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Antimicrobial Resistance and the Role of Vaccines PROGRAM ON THE GLOBAL DEMOGRAPHY OF AGING AT HARVARD UNIVERSITY Working Paper Series Antimicrobial Resistance and the Role of Vaccines David E. Bloom, Steven Black, David Salisbury, and Rino Rappuoli June 2019 PGDA Working Paper No. 170 http://www.hsph.harvard.edu/pgda/working/ Research reported in this publication was supported in part by the National Institute on Aging of the National Institutes of Health under Award Number P30AG024409. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. SPECIAL FEATURE: INTRODUCTION Antimicrobial resistance and the role of vaccines SPECIAL FEATURE: INTRODUCTION David E. Blooma, Steven Blackb, David Salisburyc, and Rino Rappuolid,e,1 Stanley Falkow (Fig. 1) dedicated his life’s work to being reported (6). These health consequences will the study of bacteria and infectious disease. He have damaging social and economic sequelae, such was a leader in the discovery of the mechanisms as lost productivity due to increased morbidity and of antibiotic resistance and among the first to mortality, and even social distancing, as fear of inter- recognize and raise the alarm about the problem of multidrug resistance. The articles of this Spe- personal contact grows. ’ cial Feature on Antimicrobial Resistance and the Although projections of AMR s future burden Role of Vaccines are dedicated to his memory depend on several assumptions and are therefore (Box 1). uncertain, the idea that the health and economic consequences of AMR will become significant is rea- Rising antimicrobial resistance (AMR) is one of the sonable. In 2014, the Review on Antimicrobial Resis- greatest health challenges the world currently faces. tance (5), commissioned by David Cameron and Resistant pathogens, including viruses, parasites, chaired by Lord Jim O’Neill, suggested that if left un- fungi, and especially bacteria cause significant mor- checked, AMR could cause as many as 10 million an- bidity and mortality. For example, antibiotic resistance nual deaths—more than the 8.2 million deaths caused is estimated to cause 33,000 deaths annually in the by cancer today—and cost USD100 trillion in cumula- European Union and European Economic Area (1), at least 23,000 deaths annually in the United States (2), tive economic damage by 2050. A World Bank simu- and at least 38,000 deaths annually in Thailand (3). lation projects that the global economy could lose as Furthermore, resistant bacteria reportedly caused much as 3.8% of its annual gross domestic product by the deaths of more than 58,000 babies in India in 2050 in a worst-case scenario (7). 1 y (4). One estimate places current global annual AMR is not a new problem. Resistance emerged deaths from AMR at a minimum of 700,000 (5). with the advent of antimicrobial therapy, beginning While the current global death toll from AMR is with the discovery of penicillin. Multidrug resistance relatively modest compared with other major causes was identified as early as the 1950s. Antibiotic re- of mortality, the problem is expected to worsen. Any sistance occurs when bacteria become immune to use of antimicrobials, including common antibiotics previously effective drugs through some mutation in that treat every day respiratory, gastrointestinal, and their genetic code. These mutations often exact some skin infections, drives the evolution of resistance, fitness cost (in the absence of antibiotics), but pro- regardless of the appropriateness of use. Importantly, vide the resistant bacteria a survival advantage when antimicrobial use is increasing, which will likely con- antibiotics are present (8). However, sustained use of tinue in the foreseeable future, as access to antimi- antibiotic therapy—at the individual or population crobials improves in the developing world. level—exerts pressure on bacterial populations to be- The progression of AMR has daunting ramifica- come increasingly resistant. tions, including increased spread of infectious dis- Emergence of resistant clades within several bacterial ease, increased likelihood of dying from what are now species—including Escherichia coli, Salmonella typhi, considered routine illnesses, and inability to perform Staphylococcus aureus,andClostridium difficile—that certain medical procedures, such as elective surgery, resist antibiotics without imposing any fitness cost due to fear of untreatable hospital-acquired infections. have been recently detected (8). In some cases, these Cases of Neisseria gonorrhoeae are now becoming clades are also more transmissible or aggressive in almost untreatable with currently available antibiotics, causing disease than other members of the same with resistance to azithromycin and ceftriaxone species. Many of these clades have spread to different aDepartment of Global Health and Population, Harvard T. H. Chan School of Public Health, Boston, MA 02115; bUniversity of Cincinnati Department of Pediatrics, University of Cincinnati Children’s Hospital, Cincinnati, OH 45229; cCentre on Global Health Security, SW1Y 4LE London, United Kingdom; dGlaxoSmithKline (GSK), 53100 Siena, Italy; and eDepartment of Medicine, Imperial College, SW7 2AZ London, United Kingdom Author contributions: D.E.B., S.B., D.S., and R.R. wrote the paper. Conflict of interest statement: R.R. is an employee of GSK group of companies. Published under the PNAS license. 1To whom correspondence should be addressed. Email: [email protected]. www.pnas.org/cgi/doi/10.1073/pnas.1717157115 PNAS Latest Articles | 1of4 Fig. 2. A globally integrated strategy that includes antibiotics, vaccines, diagnostics, antibodies, and new tools targeting the host, the microbiome, or delivered by phages is required to fight AMR effectively. This figure was inspired by a figure in an early draft of Klemm et al. (8). therapies’ effectiveness. Similarly, improving regulation of access to antimicrobials in human and animal populations, while ensur- ing that access is not denied to anyone who needs them, can help limit the inappropriate use of drugs and the corresponding evolutionary pressure toward resistance. Widespread dissemina- tion of rapid and accurate diagnostics could help clinicians treat infections more precisely, further alleviating evolutionary pressure. Improving sanitation and hygiene, especially in low- and middle- income countries, could also make an appreciable difference. However, the reality is that no single response is sufficient for Fig. 1. Stanley Falkow, January 24, 1934–May 5, 2018, a pioneer in the fight to understand and address AMR. Image courtesy of Manuel stemming the rising tide of AMR. Antibiotic research and R. Amieva (photographer). development (R&D) faces substantial challenges, and novel and effective antibiotics are sorely needed to ensure the ability to treat infections that may otherwise be resistant to all existing parts of the globe. Their continued proliferation could make com- options. Given how fast resistance has evolved to each new class bating the burden of resistance through strategies like antibiotic of antibiotics introduced historically and the challenges in pro- stewardship (ABS) or antibiotic cycling more difficult. ducing new antibiotics, focusing on antibiotic R&D alone is While AMR poses a daunting threat, options are available for clearly insufficient. A globally integrated and multipronged strat- mounting a response. Developing new antibiotics and other antimi- egy is required. In this Special Feature, we argue that developing crobials, as well as new forms of treatment, such as monoclonal new vaccines, along with new antibiotics and new diagnostics, antibodies, provide options to ensure that otherwise pan-resistant should be a significant part of that strategy (Fig. 2). Increasing infections remain responsive to some form of treatment. Better ABS coverage of existing vaccines and developing new vaccines that in inpatient and outpatient settings can help preserve existing target antibiotic-resistant organisms can play important roles. Vaccination is also a solution that has been largely undervalued Box 1. Dedication (9). Vaccines can counteract AMR through multiple pathways (10). This Special Feature on Antimicrobial Resistance and the Role Vaccination directly reduces the incidence of sensitive and resistant of Vaccines is dedicated to the memory of microbiologist infections. It also reduces both appropriate and inappropriate use of Stanley Falkow. Professor Falkow was a pioneer in un- antimicrobials by reducing overall disease incidence, including infec- derstanding how bacteria cause disease and discovered how tions caused by susceptible pathogens and by viruses (such as influ- antibiotic resistance spreads among bacteria. In 1964, Fal- enza) that are often inappropriately treated with antibiotics. This kow was the first to physically isolate a distinct band of DNA reduced antimicrobial use further diminishes pressure toward re- comprising the episome (plasmid) with the genetic material sistance among bystander members of the normal human flora. coding for antibiotic resistance in a cesium chloride gradi- Overall, the articles in this Special Feature highlight why vaccines ent. As early as 1975, he wrote a book entitled Infectious should be seriously considered as an important tool against AMR. Multiple Drug Resistance (17) and noted that while “we owe The first reason, as Kennedy and Read (11) point out and Fig. 3 to chemotherapy [antibiotics] the debt of reducing the high shows schematically, is that resistance
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