription of medicine, particularly antibiotics.Citation18 Administering antibiotics when they are actually not needed for the treatment is another example of common misuse of them.Citation4,Citation18 Moreover, many antibiotics are of poor quality and sold over the counter in the developing countries.Citation4 For instance, in India and Vietnam, where there is insufficient enforcement of regulatory policies on prescribing medicine, over-the-counter antibiotics are prevalent.Citation4,Citation19 Such availability makes it accessible for patients to do self-treatment for diseases that do not necessarily need antibiotics for treatment.Citation4,Citation15

Moreover, antibacterial resistance can develop because physicians unnecessarily prescribe lengthy courses of antibiotics.Citation20 Financial incentives play an important factor in overprescribing antibiotics. For example, Chinese hospitals incentivize physicians to prescribe antibiotics; as a result, they will receive more money from pharmaceutical companies.Citation21,Citation22 Another factor contributing to overprescribing antibiotics by providers is patients’ expectations from them.Citation23 Studies have implicated that clinicians consider the perceived patient request for antibiotics as one of the major barriers to adhere to standard guidelines for antibiotic prescriptions.Citation23,Citation24 Providers try to avoid the dissatisfaction of their patients by meeting their demand for prescribing antibiotics.Citation23

Agricultural Use of Antibiotics

Agricultural use of antibiotics is another prominent contributor to the antimicrobial resistance in humans.Citation25,Citation26 For instance, just in the United States, approximately 80% of the antibiotics sold are applied to food that animals eat.Citation27 In 2010, 63,200 tons of antibiotics were used in livestock production worldwide which is significantly more than human consumption.Citation28 In addition to the utilization of antibiotics to treat sick animals, antibiotics are largely added to healthy animal feed and drinking water in order to prevent sickness (prophylaxis) among animals to a large extent, to further grow herds at subtherapeutic levels, and to elevate feed efficiency.Citation9,Citation27,Citation29,Citation30 For instance, one of the widely used antibiotics in animal farming worldwide to further promote the growth of livestock, particularly pigs, is colistin, a critical last-line antibiotic to treat severe infections in humans.Citation31Citation33

Increase in Income Levels

According to Klein et al, between 2000 and 2015, global antibiotic use elevated by 65%.Citation34 This significant rise in global antibiotic use is predominantly because of overconsumption of antibiotics in developing countries which is the direct result of rising incomes.Citation18,Citation34 In other words, the rise in Growth Domestic Product (GDP) as well as living standards in low and middle-income countries (LMICs) have shown to be positively correlated with antibiotic consumption.Citation34,Citation35 Moreover, an increase in income levels in developing countries has led to an increase in animal protein consumption which may require more antibiotics to be added to the food animals eat.Citation36

There has been a stark change in the pattern of antibacterial consumption across the globe within the past decade.Citation34,Citation37 In 2000, the highest antibiotic consumption rate was in the United States, France, Spain, New Zealand, and Hong Kong; however, in 2015, four of the countries with the highest rate of antibiotic consumption were low-middle income countries such as Turkey, Tunisia, Algeria, and Romania.Citation34 Rate of antibiotics in LMICs is still lower than the rate in high-income countries, due to continuous increase in income level and living standards; however, it is highly likely that in a few years this rate might eventually converge or even surpass the antibiotic consumption rate in developed countries.Citation34,Citation35

Easy Travel Routes

Studies have suggested that the modern and easy traveling routes for people, animals, and goods have also substantially contributed to the dissemination of antimicrobial resistance across the globe.Citation2,Citation38 By being exposed to resistant pathogens, human travelers are highly likely to return colonized and infected to their country.Citation39 For instance, Ruppe et al have shown that European tourists traveling to India who had absolutely no contact with the Indian health care system still tested positive for carbapenemase-producing Enterobacteriaceae (CPE) after they came back from their trip.Citation40

Biological Factors

Antibiotic resistance may happen spontaneously through mutation and bacterial evolution.Citation41 Furthermore, plasmids, small circular fragments of DNA in bacteria, can obtain a great variety of resistance genes through transposons and insertion sequences.Citation42Citation44 These plasmids can be transferred to bacteria from other species and spread the antibacterial resistance in the bacterial population.Citation45 In addition, exchanging resistance genetic factors between bacteria through horizontal gene transfer further accelerates the spread of antibiotic resistance.Citation25,Citation45,Citation46

Gaps in Knowledge

The numerous gaps in knowledge about antibiotic resistance contribute to the continuing trends of AMR since the statistics and particulars about the use of different antibiotics in both the health care setting and in animal production are not systematically gathered worldwide.Citation26,Citation47 For instance, currently, just 42 countries in the world systematically gather data regarding the use of antibiotics in livestock.Citation26 High-quality global surveillance systems are critical for determining and providing warning bells of problems associated with changes in antimicrobial exposure.Citation47 They also help with observing the efficacy of the interventions implemented to standardize the usage of antibacterial agents in order to address the issue of AMR.Citation48 Thus, the existing gap in knowledge about antibiotic usage worldwide highlights the great importance of a successful approach in engaging cooperative efforts among different international sectors such as human and veterinary medicine, agriculture, animal production, and of course, informed consumers.Citation9 Furthermore, there is a gap in awareness of people regarding the proper use and the potential hazard of antibiotics.Citation49,Citation50 For instance, results of national questionnaires in different developed and developing countries, including Japan, Australia, the United States, Sri Lanka, and Gulf Cooperation Council countries demonstrate that most people generally have limited knowledge about the correct use of antibiotics.Citation50Citation53

Methods

Search Strategy

With a thorough literature review, crucial information was compiled, assessed, and used to understand the implications and costs of AMR across the globe. Google, Google Scholar, PubMed, Microsoft Academic, Scopus, Medline, Global Health, and searches within the CDC, WHO, and comparable health organizations and websites were utilized to obtain information. The review solely included published articles written in English. Search terms including “AMR and cost,” “Antimicrobial resistance implications” and “AMR and disease burden” were utilized in order to gather information. Moreover, searches within these databases concentrated on literature that dates back no further than 2012.

The search yielded 200 articles. The titles and abstracts of these articles were reviewed in order to screen for publications that addressed the drivers of AMR and different implications and cost of AMR. After removing the duplicates and opinion articles, 78 articles were identified as relevant and met the inclusion criteria for this critical analysis project. The study flow diagram is illustrated in .

Figure 1 A flow diagram of articles included in the review.

Figure 1 A flow diagram of articles included in the review.

Findings

The literature review findings demonstrates that the cost of AMR can be categorized into three different levels: Patient level, Healthcare level, and Economic level.Citation6

Patient Perspective

Morbidity and mortality are important consequences of AMR affecting patients.Citation1,Citation6 Compared to non-resistant forms, resistant bacteria will double the chances of developing a serious health issue and triple the chances of death.Citation54 Of course, these negative outcomes will be more pronounced with elevation of the severity of the resistant infections and the susceptibility of the host.Citation55 shows the comparison between mortality rates due to AMR and major causes of mortality worldwide by 2050. Currently, across the globe, approximately 700,000 individuals lose their lives because of the drug-resistant infections each year.Citation56 indicates the mortality rates due to AMR by 2050 in different regions of the world. In the United States, 2 million people are affected every year by AMR and about 23,000 deaths occur as a result.Citation57 This number is roughly the same as the European Union which has an annual mortality rate of 25,000.Citation5,Citation58 Despite the difficulty of obtaining precise mortality rates, official reports have estimated that about 10 million people will die across the world by 2050 if strong and effective action against AMR is not taken.Citation4,Citation59

Table 1 Mortality Rates by 2050 by ConditionCitation66

Table 2 Mortality Rates by 2050 Due to AMR in Different RegionsCitation66

Antimicrobial resistance also sabotages decades of global fights against many infectious diseases like tuberculosis, HIV, and malaria.Citation56 The number of HIV cases resistant to medicine are on the rise, particularly in Sub-Saharan Africa where 60% of patients with HIV have developed resistance to HIV medicine.Citation60,Citation61 Unsurprisingly, patients with resistance to HIV drugs have a higher risk of dying from HIV.Citation62 According to the HIV drug resistance report in 2017, such continuous trends in resistance to HIV medicine threaten the global goal of putting an end to AIDS by 2030.Citation63 In addition to tuberculosis and HIV, in the past 50 years, Plasmodium falciparum, the causative agent of malaria, has become resistant to anti-malarial medicines and this trend is predominantly seen in southeast Asia.Citation64 The increase in resistance to malaria drugs obstructs malaria control which attempts to decrease the average 445,000 deaths that take place annually due to this deadly disease.Citation65

Healthcare Perspective

AMR has disastrous impacts on healthcare costs.Citation6 According to the CDC, in the United States alone, antibiotic resistance could add about $1,400 to the hospital bill for treating patients with any bacterial infections.Citation8,Citation67 This additional cost could go up significantly to more than $2 billion every year.Citation8 According to different studies, it is projected that AMR could cost from $300 billion to more than $1 trillion annually by 2050 worldwide.Citation4,Citation28 High costs associated with expensive and intensive treatments and escalation in resource utilization are the direct monetary effects of AMR on health care.Citation3,Citation4 Treating patients with resistant infections by using a combination of regimens may be ineffective; as a result, compared to other patients, they may need longer hospitalization stays as well as more intensive care units (ICUs) and isolation beds in order to prevent the spread of the infection.Citation55 Also, nosocomial outbreaks with resistant pathogens may result in the closure of a wing of a hospital and the cancellation of elective surgeries, costing the hospital money.Citation55

In addition to direct monetary effects, AMR generates a burden on the health care system through secondary effects.Citation68 These effects happen when the procedures that utilize antibiotics, which are essential to decrease the risk of any infection after surgery, cannot be successfully carried out due to the prevalence of antimicrobial resistance.Citation68 Furthermore, AMR will challenge performing organ transplants because they expose the patients to different infections.Citation66,Citation69 For instance, Santoro-Lopes and de Gouvea performed a comprehensive review on different multi-resistant infections that may occur after liver transplantation.Citation70 In their work, they have discussed that multi-drug resistant pathogens can increase the likelihood of transplant failure and death.Citation70 Another secondary effect of antimicrobial resistance will be on cancer treatments.Citation66 Due to AMR, chemotherapy cannot be performed on patients with cancer.Citation71 Chemotherapy impairs the immune system and makes patients with cancer vulnerable to different infections.Citation59 Thus, the prevalence of AMR prohibits physicians from administering antibiotics to patients with cancer.Citation3,Citation66,Citation68 There is limited data on the exact cost of different secondary effects of AMR which limits our understanding regarding what we might stand to lose.Citation66

Economic Perspective

The literature review findings indicate that the cost of AMR across the globe is extremely high and different in each country.Citation66,Citation72 The CDC estimated that the cost of antimicrobial resistance is $55 billion every year in the United States, $20 billion for health care and about $35 billion for loss of productivity.Citation3,Citation8 Recent research by the World Bank indicates that antimicrobial resistance would elevate the rate of poverty and impact low-income countries compared to the rest of the world.Citation28 Studies show that annual global GDP could decrease by approximately 1% and there would be a 5–7% loss in developing countries by 2050.Citation71,Citation72 This percentage ultimately translates into $100-210 trillion.Citation28,Citation66 Multidrug- resistant TB alone could cost the world $16.7 trillion by 2050.Citation73,Citation74

Furthermore, due to AMR, the gap between the developing countries and the developed countries will become more pronounced; as a result, inequity will substantially increase.Citation28 Most of the people who are pushed into extreme poverty as a result of AMR will be specifically from low-income countries.Citation28 This highlights the fact that the underprivileged population of the world will eventually be affected the most because these countries are more contingent on labor income which will be reduced if there is a high prevalence of infectious diseases.Citation28

In addition to the direct impact on GDP, antimicrobial resistance has a major influence on labor through the loss of productivity caused by sickness and premature death.Citation68 Deaths because of antimicrobial resistance decrease the workforce, which in turn negatively impacts the size of the population as well as the quality of the country’s human capital.Citation68,Citation75 Taylor et al have created a theoretical model in order to estimate the economic impacts of AMR on the labor force in the future. In their work, they have compared a baseline (absence of AMR) with the current trend in AMR as well as worse alternatives that might happen if appropriate measures are not taken. According to their results, if there is no change in the current pattern of AMR, in ten years, the world working-age population will decrease by two years. This change will be more pronounced in Eurasia compared to the rest of the world.Citation75 In addition, in terms of annual GDP loss, if there is no change in the trends of AMR, the world will lose about $28 billion in ten years. According to this model, with a $20 billion loss in GDP, the European Union and The Organization for Economic Co-operation and Development (OECD) countries stand to lose more than the rest of the world.Citation75

The global trade will also be heavily affected by antimicrobial resistance if the continuous trends in AMR still persist.Citation32 The World Bank report demonstrates that global exports might decrease significantly by 2050 due to the effects of antimicrobial resistance on labor-intensive sectors.Citation28 Thus, it can be concluded that the undesirable outcomes of AMR on the global economy are projected to be even more severe than the global financial recession due to its long-term impacts on the economy.Citation28

Impacts of AMR on livestock output will also be significant.Citation30 Just like humans, the effect of AMR on animals will be due to mortality and morbidity. The increase in resistance to antimicrobials will make treatments on animals ineffective and cause the infections to become more severe.Citation26 Ultimately, this will lead to decreased production and trade of livestock, resulting in elevated prices of protein due to the decrease in protein sources such as milk, egg, and meat.Citation26,Citation28 Shortage of protein will be a major concern, considering that the demand for animal proteins is on the rise worldwide.Citation36 According to the World Bank, AMR will have drastic impacts on livestock production in low-middle income countries.Citation32 Estimates have indicated that if the persistent trends in AMR do not slow down, there will be an 11% loss in livestock production by 2050.Citation28 Such a substantial loss in animal production will lead to a decline in income generation which will exacerbate the economic situation.Citation26

Conclusion

Antimicrobials are the pillars of modern medicine and have substantially contributed to the progress of health care during the last half-century.Citation76 Thus, the persistent trends in AMR should be stopped or it will set us back to the dark ages of medicine.Citation48 Antibiotic resistance is a naturally occurring mechanism that can be slowed down gradually but not stopped completely because resistance is an inevitable consequence of the drug selective pressure.Citation8,Citation21 Thus, combating AMR requires collective action, political momentum, and robust multisectoral collaboration and partnerships between all stakeholders worldwide including governmental and non-governmental agencies, researchers, providers, public health practitioners, pharmaceutical companies, hospital administrations, policymakers, agriculture industry leaders, and patients.Citation71,Citation77 The main goal of this partnership should be decelerating the continuous trends in AMR so that the adverse impacts on society and the economy can be controlled. This will be achieved by establishing a governance mechanism in order to bring harmony to strategic and operational planning.Citation71 Although the cost of abiding by the guidelines and frameworks can be high, it is well established that the return on such investment will unquestionably have significant positive outcomes.Citation78 It also provides hope that the adverse impacts of antimicrobial resistance can be mitigated and may not lead to irreversible results for society as a whole.

Disclosure

The author reports no conflicts of interest in this work.

References