Viewpoint Cite This: ACS Infect. Dis. XXXX, XXX, XXX−XXX
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The Fight Against Antimicrobial Resistance Is Confounded by a Global Increase in Antibiotic Usage Mark A. T. Blaskovich* Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, 306 Carmody Road, Brisbane, Queensland 4072, Australia ABSTRACT: Antimicrobial resistance is a serious threat to global health. Despite numerous initiatives designed to curb excessive and inappropriate use of antibiotics, a recent report (Klein et al. (2018) Proc. Natl. Acad. Sci. U. S. A., 115, E3463) finds that there was a substantial increase in global antibiotic consumption by humans from 2000 to 2015 and predicts a further 200% increase by 2030. Alarmingly, much of this growth is occurring in “last-resort” antibiotics. The study excludes the extensive use of antibiotics in agriculture and aquaculture. This Viewpoint examines the report’s findings and discusses them in the context of other recent developments in antimicrobial resistance.
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nonbacterial infections such as viral diarrheal illnesses that can lead to inappropriate antibiotic usage). The report predicts that, if the same trends continue, by 2030 global consumption will be 200% higher than in 2015, a decidedly alarming outlook. Also of concern was the increase in consumption in all countries of newer and last-resort antibiotic classes, such as glycylcyclines, oxazolidinones, carbapenems, and polymyxins. The trends in consumption varied depending on antibiotic class and country. Excessive use of these precious drugs will drive a more rapid development of resistance, and with few new therapies in the pipeline, the current last-resort antibiotics need to be preserved as long as possible. It is important to note that this report was only measuring human antibiotic consumption. Given that up to two-thirds of overall antibiotic usage is for animals (up to 80% in the USA), the trends in human use may be overshadowed by agricultural use.2,3 A 2015 report4 led by the some of the same authors estimated antibiotic consumption by livestock in 228 countries and predicted an overall 67% increase in global consumption from 2010 to 2030, with up to 99% increase in Brazil, Russia, India, China, and South Africa. Studies have associated the presence of antimicrobial resistant bacteria in animals with transmission to humans through the environment, food products, and direct contact. Notably, actual data on antimicrobial use in livestock are scarce, as the agricultural industry is reluctant to provide summaries of antibiotic consumption and there is little public surveillance. For this study,4 the authors relied on data from 32 HICs and then extrapolated to MLICs assuming a similar rate of usage. Even this study did not account for all antibiotic use, as there is yet another category of antibiotic usage missing: aquaculture use may represent a significant and growing source of aquatic contamination. Bacterial resistance to antibiotics is developing into a global crisis which is already affecting the world’s health and economic well-being. As succinctly outlined by the World Health
he past decade has seen a well-deserved and overdue increase in attention focused on the global threat posed by antimicrobial resistance (AMR). Numerous reports at a national and international level have highlighted the problems posed by AMR and provided strategies designed to prevent us entering a “post-antibiotic” era. A key component of most, if not all, of these plans are efforts to improve antimicrobial stewardship. These initiatives are designed to reduce the excessive use of our existing antibiotics and alleviate some of the pressure leading to the development of resistance. It is therefore both disconcerting and disheartening to see the results of a recent publication in the PNAS.1 This analysis found that global antibiotic usage has not been reduced and is in fact still dramatically increasing. There was an overall growth in antibiotic consumption per person of 39% in the period from 2000 to 2015, equating to a 65% proliferation in total antibiotic use, when also accounting for the increase in population. The study examined trends in 76 countries. Most of this growth in antibiotic therapy occurred in low- and middle-income countries (LMICs); indeed, in high-income countries (HICs), there was a 4% decrease. For HICs, the USA, France, and Italy were the most prolific users. India, China, and Pakistan led the LMICs, with 63% (103%), 65% (79%), and 21% (65%) overall increases in consumption per person (or overall), respectively. The LMIC increase correlated with the increase in gross domestic product (GDP) per capita. This likely results from one of the conundrums of antibiotic usage in those countries; it is often poorly regulated (readily available over the counter without prescription), while at the same time, antibiotics are unaffordable for much of the population. As LMIC economies become more developed, improvements in medical treatment and the ability to pay for medications will consequentially lead to more antibiotics being employed, not necessarily due to inappropriate usage. The authors suggest other reasons why GDP growth in LMICs may cause increased antibiotic use, including an increased incidence of bacterial infections caused by urbanization. This can be caused by factors such as poor air quality leading to respiratory illnesses and facilitated transmission of diseases in a more crowded environment (including © XXXX American Chemical Society
Received: May 1, 2018
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DOI: 10.1021/acsinfecdis.8b00109 ACS Infect. Dis. XXXX, XXX, XXX−XXX
ACS Infectious Diseases
Viewpoint
study highlights the ethical issue of how does one balance the ability to save thousands of lives now, when the treatment poses a potential danger to saving lives in the future? For both HICs and LMICs, an advance that could have the greatest beneficial impact on reducing inappropriate human antibiotic use in the near future is the development and deployment of an inexpensive, rapid point-of-care diagnostic, one that could confirm the presence of a bacterial infection and, importantly, distinguish between viral and bacterial infections. This would allow for a physician to conclusively tell a patient that an antibiotic is not needed, as opposed to writing a prescription “just in case” an infection is present. The significance of such a development is recognized by both the £8m Longitude Prize14 and a $US20m “Antimicrobial Resistance Diagnostic Challenge” run by the USA National Institutes of Health (NIH),15 with both awards designed to foster research into this area. “Nonantibiotic” approaches are also important and the subject of considerable research. These include preventative measures, such as the antibacterial vaccines mentioned earlier, as well as novel treatment regimens, such as phage therapy (not really novel, but undergoing a renaissance), antibody-based therapies, immune modulation, and microbiome manipulation.16 The elephant in the room is the excessive use of antibiotics in the agricultural and aquacultural industry. There is substantial progress in recognizing that this is an issue and implementing solutions with, for example, China banning the use of colistin in 201617 and the USA Food and Drug Administration (FDA) introducing policies to restrict certain classes of antibiotics from animal use in 2013.18 Nonetheless, when the agricultural sector is unable to provide an accurate estimation of antibiotic usage and observational studies show rampant unregulated use in MLICs such as India,19 there is obviously much more to be done. The identification of high levels of resistance in bacteria found on livestock farms2 and the presence of high levels of antibiotics in agricultural runoff2,20 all indicate that we must do more to address this issue. To summarize, the warnings of an impending global health crisis due to antimicrobial resistance are leading to substantial policy and research efforts at a national and international level, but these are yet to translate into progress in addressing one of the main drivers of resistance, excessive antibiotic usage.
Organization, we face a return to a pre-antibiotic era (or alternatively are heading to a “post-antibiotic” era), where infections are no longer treatable.5 Recent high publicity cases, such as 6 patients in the northwest USA dying from a strain of extensively drug-resistant Acinetobacter baumannii with enhanced virulence,6 a fatal outbreak of hypervirulent Klebsiella pneumoniae in China in 2016,7 and “supergonorrhea” in England8 and Australia9 are likely to become much more common in the future. Indeed, the Public Health England reported 32 cases of “pan-resistant” infections (bacterial infections resistant to every antibiotic tested as part of a standard antibiotic panel) between April 2013 and February 2018,10 and the USA Centers for Disease Control and Prevention (CDC) reported 221 instances of “unusual resistance genes in ‘nightmare bacteria’” in 2017.11 Inappropriate antibiotic usage is one of the major drivers of resistance, recognized in 1945 in Alexander Fleming’s Nobel Lecture on the discovery of penicillin. Fleming outlined the scenario of Patient X, who “buys some penicillin and gives himself, not enough to kill the streptococci but enough to educate them to resist penicillin. He then infects his wife. Mrs. X gets pneumonia and is treated with penicillin. As the streptococci are now resistant to penicillin the treatment fails.”12 The trends in antibiotic usage that have now been discerned between 2000 and 2015 suggest that, at least in HICs, the education and stewardship programs developed over the past decade are having some impact in arresting the growth in antibiotic usage. However, given estimates that approximately two-thirds of antibiotics used in humans are inappropriately employed,3 there is still substantial progress to be made. A question of greater concern is how do we prevent further increases in antibiotic usage in LMICs? The substantial presence of high levels of existing resistance within many LMICs, coupled with their high baseline populations, rates of population growth, and growth in per capita GDP, all align with continued expansion of antibiotic usage, particularly of “last resort” classes. Stewardship programs, as employed in HICs, are not necessarily appropriate in countries where providing universal access to effective treatment of infections is still a challenge. The authors of the current article provide some guidance, suggesting that reducing the burden of disease is a key mechanism.1 This includes infrastructure projects to improve sanitation, both delivering clean water and effectively collecting and treating sewage. Preventative vaccines for bacterial diseases reduce the need for antibiotics, while antiviral vaccines can prevent inappropriate antibiotic use for viral infections.1 Another recent report, in The New England Journal of Medicine,13 highlights the tensions between the benefits of increased antibiotic use in LMICs and the potential pressure on antimicrobial resistance. In this study, nearly 100,000 children (aged 1 to 59 months) in three sub-Saharan African countries were given twice-yearly doses of azithromycin over four years and compared to nearly 100,000 other children given a placebo. This mass distribution of a broad-spectrum antibiotic, given without regard to the defined presence of any infection, is diametrically opposed to the principles of antibiotic stewardship but led to a decrease in overall mortality of 13.5%. The reasons for the reduction were not assessed but hypothesized to be due to reduced incidence of respiratory infections, diarrhea, and malaria. The authors acknowledged the potential pressure for causing resistance and plan to monitor for the emergence of resistance in one of the study regions for two more years. The
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Mark A. T. Blaskovich: 0000-0001-9447-2292 Notes
The author declares the following competing financial interest(s): M.A.T.B. receives research funding for the discovery and development of antibiotics and bacterial diagnostics, collaborates with and consults for a number of companies developing new antibiotics, and is an inventor on patents (related to new antibiotics and bacterial detection) that are the subject of commercialization activity.
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ABBREVIATIONS AMR, antimicrobial resistance; CDC, Centers for Disease Control and Prevention; FDA, USA Food and Drug Administration; GDP, gross domestic product; HICs, highB
DOI: 10.1021/acsinfecdis.8b00109 ACS Infect. Dis. XXXX, XXX, XXX−XXX
ACS Infectious Diseases
Viewpoint
D., Ó lafsdóttir, S., Payne, D., Projan, S., Shaunak, S., Silverman, J., Thomas, C. M., Trust, T. J., Warn, P., and Rex, J. H. (2016) Alternatives to antibioticsa pipeline portfolio review. Lancet Infect. Dis. 16 (2), 239−251. (17) Walsh, T. R., and Wu, Y. (2016) China bans colistin as a feed additive for animals. Lancet Infect. Dis. 16 (10), 1102−1103. (18) Tavernise, S. (Dec 11, 2013) F.D.A. Restricts Antibiotics Use for Livestock. In The New York Times, https://www.nytimes.com/ 2013/12/12/health/fda-to-phase-out-use-of-some-antibiotics-inanimals-raised-for-meat.html (accessed May 1, 2018). (19) The Poultry Site. (April 11, 2017) How Unregulated Use of Antibiotics is Undermining Poultry Success in India, http://www. thepoultrysite.com/articles/3717/how-unregulated-use-of-antibioticsis-undermining-poultry-success-in-india/ (accessed May 1, 2018). (20) Dungan, R. S., Snow, D. D., and Bjorneberg, D. L. (2017) Occurrence of Antibiotics in an Agricultural Watershed in SouthCentral Idaho. J. Environ. Qual. 46 (6), 1455−1461.
income countries; LMICs, low- and middle-income countries; NIH, National Institutes of Health
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REFERENCES
(1) Klein, E. Y., Van Boeckel, T. P., Martinez, E. M., Pant, S., Gandra, S., Levin, S. A., Goossens, H., and Laxminarayan, R. (2018) Global increase and geographic convergence in antibiotic consumption between 2000 and 2015. Proc. Natl. Acad. Sci. U. S. A. 115, E3463. (2) O’Neill, J. (Dec 2015) Antimicrobials in Agriculture and the Environment: Reducing Unnecessary Use and Waste; The Review on Antimicrobial Resistance, https://amr-review.org/sites/default/files/ Antimicrobials%20in%20agriculture%20and%20the%20environ ment%20-%20Reducing%20unnecessary%20use%20and%20waste.pdf (accessed May 1, 2018). (3) O’Neill, J. (May 19, 2016) Tackling Drug-Resistant Infections Globally: Final Report and Recommendations; The Review on Antimicrobial Resistance, https://amr-review.org/sites/default/files/ 160525_Final%20paper_with%20cover.pdf. (4) Van Boeckel, T. P., Brower, C., Gilbert, M., Grenfell, B. T., Levin, S. A., Robinson, T. P., Teillant, A., and Laxminarayan, R. (2015) Global trends in antimicrobial use in food animals. Proc. Natl. Acad. Sci. U. S. A. 112 (18), 5649−5654. (5) WHO. (September 9, 2015) Urgent action needed to prevent a return to pre-antibiotic era, World Health Organization, Geneva, http:// www.searo.who.int/mediacentre/releases/2015/1612/en/ (accessed May 1, 2018). (6) Jones, C. L., Clancy, M., Honnold, C., Singh, S., Snesrud, E., Onmus-Leone, F., McGann, P., Ong, A. C., Kwak, Y., Waterman, P., Zurawski, D. V., Clifford, R. J., and Lesho, E. (2015) Fatal Outbreak of an Emerging Clone of Extensively Drug-Resistant Acinetobacter baumannii With Enhanced Virulence. Clin. Infect. Dis. 61 (2), 145− 154. (7) Gu, D., Dong, N., Zheng, Z., Lin, D., Huang, M., Wang, L., Chan, E. W.-C., Shu, L., Yu, J., Zhang, R., and Chen, S. (2018) A fatal outbreak of ST11 carbapenem-resistant hypervirulent Klebsiella pneumoniae in a Chinese hospital: a molecular epidemiological study. Lancet. Infect. Dis. 18 (1), 37−46. (8) Knox, J. (March 29, 2018) UK man has world-first case of superstrength gonorrhoea. In The Guardian, https://www.theguardian.com/ society/2018/mar/28/uk-man-super-strength-gonorrhoea (accessed May 1, 2018). (9) Branco, J. (April 17, 2018) “Super gonorrhoea” resistant to all routine antibiotics found in Australia. In Brisbane Times, https://www. brisbanetimes.com.au/national/queensland/super-gonorrhoearesistant-to-all-routine-antibiotics-found-in-australia-20180417-p4za4s. html (accessed May 1, 2018). (10) Davies, M., and Gulland, A. (April 26, 2018) Figures reveal emergence of “pan-resistant” infections. In The Telegraph, https:// www.telegraph.co.uk/news/2018/04/26/figures-reveal-emergencepan-resistant-infections/ (accessed May 1, 2018). (11) CDC. (April 2018) Containing Unusual Resistance, Centers for Disease Control and Prevention, Atlanta, GA, https://www.cdc.gov/ vitalsigns/containing-unusual-resistance/ (accessed May 1, 2018). (12) Fleming, A. (December 11, 1945) Penicillin. Nobel Lecture, https://www.nobelprize.org/nobel_prizes/medicine/laureates/1945/ fleming-lecture.pdf (accessed May 1, 2018). (13) Keenan, J. D., Bailey, R. L., West, S. K., Arzika, A. M., Hart, J., Weaver, J., Kalua, K., Mrango, Z., Ray, K. J., Cook, C., Lebas, E., O’Brien, K. S., Emerson, P. M., Porco, T. C., and Lietman, T. M. (2018) Azithromycin to Reduce Childhood Mortality in Sub-Saharan Africa. N. Engl. J. Med. 378 (17), 1583−1592. (14) Longitude Prize Website, https://longitudeprize.org/ (accessed May 1, 2018). (15) Antimicrobial Resistance Rapid, Point-of-Need Diagnostic Test Challenge, https://www.cccinnovationcenter.com/challenges/ antimicrobial-resistance-diagnostic-challenge/. (16) Czaplewski, L., Bax, R., Clokie, M., Dawson, M., Fairhead, H., Fischetti, V. A., Foster, S., Gilmore, B. F., Hancock, R. E. W., Harper, D., Henderson, I. R., Hilpert, K., Jones, B. V., Kadioglu, A., Knowles, C
DOI: 10.1021/acsinfecdis.8b00109 ACS Infect. Dis. XXXX, XXX, XXX−XXX
