Confronting antimicrobial resistance together

World antimicrobial awareness week (WAAW) is an annual global campaign with the goal of minimizing the emergence and spread of antimicrobial resistance (AMR) by improving awareness and understanding of AMR and encouraging best practices among individuals, the public, governments, and health and agricultural professionals. Initiated in 2015 under the leadership of the World Health Organization (WHO), the inaugural campaign focused on the roles of healthcare professionals and patients as prescribers and consumers of antibiotics, respectively. Subsequent campaigns in 2018 and 2019 underscored the growing global threat posed by antibiotic overuse with themes of “Our time with antibiotics is running out” and “The future of antibiotics depends on us all.” Shortly after WHO’s declaration of the SARS-CoV-2 COVID-19 outbreak on March 11, 2020, the scope of WAAW was expanded from “antibiotics” to “antimicrobials” to facilitate a more inclusive global response by including antibacterial, antiviral, antifungal, and antiparasitic drugs.

This year the theme of WAAW is “Preventing Antimicrobial Resistance Together” and the focus is prudent use of antimicrobials and implementation of preventive strategies through a One Health approach. Exponential population growth has increased our interactions with other humans and animals, and it has created unprecedented environmental disruptions. One Health is a holistic, multidisciplinary approach that recognizes that the health of humans, animals, and our shared environments is inextricably intertwined.

One needs to look no further than the zoonotic origins of the COVID-19 pandemic to appreciate the critical importance of the One Health approach. Not only has COVID-19 overtaken the “Big Three” infectious diseases, tuberculosis (TB), human immunodeficiency virus (HIV)-acquired immunodeficiency syndrome (AIDS), and malaria, as a cause of death, but COVID-19-associated disruptions have stalled progress in their treatment and control in much of the world. For example, in 2020, an estimated 10 million people developed active TB worldwide and 1.5 million people died, reversing years of steady improvement (1). Case identification and administration of effective antimicrobial therapy are essential for control of this disease, yet rates of new diagnosis, case notification, and overall TB treatment, including treatment for multidrug-resistant (MDR) TB, all fell significantly as public health infrastructure buckled under the pressures of COVID-19.

An estimated 650,000 people died from HIV-related causes in 2020 and 1.5 million people became newly HIV-infected (2). There were an estimated 38.4 million people living with HIV at the end of 2021, two thirds of whom (25.6 million) are in the WHO African Region. Globally, 28.7 million people living with HIV (∼75%) were receiving antiretroviral therapy (ART) in 2021. That is the good news. The bad news is that almost 10,000,000 people remain untreated. As with TB, combination therapy is required to effectively treat HIV. HIV drug resistance leads to treatment failure and compromises the effectiveness of antiretroviral therapy in reducing HIV transmission and, ultimately, incidence and associated morbidity and mortality. Nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based regimens are the most commonly used ART regimens worldwide. However, up to 10% of adults initiating this therapy have pretreatment resistance to NNRTIs with three times higher rates in people previously exposed to antiretroviral drugs (3). In addition, nearly half of infants newly diagnosed with HIV have resistance to NNRTI before initiating treatment. The high levels of observed NNRTI resistance emphasize the need to fast-track to WHO-recommended dolutegravir-based ART. Unfortunately, disruption in HIV prevention, testing, and treatment services will make achieving this goal more difficult (4).

The story with malaria is much the same. In 2020, malaria cases rose to 241 million (from 227 million) and deaths increased by 12% to 627,000 from 2019 estimates, with most of this increase occurring in sub-Saharan Africa (5). Recent evidence for the emergence of partial resistance to artemisinin, a critical component of combination therapy in the WHO African Region, is therefore concerning. Artemisinin partial resistance likely contributed to the spread of resistance to artemisinin partner drugs in the Greater Mekong Delta. A similar development in sub-Saharan Africa could be catastrophic given its greater burden of malaria. The extent to which disruptions in diagnosis and treatment of malaria in the face of an increased burden of disease will affect drug resistance remains to be seen.

Last but far from least is bacterial AMR. Worldwide there were an estimated 4.95 million deaths associated with AMR in 2019, numbers that put this problem on par with TB, HIV, and malaria, and potentially even greater (6). Six pathogens, Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa together were responsible for 3.57 million of 4.95 million AMR-associated deaths and 929,000 of 1.27 million deaths directly attributable to AMR. The WHO priority 1 critical pathogens [carbapenem-resistant A. baumannii, carbapenem-resistant P. aeruginosa, carbapenem-resistant or extended-spectrum β-lactamase (ESBL) producing Enterobacterales] accounted for almost half of the attributable deaths.

Overuse and misuse of antibiotics in both humans and animals are major contributors to AMR. Agricultural use of antibiotics is of particular concern. It is estimated that 73% of all antimicrobials sold globally are used in animals raised for food (7). The global annual consumption of antimicrobials in food animals was estimated at 131,109 tons in 2013 and is projected to reach 200,235 tons by 2030 (8). Antimicrobial use in animals is primarily for growth promotion and mass prophylaxis and administered in feed at low doses, conditions ideal for the selection of drug resistance. As a result, food animals may be a larger reservoir of resistance genes than humans. Organisms carrying resistance genes may be transmitted to humans via food chains, and widely disseminated in the environment via animal wastes. The organisms may not only be pathogenic to humans but also can serve as a reservoir for the transmission of drug-resistance genes to human pathogens. Agricultural use of antibiotics has been implicated in the emergence of ESBL-producing E. coli, fluoroquinolone-resistant Campylobacter species, and multidrug-resistant Salmonella species (9–11). Antibiotics present in human, animal, and industrial waste can contaminate the environment with the potential to harm the fragile ecosystem and human health (12, 13). Numerous factors drive the global dissemination of AMR, including intensive food production, globalization of food distribution, international travel, climate change, increased population density or growth, and urbanization.

Not surprisingly, COVID-19 has likely made matters with respect to AMR worse, although how much worse remains to be seen. Factors that potentially could lead to increased rates of AMR include over-prescribing of antibiotics to patients who do not have a bacterial infection, access to over-the-counter antibiotics and self-medication, increasing numbers of patients requiring intensive care and ventilatory support, prolonged hospitalizations, disruptions in antimicrobial stewardship programs and infection prevention programs, and overwhelmed clinical microbiology services with reduced access to diagnostics and slow turnaround of test results (14–18). Effects on antibiotic utilization have been variable. The overall rate of antibiotic prescription to patients with COVID-19 is high, 75% in one study (14), and given the low rate of bacterial coinfection rate (15), probably excessive. However, studies in Canada and Sweden reported an overall drop in antibiotic usage, particularly in the outpatient setting (19, 20).

Numerous case reports have described increased rates of AMR infections (17, 21). A survey of 46 medical centers in Mexico found an increase in AMR during the COVID-19 pandemic including increases in methicillin-resistant S. aureus, carbapenem-resistant K. pneumoniae, and antibiotic-resistant A. baumannii and P. aeruginosa (22). A systematic review and meta-analysis of the burden of AMR in patients with COVID-19 found a high rate of AMR organisms (pooled prevalence of 24%) in patients with bacterial coinfections (23). The most common multiple drug-resistant organisms reported were methicillin-resistant S. aureus, carbapenem-resistant A. baumannii, K. pneumoniae, P. aeruginosa, and multidrug-resistant Candida auris. Whether this will translate into an increased burden of AMR overall and over time is unclear.

With the exception of two world wars, the COVID-19 pandemic has been the most disruptive force in human health and human history in the last 100-plus years. More than just a reminder, it is a textbook example of how important One Health is for human health and health of the planet. Viewed within this context this year’s theme of “Preventing Antimicrobial Resistance Together” is especially relevant. AMR is a systemic and global problem of huge proportions against which progress has been stalled during COVID-19. Reducing the burden of infection is important for meeting the challenge of AMR: an infection prevented is one less requiring treatment. TB, HIV-AIDS, and malaria have proven the value of rapid diagnostics for case identification so that appropriately targeted and effective therapy can be administered and, in the case of TB and HIV-AIDS, further transmission of disease prevented. Pre-exposure prophylaxis with effective antiviral agents to prevent HIV infection is a promising tool for controlling HIV-AIDS. The availability of vaccine for malaria has the potential to significantly reduce incidence, morbidity, and mortality of that disease. New and more effective regimens against MDR TB have the potential to lessen the burden of that infection (24). Highly effective vaccines for COVID-19 have been essential for bringing the pandemic and its disruptions under control although global vaccine coverage remains a challenge.

These same tools are applicable to the problem of bacterial AMR. Vaccines for respiratory viruses, especially COVID-19 and influenza, lessen the use of antibacterial agents for which infections these are inappropriately prescribed and by preventing hospitalization. There is a coming revolution in improved diagnostics that can accurately and quickly discriminate bacterial from nonbacterial disease, identify those for whom an antibacterial agent is indicated, and detect the presence of drug resistance. Development of immunotherapies and bacteriophage therapies to treat infections is in its infancy. These nonantibiotic approaches could reduce the need for prolonged courses of antibiotic therapy and hence selection of drug-resistant organisms. More importantly as a society, we need to come to grips with the agricultural use of antibiotics and the problem of environmental contamination through the adoption of more sustainable farming practices that do not rely on the use of these drugs. We need to bring a One Health approach preventing antimicrobial resistance together.

GRANTS

Research reported in this publication was supported in part by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number UM1AI104681.

DISCLAIMERS

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

DISCLOSURES

H.F.C. reports participation on a Merck DSMB for Molnupiravir paid directly to him, Stock ownership in Moderna and Merck and consultancy for Lilly. V.G.F. reports grants to his institution from the NIH, MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck, Medical Biosurfaces, Locus, Affinergy, Contrafect, Karius, Genentech, Regeneron, Basilea, and Janssen; royalties from UpToDate; personal Fees from Novartis, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co., MedImmune, Bayer, Basilea, Affinergy, Janssen, Contrafect, Regeneron, Destiny, Ampliphi Biosciences, Integrated Biotherapeutics, C3J, Armata, Valanbio, Akagera, Aridis, and Roche; editorial stipend from Infectious Diseases of America; pending patent for a host gene expression signature diagnostic for sepsis; and stock options with Valanbio and ArcBio.

AUTHOR CONTRIBUTIONS

H.F.C. drafted manuscript; H.F.C. and V.G.F. edited and revised manuscript; H.F.C. and V.G.F. approved final version of manuscript.