Antimicrobial resistance: Difference between revisions

{{cs1 config|mode=cs1|name-list-style=vanc|display-authors=6}}

'''Antimicrobial resistance''' ('''AMR''') occurs when [[microbe]]s evolve mechanisms that protect them from the effects of [[antimicrobials]] (drugs used to treat infections).<ref name="WHO2014">{{cite web|title=Antimicrobial resistance Fact sheet N°194|url=https://www.who.int/mediacentre/factsheets/fs194/en/|website=who.int|access-date=7 March 2015|date=April 2014|archive-url=https://web.archive.org/web/20150310081111/http://www.who.int/mediacentre/factsheets/fs194/en/|archive-date=10 March 2015|url-status=live}}</ref> All classes of microbes can evolve resistance whereto the point that one or more drugs used to fight them are no longer effective. [[Fungi]] evolve [[antifungal]] resistance, [[virus]]es evolve [[antiviral]] resistance, [[protozoa]] evolve [[antiprotozoal]] resistance, and [[bacteria]] evolve [[antibiotic]] resistance. Together all of these come under the umbrella of antimicrobial resistance. Microbes resistant to multiple antimicrobials are called [[Multiple drug resistance|multidrug resistant]] (MDR) and are sometimes referred to as '''superbugs'''.<ref name="Magiorakos">{{cite journal | vauthors = Magiorakos AP, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CG, Harbarth S, Hindler JF, Kahlmeter G, Olsson-Liljequist B, Paterson DL, Rice LB, Stelling J, Struelens MJ, Vatopoulos A, Weber JT, Monnet DL | display-authors = 6 | title = Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance | journal = Clinical Microbiology and Infection | volume = 18 | issue = 3 | pages = 268–281 | date = March 2012 | pmid = 21793988 | doi = 10.1111/j.1469-0691.2011.03570.x | doi-access = free }}</ref> Although antimicrobial resistance is a naturally occurring process, it is often the result of improper usage of the drugs and management of the infections.<ref name=":9">{{cite journal | vauthors = Tanwar J, Das S, Fatima Z, Hameed S | title = Multidrug resistance: an emerging crisis | journal = Interdisciplinary Perspectives on Infectious Diseases | volume = 2014 | pages = 541340 | date = 2014 | pmid = 25140175 | pmc = 4124702 | doi = 10.1155/2014/541340 | doi-access = free }}</ref><ref name=":10">{{cite journal | vauthors = Saha M, Sarkar A | title = Review on Multiple Facets of Drug Resistance: A Rising Challenge in the 21st Century | journal = Journal of Xenobiotics | volume = 11 | issue = 4 | pages = 197–214 | date = December 2021 | pmid = 34940513 | pmc = 8708150 | doi = 10.3390/jox11040013 | doi-access = free }}</ref>

The [[World Health Organization|WHO]] defines antimicrobial resistance as a microorganism's [[drug resistance|resistance to an antimicrobial drug]] that was once able to treat an infection by that microorganism.<ref name=WHO2014/> A person cannot become resistant to antibiotics. Resistance is a property of the microbe, not a person or other organism infected by a microbe.<ref>{{cite web|url=https://www.cdc.gov/getsmart/antibiotic-use/antibiotic-resistance-faqs.html#antibiotic-resistance-concerns|title=CDC: Get Smart: Know When Antibiotics Work|publisher=Cdc.gov|access-date=12 June 2013|archive-url=https://web.archive.org/web/20150429180658/http://www.cdc.gov/getsmart/antibiotic-use/antibiotic-resistance-faqs.html#antibiotic-resistance-concerns|archive-date=29 April 2015|url-status=live|date=29 May 2018}}</ref> All types of microbes can develop drug resistance. Thus, there are antibiotic, antifungal, antiviral and antiparasitic resistance.<ref name=":9Tanwar_2014" /><ref name=":10Saha_2021" />

Global deaths attributable to AMR numbered 1.27 million in 2019. That year, AMR may have contributed to 5<!--~4.95 million (3.62–6.57)--> million deaths and one in five people who died due to AMR were children under five years old.<ref name=":8Murray_2022" />

!Deaths per 100,000 attributable to AMR<ref name=":8Murray_2022" />

The [[European Centre for Disease Prevention and Control]] calculated that in 2015 there were 671,689 infections in the EU and European Economic Area caused by antibiotic-resistant bacteria, resulting in 33,110 deaths. Most were acquired in healthcare settings.<ref>{{cite journal | vauthors = Cassini A, Högberg LD, Plachouras D, Quattrocchi A, Hoxha A, Simonsen GS, Colomb-Cotinat M, Kretzschmar ME, Devleesschauwer B, Cecchini M, Ouakrim DA, Oliveira TC, Struelens MJ, Suetens C, Monnet DL | display-authors = 6 | title = Attributable deaths and disability-adjusted life-years caused by infections with antibiotic-resistant bacteria in the EU and the European Economic Area in 2015: a population-level modelling analysis | journal = The Lancet. Infectious Diseases | volume = 19 | issue = 1 | pages = 56–66 | date = January 2019 | pmid = 30409683 | pmc = 6300481 | doi = 10.1016/S1473-3099(18)30605-4 }}</ref><ref>{{cite web |title=Antibiotic-resistant bacteria responsible for over 33,000 deaths in Europe in 2015, study finds |url=https://pharmaceutical-journal.com/article/news/antibiotic-resistant-bacteria-responsible-for-over-33000-deaths-in-europe-in-2015-study-finds |access-date=2023-03-28 |website=The Pharmaceutical Journal |date=7 November 2018 |language=en-US |archive-date=28 March 2023 |archive-url=https://web.archive.org/web/20230328155238/https://pharmaceutical-journal.com/article/news/antibiotic-resistant-bacteria-responsible-for-over-33000-deaths-in-europe-in-2015-study-finds |url-status=live }}</ref> In 2019 there were 133,000 deaths caused by AMR.<ref>{{cite journal | title = The burden of bacterial antimicrobial resistance in the WHO European region in 2019: a cross-country systematic analysis | journal = The Lancet. Public Health | volume = 7 | issue = 11 | pages = e897–e913 | date = November 2022 | pmid = 36244350 | pmc = 9630253 | doi = 10.1016/S2468-2667(22)00225-0 | hdl = 10023/26218 | last1vauthors = Mestrovic | first1 = Tomislav | last2 =T, Robles Aguilar | first2 = Gisela | last3 =G, Swetschinski | first3 = Lucien R. | last4 =LR, Ikuta | first4 = Kevin S. | last5 =KS, Gray | first5 = Authia P. | last6 =AP, Davis Weaver | first6 = Nicole | last7 =N, Han | first7 = Chieh | last8 =C, Wool | first8 = Eve E. | last9 =EE, Gershberg Hayoon | first9 = Anna | last10 =A, Hay | first10 = Simon I. | last11 =SI, Dolecek | first11 = Christiane | last12 =C, Sartorius | first12 = Benn | last13 =B, Murray | first13 = Christopher J L. | last14 =CJ, Addo | first14 = Isaac Yeboah | last15 =IY, Ahinkorah | first15 = Bright Opoku | last16 =BO, Ahmed | first16 = Ayman | last17 =A, Aldeyab | first17 = Mamoon A. | last18 =MA, Allel | first18 = Kasim | last19 =K, Ancuceanu | first19 = Robert | last20 =R, Anyasodor | first20 = Anayochukwu Edward | last21 =AE, Ausloos | first21 = Marcel | last22 =M, Barra | first22 = Fabio | last23 =F, Bhagavathula | first23 = Akshaya Srikanth | last24 =AS, Bhandari | first24 = Dinesh | last25 =D, Bhaskar | first25 = Sonu | last26 =S, Cruz-Martins | first26 = Natália | last27 =N, Dastiridou | first27 = Anna | last28 =A, Dokova | first28 = Klara | last29 =K, Dubljanin | first29 = Eleonora | last30 =E, Durojaiye | first30 = Oyewole Christopher | display-authors = 1OC }}</ref>

Antimicrobial resistance is mainly caused by the overuse/misuse of antimicrobials. This leads to microbes either evolving a defense against drugs used to treat them, or certain strains of microbes that have a natural resistance to antimicrobials becoming much more prevalent than the ones that are easily defeated with medication.<ref>{{cite web|url=http://cambridgemedicine.org/files/10-7244/cmj-2017-03-001/,%20http://cambridgemedicine.org/78-2/|title=Antimicrobial Resistance " Cambridge Medicine Journal|language=en|access-date=2020-02-27}}{{Dead link|date=July 2023 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> While antimicrobial resistance does occur naturally over time, the use of antimicrobial agents in a variety of settings both within the healthcare industry and outside of has led to antimicrobial resistance becoming increasingly more prevalent.<ref name=":0Holmes_2016">{{cite journal | vauthors = Holmes AH, Moore LS, Sundsfjord A, Steinbakk M, Regmi S, Karkey A, Guerin PJ, Piddock LJ | display-authors = 6 | title = Understanding the mechanisms and drivers of antimicrobial resistance | journal = Lancet | volume = 387 | issue = 10014 | pages = 176–87 | date = January 2016 | pmid = 26603922 | doi = 10.1016/S0140-6736(15)00473-0 | hdl-access = free | hdl = 10044/1/32225 | s2cid = 1944665 | url = http://pure-oai.bham.ac.uk/ws/files/25678970/Understanding_the_Mechanisms_and_Drivers_of_AMR_25_Aug_2015.docx | access-date = 5 December 2021 | archive-date = 14 April 2022 | archive-url = https://web.archive.org/web/20220414151453/http://pure-oai.bham.ac.uk/ws/files/25678970/Understanding_the_Mechanisms_and_Drivers_of_AMR_25_Aug_2015.docx | url-status = live }}</ref>

Although many microbes develop resistance to antibiotics over time though natural mutation, overprescribing and inappropriate prescription of antibiotics have accelerated the problem. It is possible that as many as 1 in 3 prescriptions written for antibiotics are unnecessary.<ref name="auto2CDC_2016">{{cite web |date=2016-01-01 |title=CDC Newsroom |url=https://www.cdc.gov/media/releases/2016/p0503-unnecessary-prescriptions.html |access-date=2023-02-28 |website=CDC |language=en-us |archive-date=9 March 2023 |archive-url=https://web.archive.org/web/20230309053532/https://www.cdc.gov/media/releases/2016/p0503-unnecessary-prescriptions.html |url-status=live }}</ref> Every year, approximately 154 million prescriptions for antibiotics are written. Of these, up to 46 million are unnecessary or inappropriate for the condition that the patient has.<ref name="auto2CDC_2016"/> Microbes may naturally develop resistance through genetic mutations that occur during cell division, and although random mutations are rare, many microbes reproduce frequently and rapidly, increasing the chances of members of the population acquiring a mutation that increases resistance.<ref name="autoMichael_2014">{{cite journal | vauthors = Michael CA, Dominey-Howes D, Labbate M | title = The antimicrobial resistance crisis: causes, consequences, and management | journal = Frontiers in Public Health | volume = 2 | pages = 145 | date = 2014 | pmid = 25279369 | pmc = 4165128 | doi = 10.3389/fpubh.2014.00145 | doi-access = free }}</ref> Many individuals stop taking antibiotics when they begin to feel better. When this occurs, it is possible that the microbes that are less susceptible to treatment still remain in the body. If these microbes are able to continue to reproduce, this can lead to an infection by bacteria that are less susceptible or even resistant to an antibiotic.<ref name="autoMichael_2014"/>

Antimicrobial resistance can evolve naturally due to continued exposure to antimicrobials. [[Natural selection]] means that organisms that are able to adapt to their environment, survive, and continue to produce offspring.<ref>{{cite web|url=https://evolution.berkeley.edu/evolibrary/article/evo_25|title=Natural selection|website=evolution.berkeley.edu|access-date=2020-03-10|archive-date=30 October 2019|archive-url=https://web.archive.org/web/20191030201404/https://evolution.berkeley.edu/evolibrary/article/evo_25|url-status=live}}</ref> As a result, the types of microorganisms that are able to survive over time with continued attack by certain antimicrobial agents will naturally become more prevalent in the environment, and those without this resistance will become obsolete.<ref name=":0Holmes_2016" />

Over time, most of the strains of bacteria and infections present will be the type resistant to the antimicrobial agent being used to treat them, making this agent now ineffective to defeat most microbes. With the increased use of antimicrobial agents, there is a speeding up of this natural process.<ref name=":1Ferri_2017">{{cite journal | vauthors = Ferri M, Ranucci E, Romagnoli P, Giaccone V | title = Antimicrobial resistance: A global emerging threat to public health systems | journal = Critical Reviews in Food Science and Nutrition | volume = 57 | issue = 13 | pages = 2857–2876 | date = September 2017 | pmid = 26464037 | doi = 10.1080/10408398.2015.1077192 | s2cid = 24549694 }}</ref>

In 89% of countries, antibiotics can only be prescribed by a doctor and supplied by a pharmacy.<ref>{{cite web |title=Global Database for Tracking Antimicrobial Resistance (AMR) Country Self- Assessment Survey (TrACSS) |url=http://amrcountryprogress.org/ |access-date=2023-03-28 |website=amrcountryprogress.org |language=en |archive-date=28 March 2023 |archive-url=https://web.archive.org/web/20230328115257/http://amrcountryprogress.org/ |url-status=live }}</ref> [[Self-medication]] by consumers is defined as "the taking of medicines on one's own initiative or on another person's suggestion, who is not a certified medical professional", and it has been identified as one of the primary reasons for the evolution of antimicrobial resistance.<ref name=":2Rather_2017">{{cite journal | vauthors = Rather IA, Kim BC, Bajpai VK, Park YH | title = Self-medication and antibiotic resistance: Crisis, current challenges, and prevention | journal = Saudi Journal of Biological Sciences | volume = 24 | issue = 4 | pages = 808–812 | date = May 2017 | pmid = 28490950 | pmc = 5415144 | doi = 10.1016/j.sjbs.2017.01.004 }}</ref> Self-medication with antibiotics is an unsuitable way of using them but a common practice in resource-constrained countries. The practice exposes individuals to the risk of bacteria that have developed antimicrobial resistance.<ref name=nft1>{{cite journal | vauthors = Torres NF, Chibi B, Middleton LE, Solomon VP, Mashamba-Thompson TP | title = Evidence of factors influencing self-medication with antibiotics in low and middle-income countries: a systematic scoping review | journal = Public Health | volume = 168 | pages = 92–101 | date = March 2019 | pmid = 30716570 | doi = 10.1016/j.puhe.2018.11.018 | s2cid = 73434085 }}</ref> Many people resort to this out of necessity, when access to a physician is unavailable due to lockdowns and GP surgery closures, or when the patients have a limited amount of time or money to see a prescribing doctor.<ref>{{cite journal | vauthors = Ayukekbong JA, Ntemgwa M, Atabe AN | title = The threat of antimicrobial resistance in developing countries: causes and control strategies | journal = Antimicrobial Resistance and Infection Control | volume = 6 | issue = 1 | pages = 47 | date = 2017-05-15 | pmid = 28515903 | pmc = 5433038 | doi = 10.1186/s13756-017-0208-x | doi-access = free }}</ref> This increased access makes it extremely easy to obtain antimicrobials and an example is India, where in the state of [[Punjab]] 73% of the population resorted to treating their minor health issues and chronic illnesses through self-medication.<ref name=":2Rather_2017" />

Self-medication is higher outside the hospital environment, and this is linked to higher use of antibiotics, with the majority of antibiotics being used in the community rather than hospitals. The prevalence of self-medication in [[Developing country|low- and middle-income countries]] (LMICs) ranges from 8.1% to very high at 93%. Accessibility, affordability, and conditions of health facilities, as well as the health-seeking behavior, are factors that influence self-medication in low- and middle-income countries (LMICs).<ref name=nft1 /> Two significant issues with self-medication are the lack of knowledge of the public on, firstly, the dangerous effects of certain antimicrobials (for example [[ciprofloxacin]] which can cause [[Tendinopathy|tendonitis]], [[tendon rupture]] and [[aortic dissection]])<ref>{{cite journal | vauthors = Chen C, Patterson B, Simpson R, Li Y, Chen Z, Lv Q, Guo D, Li X, Fu W, Guo B | display-authors = 6 | title = Do fluoroquinolones increase aortic aneurysm or dissection incidence and mortality? A systematic review and meta-analysis | journal = Frontiers in Cardiovascular Medicine | volume = 9 | pages = 949538 | date = 2022-08-09 | pmid = 36017083 | pmc = 9396038 | doi = 10.3389/fcvm.2022.949538 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Shu Y, Zhang Q, He X, Liu Y, Wu P, Chen L | title = Fluoroquinolone-associated suspected tendonitis and tendon rupture: A pharmacovigilance analysis from 2016 to 2021 based on the FAERS database | journal = Frontiers in Pharmacology | volume = 13 | pages = 990241 | date = 2022-09-06 | pmid = 36147351 | pmc = 9486157 | doi = 10.3389/fphar.2022.990241 | doi-access = free }}</ref> and, secondly, broad microbial resistance and when to seek medical care if the infection is not clearing. In order to determine the public's knowledge and preconceived notions on antibiotic resistance, a screening of 3,537 articles published in Europe, Asia, and North America was done. Of the 55,225 total people surveyed in the articles, 70% had heard of antibiotic resistance previously, but 88% of those people thought it referred to some type of physical change in the human body.<ref name=":2Rather_2017" />

Important to the conversation of antibiotic use is the veterinary medical system. Veterinary oversight is required by law for all medically important antibiotics. <ref>{{Cite web |title=Antimicrobials {{!}} American Veterinary Medical Association |url=https://www.avma.org/resources-tools/one-health/antimicrobial-use-and-antimicrobial-resistance |access-date=2024-04-24 |website=www.avma.org |language=en |archive-date=24 April 2024 |archive-url=https://web.archive.org/web/20240424183923/https://www.avma.org/resources-tools/one-health/antimicrobial-use-and-antimicrobial-resistance |url-status=live }}</ref> Veterinarians use the Pharmacokinetic/pharmacodynamic model (PK/PD) approach to ensuring that the correct dose of the drug is delivered to the correct place at the correct timing.<ref>{{Citecite journal |last1 vauthors = Caneschi |first1=AliceA, |last2=Bardhi |first2=AnisaA, |last3=Barbarossa |first3=AndreaA, |last4=Zaghini |first4=AnnaA |date=March 2023title |title= The Use of Antibiotics and Antimicrobial Resistance in Veterinary Medicine, a Complex Phenomenon: A Narrative Review | journal = Antibiotics |language=en |volume = 12 | issue = 3 | pages = 487 |doi=10.3390/antibiotics12030487 |doi-accessdate =free March 2023 | pmid = 36978354 | pmc = 10044628 |issn doi =2079 10.3390/antibiotics12030487 | doi-6382access = free }}</ref>

Farmers typically use antibiotics in animal feed to improve growth rates and prevent infections. However, this is illogical as antibiotics are used to treat infections and not prevent infections. 80% of antibiotic use in the U.S. is for agricultural purposes and about 70% of these are medically important.<ref>{{cite journal |last1 vauthors = Martin |first1=MichaelMJ, J. |last2=Thottathil |first2=SapnaSE, E |last3=Newman TB |first3=Thomas B.title |title= Antibiotics Overuse in Animal Agriculture: A Call to Action for Health Care Providers | journal = American Journal of Public Health |pages volume =2409–2410 105 |doi issue =10.2105/AJPH.2015.302870 12 | pages = 2409–2410 | date = December 2015|volume=105 |issue=12 |pmid = 26469675 | pmc = 4638249 | doi = 10.2105/AJPH.2015.302870 }}</ref> Overusing antibiotics gives the bacteria time to adapt leaving higher doses or even stronger antibiotics needed to combat the infection. Though antibiotics for growth promotion were banned throughout the EU in 2006, 40 countries worldwide still use antibiotics to promote growth.<ref>{{cite web |title=Farm antibiotic use |url=https://www.saveourantibiotics.org/the-issue/antibiotic-overuse-in-livestock-farming/ |website=www.saveourantibiotics.org |language=en |access-date=21 March 2024 |archive-date=3 April 2024 |archive-url=https://web.archive.org/web/20240403061957/https://www.saveourantibiotics.org/the-issue/antibiotic-overuse-in-livestock-farming/ |url-status=live }}</ref>

By mapping antimicrobial consumption in livestock globally, it was predicted that in 228 countries there would be a total 67% increase in consumption of antibiotics by livestock by 2030. In some countries such as Brazil, Russia, India, China, and South Africa it is predicted that a 99% increase will occur.<ref name=":1Ferri_2017" /> Several countries have restricted the use of antibiotics in livestock, including Canada, China, Japan, and the US. These restrictions are sometimes associated with a reduction of the [[prevalence]] of antimicrobial resistance in humans.<ref name="Innes">{{cite journal | vauthors = Innes GK, Randad PR, Korinek A, Davis MF, Price LB, So AD, Heaney CD | title = External Societal Costs of Antimicrobial Resistance in Humans Attributable to Antimicrobial Use in Livestock | journal = Annual Review of Public Health | volume = 41 | issue = 1 | pages = 141–157 | date = April 2020 | pmid = 31910712 | pmc = 7199423 | doi = 10.1146/annurev-publhealth-040218-043954 }}</ref>

In the United states the [[Veterinary Feed Directive]] went into practice in 2017 dictating that ''All medically important antibiotics to be used in feed or water for food animal species require a veterinary feed directive (VFD) or a prescription.''<ref>{{Cite web |title=Veterinary feed directive (VFD) basics {{!}} American Veterinary Medical Association |url=https://www.avma.org/resources-tools/one-health/antimicrobial-use-and-antimicrobial-resistance/veterinary-feed-directive-basics |access-date=2024-04-24 |website=www.avma.org |language=en |archive-date=24 April 2024 |archive-url=https://web.archive.org/web/20240424183927/https://www.avma.org/resources-tools/one-health/antimicrobial-use-and-antimicrobial-resistance/veterinary-feed-directive-basics |url-status=live }}</ref>

Most [[pesticide]]s protect crops against insects and plants, but in some cases antimicrobial pesticides are used to protect against various microorganisms such as bacteria, viruses, fungi, algae, and protozoa. The overuse of many pesticides in an effort to have a higher yield of crops has resulted in many of these microbes evolving a tolerance against these antimicrobial agents. Currently there are over 4000 antimicrobial pesticides registered with the US [[United States Environmental Protection Agency|Environmental Protection Agency]] (EPA) and sold to market, showing the widespread use of these agents.<ref>{{cite web|url=https://www.epa.gov/pesticide-registration/what-are-antimicrobial-pesticides|title=What are Antimicrobial Pesticides?|last=US EPA|first=OCSPP|date=2013-03-15|website=US EPA|language=en|access-date=2020-02-28|archive-date=27 November 2022|archive-url=https://web.archive.org/web/20221127101423/https://www.epa.gov/pesticide-registration/what-are-antimicrobial-pesticides|url-status=live}}</ref> It is estimated that for every single meal a person consumes, 0.3&nbsp;g of pesticides is used, as 90% of all pesticide use is in agriculture. A majority of these products are used to help defend against the spread of infectious diseases, and hopefully protect public health. But out of the large amount of pesticides used, it is also estimated that less than 0.1% of those antimicrobial agents, actually reach their targets. That leaves over 99% of all pesticides used available to contaminate other resources.<ref>{{cite journal | vauthors = Ramakrishnan B, Venkateswarlu K, Sethunathan N, Megharaj M | title = Local applications but global implications: Can pesticides drive microorganisms to develop antimicrobial resistance? | journal = The Science of the Total Environment | volume = 654 | pages = 177–189 | date = March 2019 | pmid = 30445319 | doi = 10.1016/j.scitotenv.2018.11.041 | s2cid = 53568193 | bibcode = 2019ScTEn.654..177R }}</ref> In soil, air, and water these antimicrobial agents are able to spread, coming in contact with more microorganisms and leading to these microbes evolving mechanisms to tolerate and further resist pesticides. The use of antifungal [[azole]] pesticides that drive environmental azole resistance have been linked to azole resistance cases in the clinical setting.<ref>{{cite journal | vauthors = Rhodes J, Abdolrasouli A, Dunne K, Sewell TR, Zhang Y, Ballard E, Brackin AP, van Rhijn N, Chown H, Tsitsopoulou A, Posso RB, Chotirmall SH, McElvaney NG, Murphy PG, Talento AF, Renwick J, Dyer PS, Szekely A, Bowyer P, Bromley MJ, Johnson EM, Lewis White P, Warris A, Barton RC, Schelenz S, Rogers TR, Armstrong-James D, Fisher MC | display-authors = 6 | title = Population genomics confirms acquisition of drug-resistant Aspergillus fumigatus infection by humans from the environment | journal = Nature Microbiology | volume = 7 | issue = 5 | pages = 663–674 | date = May 2022 | pmid = 35469019 | pmc = 9064804 | doi = 10.1038/s41564-022-01091-2 }}</ref> The same issues confront the novel antifungal classes (e.g. [[orotomide]]s) which are again being used in both the clinic and agriculture.<ref name="auto1Verweij_2022">{{cite journal | vauthors = Verweij PE, Arendrup MC, Alastruey-Izquierdo A, Gold JA, Lockhart SR, Chiller T, White PL | title = Dual use of antifungals in medicine and agriculture: How do we help prevent resistance developing in human pathogens? | journal = Drug Resistance Updates | volume = 65 | pages = 100885 | date = December 2022 | pmid = 36283187 | doi = 10.1016/j.drup.2022.100885 | pmc = 10693676 | s2cid = 253052170 | doi-access = free }}</ref>

[[Permafrost]] is a term used to refer to any ground that remained frozen for two years or more, with the oldest known examples continuously frozen for around 700,000 years.<ref name="MIT2022">{{cite web |url=https://climate.mit.edu/explainers/permafrost |title=Permafrost |last1 vauthors = McGee |first1=DavidD, |last2=Gribkoff |first2=ElizabethE |date=4 August 2022 |website=MIT Climate Portal |access-date=27 September 2023 |archive-date=27 September 2023 |archive-url=https://web.archive.org/web/20230927153347/https://climate.mit.edu/explainers/permafrost |url-status=live }}</ref> In the recent decades, permafrost has been rapidly thawing due to [[climate change]].<ref name="AR6_WG1_Chapter922">Fox-Kemper, B., H.T. Hewitt, C. Xiao, G. Aðalgeirsdóttir, S.S. Drijfhout, T.L. Edwards, N.R. Golledge, M. Hemer, R.E. Kopp, G.&nbsp; Krinner, A. Mix, D. Notz, S. Nowicki, I.S. Nurhati, L. Ruiz, J.-B. Sallée, A.B.A. Slangen, and Y. Yu, 2021: [https://www.ipcc.ch/report/ar6/wg1/downloads/report/IPCC_AR6_WGI_Chapter09.pdf Chapter 9: Ocean, Cryosphere and Sea Level Change] {{Webarchive|url=https://web.archive.org/web/20221024162651/https://www.ipcc.ch/report/ar6/wg1/downloads/report/IPCC_AR6_WGI_Chapter09.pdf |date=24 October 2022 }}. In [https://www.ipcc.ch/report/ar6/wg1/ Climate Change 2021: The Physical Science Basis. Contribution of Working Group I to the Sixth Assessment Report of the Intergovernmental Panel on Climate Change] {{Webarchive|url=https://web.archive.org/web/20230526182346/https://www.ipcc.ch/report/ar6/wg1/downloads/report/IPCC_AR6_WGI_Chapter09.pdf |date=26 May 2023 }} [Masson-Delmotte, V., P. Zhai, A. Pirani, S.L.&nbsp; Connors, C. Péan, S. Berger, N. Caud, Y. Chen, L. Goldfarb, M.I. Gomis, M. Huang, K. Leitzell, E. Lonnoy, J.B.R. Matthews, T.K. Maycock, T. Waterfield, O. Yelekçi, R. Yu, and B. Zhou (eds.)]. Cambridge University Press, Cambridge, United Kingdom and New York, NY, USA, pp. 1211–1362, doi:10.1017/9781009157896.011.</ref>{{rp|1237}} The cold preserves any [[organic matter]] inside the permafrost, and it is possible for microorganisms to resume their life functions once it thaws. While some common [[pathogen]]s such as [[influenza]], [[smallpox]] or the bacteria associated with [[pneumonia]] have failed to survive intentional attempts to revive them,<ref name="Doucleff2020">{{cite web |url=https://www.npr.org/sections/goatsandsoda/2020/05/19/857992695/are-there-zombie-viruses-like-the-1918-flu-thawing-in-the-permafrost |title=Are There Zombie Viruses — Like The 1918 Flu — Thawing In The Permafrost? |first1 vauthors = Michaeleen |last1=DoucleffD |website=NPR.org |access-date=4 April 2023|archive-date=24 April 2023 |archive-url=https://web.archive.org/web/20230424072912/https://www.npr.org/sections/goatsandsoda/2020/05/19/857992695/are-there-zombie-viruses-like-the-1918-flu-thawing-in-the-permafrost |url-status=live }}</ref> more cold-adapted microorganisms such as [[anthrax]], or several ancient [[plant]] and [[amoeba]] viruses, have successfully survived prolonged thaw.<ref name="Doucleff2016">{{cite web|url=https://www.npr.org/sections/goatsandsoda/2016/08/03/488400947/anthrax-outbreak-in-russia-thought-to-be-result-of-thawing-permafrost|title=Anthrax Outbreak In Russia Thought To Be Result Of Thawing Permafrost|website=NPR.org |url-status=live|archive-url=https://web.archive.org/web/20160922013246/http://www.npr.org/sections/goatsandsoda/2016/08/03/488400947/anthrax-outbreak-in-russia-thought-to-be-result-of-thawing-permafrost|archive-date=2016-09-22|access-date=2016-09-24}}</ref><ref>{{cite journal |last1=Ng |first1vauthors =Terry FeiNg FanTF, |last2=Chen |first2=Li-FangLF, |last3=Zhou |first3=YanchenY, |last4=Shapiro |first4=BethB, |last5=Stiller |first5=MathiasM, |last6=Heintzman |first6=PeterPD, D. |last7=Varsani |first7=ArvindA, |last8=Kondov |first8=NikolaNO, O. |last9=Wong |first9=WaltW, |last10=Deng |first10=XutaoX, |last11=Andrews |first11=ThomasTD, D. |last12=Moorman |first12=BrianBJ, J. |last13=Meulendyk |first13=ThomasT, |last14=MacKay |first14=GlenG, |last15=Gilbertson |first15=RobertRL, |last16=Delwart E |first16 display-authors =Eric 6 | title = Preservation of viral genomes in 700-y-old caribou feces from a subarctic ice patch | journal = Proceedings of the National Academy of Sciences |date=27of Octoberthe 2014United States of America | volume = 111 | issue = 47 | pages = 16842–16847 |doi date =10.1073/pnas.1410429111 November 2014 | pmid = 25349412 | pmc = 4250163 |bibcode doi =2014PNAS 10.1073/pnas.11116842N1410429111 | doi-access = free | bibcode = 2014PNAS..11116842N }}</ref><ref name="Legendre 2015 E5327–E5335">{{cite journal |last1 vauthors = Legendre|first1=Matthieu|last2= M, Lartigue|first2=Audrey|last3= A, Bertaux|first3=Lionel|last4= L, Jeudy|first4=Sandra|last5= S, Bartoli|first5=Julia|last6= J, Lescot|first6=Magali|last7= M, Alempic|first7=Jean-Marie|last8= JM, Ramus|first8=Claire|last9= C, Bruley|first9=Christophe|last10= C, Labadie |first10=Karine|last11=K, Shmakova L, Rivkina E, Couté Y, Abergel C, Claverie JM |first11 display-authors =Lyubov|date=2015 6 | title = In-depth study of Mollivirus sibericum, a new 30,000-y-old giant virus infecting Acanthamoeba | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 112 | issue = 38 | pages = E5327–E5335 | date = September 2015 | pmid = 26351664 | pmc = 4586845 | doi = 10.1073/pnas.1510795112 |jstor doi-access =26465169|pmid=26351664|pmc=4586845 free | bibcode = 2015PNAS..112E5327L |doi-access jstor =free 26465169 }}</ref><ref name="Alempic2023">{{cite journal |last1 vauthors = Alempic|first1=Jean-Marie|last2= JM, Lartigue|first2=Audrey |last3=A, Goncharov|first3=Artemiy|last4= AE, Grosse|first4=Guido|last5= G, Strauss |first5=Jens|last6=J, Tikhonov|first6=Alexey N.AN, |last7=Fedorov|first7=Alexander N.|last8=AN, Poirot|first8=Olivier|last9= O, Legendre|first9=Matthieu |last10=M, Santini|first10=Sébastien |last11=S, Abergel|first11=Chantal |last12=C, Claverie JM |first12=Jean display-Michelauthors |date=18 February6 2023| title = An Update on Eukaryotic Viruses Revived from Ancient Permafrost | journal = Viruses | volume = 15 | issue = 2 | page = 564 |doi date =10.3390/v15020564 February 2023 | pmid = 36851778 | pmc = 9958942 | doi = 10.3390/v15020564 | doi-access = free }}</ref><ref name="Alund2023">{{cite news |url=https://www.usatoday.com/story/news/health/2023/03/09/zombie-virus-frozen-permafrost-revived-after-50-000-years/11434218002/ |title=Scientists revive 'zombie virus' that was frozen for nearly 50,000 years |first1=Natalie Neysa |last1=Alund |date=9 March 2023 |website=[[USA Today]] |access-date=2023-04-23 |archive-date=2023-04-24 |archive-url=https://web.archive.org/web/20230424073604/https://www.usatoday.com/story/news/health/2023/03/09/zombie-virus-frozen-permafrost-revived-after-50-000-years/11434218002/ |url-status=live }}</ref>

Some scientists have argued that the inability of known [[disease causative agent|causative agent]]s of [[contagious disease]]s to survive being frozen and thawed makes this threat unlikely. Instead, there have been suggestions that when modern pathogenic bacteria interact with the ancient ones, they may, through [[horizontal gene transfer]], pick up [[genetic sequence]]s which are associated with antimicrobial resistance, exacerbating an already difficult issue.<ref name="Sajjad2020">{{cite journal |last1 vauthors = Sajjad|first1=Wasim |last2=W, Rafiq |first2=MuhammadM, |last3=Din|first3=Ghufranud|last4= G, Hasan|first4=Fariha |last5=F, Iqbal|first5=Awais |last6=A, Zada|first6=Sahib|last7= S, Ali|first7=Barkat|last8= B, Hayat|first8=Muhammad |last9=M, Irfan|first9=Muhammad|last10= M, Kang|first10=Shichang S |date display-authors =15 September6 2020| title = Resurrection of inactive microbes and resistome present in the natural frozen world: Reality or myth? | journal = The Science of the Total Environment | volume = 735 |page pages = 139275 | date = September 2020 | pmid = 32480145 | doi = 10.1016/j.scitotenv.2020.139275|pmid=32480145 |bibcode=2020ScTEn.735m9275S |s2cid = 219169932 | doi-access = | bibcode = 2020ScTEn.73539275S }}</ref> Antibiotics to which permafrost bacteria have displayed at least some resistance include [[chloramphenicol]], [[streptomycin]], [[kanamycin]], [[gentamicin]], [[tetracycline]], [[spectinomycin]] and [[neomycin]].<ref name="Miner2021">{{cite journal |last1=Miner |first1vauthors =Kimberley R.Miner KR, |last2=D'Andrilli |first2=JulianaJ, |last3=Mackelprang |first3=RachelR, |last4=Edwards |first4=ArwynA, |last5=Malaska |first5=MichaelMJ, J. |last6=Waldrop |first6=MarkMP, P. |last7=Miller |first7=Charles E.CE |date=30 September 2021 |title=Emergent biogeochemical risks from Arctic permafrost degradation |journal=Nature Climate Change |volume=11 |issue=1 |pages=809–819 |doi=10.1038/s41558-021-01162-y |bibcode=2021NatCC..11..809M |s2cid=238234156 }}</ref> However, other studies show that resistance levels in ancient bacteria to modern antibiotics remain lower than in the contemporary bacteria from the [[active layer]] of thawed ground above them,<ref name="Perron2015">{{cite journal |last1 vauthors = Perron|first1=Gabriel G.|last2=GG, Whyte |first2=Lyle|last3=L, Turnbaugh|first3=Peter PJ, Goordial J.|last4=Goordial|first4=Jacqueline|last5=, Hanage|first5=William P.|last6=WP, Dantas|first6=Gautam |last7=Desai|first7=Michael M.G, Desai |date=25MM March| 2015|title = Functional Characterizationcharacterization of Bacteriabacteria Isolatedisolated from Ancientancient Arcticarctic Soilsoil Exposesexposes Diversediverse Resistanceresistance Mechanismsmechanisms to Modernmodern Antibioticsantibiotics | journal = PLOS ONE | volume = 10 | issue = 3 | pages = e0069533 | date = 25 March 2015 | pmid = 25807523 | pmc = 4373940 | doi = 10.1371/journal.pone.0069533 |pmid=25807523 |pmcdoi-access =4373940 free | bibcode = 2015PLoSO..1069533P |doi-access=free}}</ref> which may mean that this risk is "no greater" than from any other soil.<ref name="Wu2022">{{cite journal|last1 vauthors = Wu|first1=Rachel|last2= R, Trubl|first2=Gareth|last3=Tas|first3=Neslihan |last4=G, Taş N, Jansson|first4=Janet K.JK |date=15 April 2022|title=Permafrost as a potential pathogen reservoir|journal=One Earth |volume=5|issue=4|pages=351–360 |doi=10.1016/j.oneear.2022.03.010 |bibcode=2022OEart...5..351W |s2cid=248208195 |doi-access=free}}</ref>

Delaying or minimizing the use of antibiotics for certain conditions may help safely reduce their use.<ref name=":15Spurling_2023">{{cite journal |last1 vauthors = Spurling |first1=GeoffreyGK, KP |last2=Dooley |first2=LizL, |last3=Clark |first3=JustinJ, |last4=Askew |first4=Deborah ADA |date=2023-10-04 |editor-last=Cochrane Acute Respiratory Infections Group |title = Immediate versus delayed versus no antibiotics for respiratory infections | journal = The Cochrane Database of Systematic Reviews |language=en |volume = 2023 | issue = 10 | pages = CD004417 | date = October 2023 | pmid = 37791590 | pmc = 10548498 | doi = 10.1002/14651858.CD004417.pub6 |pmc=10548498 |pmid=37791590 |pmc-embargo-date = October 4, 2024 | editor-last = Cochrane Acute Respiratory Infections Group }}</ref> Antimicrobial treatment duration should be based on the infection and other health problems a person may have.<ref name=NPS2013/><!-- "When optimising therapy for an infection consider the person's immune status, the infecting agent and the focus of infection." --> For many infections once a person has improved there is little evidence that stopping treatment causes more resistance.<ref name=NPS2013/><!-- "There does not appear to be strong evidence to support the notion that stopping antibiotics before the end of the recommended treatment contributes to increasing resistance" --> Some, therefore, feel that stopping early may be reasonable in some cases.<ref name=NPS2013/><!-- "Therefore, in selected cases, it may be appropriate to stop antibiotic therapy early." --> Other infections, however, do require long courses regardless of whether a person feels better.<ref name=NPS2013/><!-- "For some infections, such as Staphylococcus aureus bacteraemia, enterococcal endocarditis or tuberculosis, clear evidence favours prolonged treatment to prevent relapse" -->

Delaying antibiotics for ailments such as a sore throat and otitis media may have not different in the rate of complications compared with immediate antibiotics, for example.<ref name=":15Spurling_2023" /> When treating respiratory tract infections, clinical judgement is required as to the appropriate treatment (delayed or immediate antibiotic use).<ref name=":15Spurling_2023" />

The study, "Shorter and Longer Antibiotic Durations for Respiratory Infections: To Fight Antimicrobial Resistance—A Retrospective Cross-Sectional Study in a Secondary Care Setting in the UK," highlights the urgency of reevaluating antibiotic treatment durations amidst the global challenge of antimicrobial resistance (AMR). It investigates the effectiveness of shorter versus longer antibiotic regimens for respiratory tract infections (RTIs) in a UK secondary care setting, emphasizing the need for evidence-based prescribing practices to optimize patient outcomes and combat AMR. <ref>{{cite journal | vauthors = Abdelsalam Elshenawy R, Umaru N, Aslanpour Z | title = Shorter and Longer Antibiotic Durations for Respiratory Infections: To Fight Antimicrobial Resistance—AResistance-A Retrospective Cross-Sectional Study in a Secondary Care Setting in the UK | journal = Pharmaceuticals | volume = 17 | issue = 3 | pages = 339 | date = March 6, 2024 |pages pmid =339 38543125 |author=Abdelsalam Elshenawy,pmc Rasha= 10975983 | doi = 10.3390/ph17030339 | doi-access=free |pmid=38543125 |pmc=10975983free }}</ref>

By comparison there is a lack of national and international monitoring programs for antifungal resistance.<ref name=":11Fisher_2022" />

The [[WHO AWaRe]] (Access, Watch, Reserve) guidance and antibiotic book has been introduced to guide antibiotic choice for the 30 most common infections in adults and children to reduce inappropriate prescribing in primary care and hospitals. [[Narrow-spectrum antibiotic|Narrow spectrum antibiotics]]s are preferred due to their lower resistance potential, and [[broad-spectrum antibiotic]]s are only recommended for people with more severe symptoms. Some antibiotics are more likely to confer resistance, so are kept as reserve antibiotics in the AWaRe book.<ref name=":13WHO_2022" />

People can help tackle resistance by using antibiotics only when infected with a bacterial infection and prescribed by a doctor; completing the full prescription even if the user is feeling better, never sharing antibiotics with others, or using leftover prescriptions.<ref name="who.int" /> Taking antibiotics when not needed won't help the user, but instead give bacteria the option to adapt and leave the user with the side effects that come with the certain type of antibiotic.<ref name="auto3CDC_2022">{{cite web |title=Are you using antibiotics wisely? |url=https://www.cdc.gov/antibiotic-use/do-and-dont.html |website=Centers for Disease Control and Prevention |language=en-us |date=3 January 2022 |access-date=21 March 2024 |archive-date=21 March 2024 |archive-url=https://web.archive.org/web/20240321051000/https://www.cdc.gov/antibiotic-use/do-and-dont.html |url-status=live }}</ref> The CDC recommends that you follow these behaviors so that you avoid these negative side effects and keep the community safe from spreading drug-resistant bacteria.<ref name="auto3CDC_2022"/> Practicing basic bacterial infection prevention courses, such as hygiene, also helps to prevent the spread of antibiotic-resistant bacteria.<ref>{{Cite web|url=https://www.cedars-sinai.org/health-library/articles.html|title=Articles|website=Cedars-Sinai|access-date=23 March 2024|archive-date=30 May 2020|archive-url=https://web.archive.org/web/20200530132825/https://www.cedars-sinai.org/health-library/articles.html|url-status=dead}}</ref>

Infectious disease control through improved [[WASH|water, sanitation and hygiene (WASH)]] infrastructure needs to be included in the antimicrobial resistance (AMR) agenda. The "Interagency Coordination Group on Antimicrobial Resistance" stated in 2018 that "the spread of pathogens through unsafe water results in a high burden of gastrointestinal disease, increasing even further the need for antibiotic treatment."<ref name=":4IACG">IACG (2018) [https://www.who.int/antimicrobial-resistance/interagency-coordination-group/IACG_Optimize_use_of_antimicrobials_120718.pdf?ua=1 Reduce unintentional exposure and the need for antimicrobials, and optimize their use IACG Discussion Paper] {{Webarchive|url=https://web.archive.org/web/20210706080228/https://www.who.int/antimicrobial-resistance/interagency-coordination-group/IACG_Optimize_use_of_antimicrobials_120718.pdf?ua=1 |date=6 July 2021 }}, Interagency Coordination Group on Antimicrobial Resistance, [https://web.archive.org/web/20180726093245/http://www.who.int/antimicrobial-resistance/interagency-coordination-group/public-consultation-discussion-papers/en/ public consultation process] at WHO, Geneva, Switzerland</ref> This is particularly a problem in [[developing countries]] where the spread of infectious diseases caused by inadequate WASH standards is a major driver of antibiotic demand.<ref name="Araya">{{cite web|url=https://amr-review.org/sites/default/files/LSE%20AMR%20Capstone.pdf|title=The Impact of Water and Sanitation on Diarrhoeal Disease Burden and Over-Consumption of Anitbiotics.| vauthors = Araya P |date=May 2016|access-date=12 November 2017|archive-url=https://web.archive.org/web/20171001195326/https://amr-review.org/sites/default/files/LSE%20AMR%20Capstone.pdf|archive-date=1 October 2017|url-status=live}}</ref> Growing usage of antibiotics together with persistent infectious disease levels have led to a dangerous cycle in which reliance on antimicrobials increases while the efficacy of drugs diminishes.<ref name="Araya" /> The proper use of infrastructure for water, sanitation and hygiene (WASH) can result in a 47–72 percent decrease of diarrhea cases treated with antibiotics depending on the type of intervention and its effectiveness.<ref name="Araya" /> A reduction of the diarrhea disease burden through improved infrastructure would result in large decreases in the number of diarrhea cases treated with antibiotics. This was estimated as ranging from 5 million in Brazil to up to 590&nbsp;million in India by the year 2030.<ref name="Araya" /> The strong link between increased consumption and resistance indicates that this will directly mitigate the accelerating spread of AMR.<ref name="Araya" /> Sanitation and water for all by 2030 is [[Sustainable Development Goal 6|Goal Number 6]] of the [[Sustainable Development Goals]].<ref>{{cite web |title=Goal 6: Ensure availability and sustainable management of water and sanitation for all |url=https://sdgs.un.org/goals/goal6 |access-date=2023-04-17 |website=United Nations Department of Economic and Social Affairs |archive-date=24 September 2020 |archive-url=https://archive.today/20200924190731/https://sdgs.un.org/goals/goal6 |url-status=live }}</ref>

Water supply and sanitation infrastructure in health facilities offer significant co-benefits for combatting AMR, and investment should be increased.<ref name=":4IACG" /> There is much room for improvement: WHO and UNICEF estimated in 2015 that globally 38% of health facilities did not have a source of water, nearly 19% had no toilets and 35% had no water and soap or alcohol-based hand rub for handwashing.<ref>WHO, UNICEF (2015). [https://www.susana.org/en/knowledge-hub/resources-and-publications/library/details/2374 Water, sanitation and hygiene in health care facilities – Status in low and middle income countries and way forward] {{Webarchive|url=https://web.archive.org/web/20180912092005/https://www.susana.org/en/knowledge-hub/resources-and-publications/library/details/2374 |date=12 September 2018 }}. World Health Organization (WHO), Geneva, Switzerland, {{ISBN|978 92 4 150847 6}}</ref>

Manufacturers of antimicrobials need to improve the treatment of their wastewater (by using [[industrial wastewater treatment]] processes) to reduce the release of residues into the environment.<ref name=":4IACG" />

Unlike resistance to antibacterials, antifungal resistance can be driven by [[Arable land|arable farming]], currently there is no regulation on the use of similar antifungal classes in agriculture and the clinic.<ref name=":11Fisher_2022" /><ref name="auto1Verweij_2022"/>

The [[United States Department of Agriculture]] (USDA) and the [[Food and Drug Administration]] (FDA) collect data on antibiotic use in humans and in a more limited fashion in animals.<ref name="gao">{{cite web|url=http://www.gao.gov/assets/330/323097.html|title=GAO-11-801, Antibiotic Resistance: Agencies Have Made Limited Progress Addressing Antibiotic Use in Animals|publisher=gao.gov|access-date=25 January 2014|archive-url=https://web.archive.org/web/20131105120254/http://www.gao.gov/assets/330/323097.html|archive-date=5 November 2013|url-status=live}}</ref> About 80% of antibiotic use in the U.S. is for agriculture purposes, and about 70% of these are medically important.<ref>{{cite journal |last1 vauthors = Martin |first1=MichaelMJ, J. |last2=Thottathil |first2=SapnaSE, E |last3=Newman TB |first3=Thomas B.title |title= Antibiotics Overuse in Animal Agriculture: A Call to Action for Health Care Providers | journal = American Journal of Public Health |pages volume =2409–2410 105 |doi issue =10.2105/AJPH.2015.302870 12 | pages = 2409–2410 | date = December 2015|volume=105 |issue=12 |pmid = 26469675 | pmc = 4638249 | doi = 10.2105/AJPH.2015.302870 }}</ref> This gives reason for concern about the antibiotic resistance crisis in the U.S. and more reason to monitor it. The FDA first determined in 1977 that there is evidence of emergence of antibiotic-resistant bacterial strains in livestock. The long-established practice of permitting OTC sales of antibiotics (including penicillin and other drugs) to lay animal owners for administration to their own animals nonetheless continued in all states.

The increasing interconnectedness of the world and the fact that new classes of antibiotics have not been developed and approved for more than 25 years highlight the extent to which antimicrobial resistance is a global health challenge.<ref>{{cite web|url=https://www.rand.org/randeurope/research/health/focus-on-antimicrobial-resistance.html|title=RAND Europe Focus on Antimicrobial Resistance (AMR)|website=www.rand.org|access-date=23 April 2018|archive-url=https://web.archive.org/web/20180421004546/https://www.rand.org/randeurope/research/health/focus-on-antimicrobial-resistance.html|archive-date=21 April 2018|url-status=live}}</ref> A global action plan to tackle the growing problem of resistance to antibiotics and other antimicrobial medicines was endorsed at the Sixty-eighth [[World Health Assembly]] in May 2015.<ref name=":1a">{{cite web |url= http://www.wpro.who.int/entity/drug_resistance/resources/global_action_plan_eng.pdf |title= Global Action Plan on Antimicrobial Resistance | publisher = WHO |access-date=14 November 2017|archive-url= https://web.archive.org/web/20171031170522/http://www.wpro.who.int/entity/drug_resistance/resources/global_action_plan_eng.pdf |archive-date=31 October 2017|url-status=dead}}</ref> One of the key objectives of the plan is to improve awareness and understanding of antimicrobial resistance through effective communication, education and training. This global action plan developed by the World Health Organization was created to combat the issue of antimicrobial resistance and was guided by the advice of countries and key stakeholders. The WHO's global action plan is composed of five key objectives that can be targeted through different means, and represents countries coming together to solve a major problem that can have future health consequences.<ref name=":1Ferri_2017" /> These objectives are as follows:

In 2016 the Secretary-General of the [[United Nations]] convened the Interagency Coordination Group (IACG) on Antimicrobial Resistance.<ref name=":5WHO_2">{{cite web|url=https://www.who.int/antimicrobial-resistance/interagency-coordination-group/en/|archive-url=https://web.archive.org/web/20170320110535/http://www.who.int/antimicrobial-resistance/interagency-coordination-group/en/|url-status=dead|archive-date=20 March 2017|title=WHO {{!}} UN Interagency Coordination Group (IACG) on Antimicrobial Resistance|website=WHO|access-date=7 August 2019}}</ref> The IACG worked with international organizations and experts in human, animal, and plant health to create a plan to fight antimicrobial resistance.<ref name=":5WHO_2" /> Their report released in April 2019 highlights the seriousness of antimicrobial resistance and the threat it poses to world health. It suggests five recommendations for member states to follow in order to tackle this increasing threat. The IACG recommendations are as follows:<ref>{{cite report |url=https://www.who.int/docs/default-source/documents/no-time-to-wait-securing-the-future-from-drug-resistant-infections-en.pdf |title=No Time to Wait: Securing the Future from Drug-Resistant Infections |last=Interagency Coordination Group (IACG) |date=April 2019 |access-date=2023-04-19 |archive-date=19 April 2023 |archive-url=https://web.archive.org/web/20230419181246/https://www.who.int/docs/default-source/documents/no-time-to-wait-securing-the-future-from-drug-resistant-infections-en.pdf |url-status=live }}</ref>

The six pathogens causing most deaths associated with resistance are ''Escherichia coli'', ''Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pneumoniae, Acinetobacter baumannii'', and ''Pseudomonas aeruginosa''. They were responsible for 929,000 deaths attributable to resistance and 3.57 million deaths associated with resistance in 2019.<ref name=":8Murray_2022">{{cite journal | vauthors = Murray CJ, Ikuta KS, Sharara F, Swetschinski L, Robles Aguilar GRG, Gray A, etalHan C, Bisignano C, Rao P, Wool E, Johnson SC, Browne AJ, Chipeta MG, Fell F, Hackett S, Haines-Woodhouse G, Kashef Hamadani BH, Kumaran EA, McManigal B, Achalapong S, Agarwal R, Akech S, Albertson S, Amuasi J, Andrews J, Aravkin A, Ashley E, Babin FX, Bailey F, Baker S | collaboration = Antimicrobial Resistance Collaborators | title = Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis | language = English | journal = Lancet | volume = 399 | issue = 10325 | pages = 629–655 | date = February 2022 | pmid = 35065702 | pmc = 8841637 | doi = 10.1016/S0140-6736(21)02724-0 | s2cid = 246077406 }}</ref>

Infections by fungi are a cause of high morbidity and mortality in [[Immunodeficiency|immunocompromised]] persons, such as those with HIV/AIDS, tuberculosis or receiving [[chemotherapy]].<ref>{{cite journal | vauthors = Xie JL, Polvi EJ, Shekhar-Guturja T, Cowen LE | title = Elucidating drug resistance in human fungal pathogens | journal = Future Microbiology | volume = 9 | issue = 4 | pages = 523–42 | year = 2014 | pmid = 24810351 | doi = 10.2217/fmb.14.18 }}</ref> The fungi [[Candida (fungus)|''Candida'']], ''[[Cryptococcus neoformans]]'' and ''[[Aspergillus fumigatus]]'' cause most of these infections and antifungal resistance occurs in all of them.<ref>{{cite journal | vauthors = Srinivasan A, Lopez-Ribot JL, Ramasubramanian AK | title = Overcoming antifungal resistance | journal = Drug Discovery Today: Technologies | volume = 11 | pages = 65–71 | date = March 2014 | pmid = 24847655 | pmc = 4031462 | doi = 10.1016/j.ddtec.2014.02.005 }}</ref> Multidrug resistance in fungi is increasing because of the widespread use of antifungal drugs to treat infections in immunocompromised individuals and the use of some agricultural antifungals.<ref name=":11Fisher_2022" /><ref>{{cite journal | vauthors = Costa C, Dias PJ, Sá-Correia I, Teixeira MC | title = MFS multidrug transporters in pathogenic fungi: do they have real clinical impact? | journal = Frontiers in Physiology | volume = 5 | pages = 197 | date = 2014 | pmid = 24904431 | pmc = 4035561 | doi = 10.3389/fphys.2014.00197 | doi-access = free }}</ref> Antifungal resistant disease is associated with increased mortality.

Some fungi (e.g. [[Candida krusei]] and [[fluconazole]]) exhibit intrinsic resistance to certain antifungal drugs or classes, whereas some species develop antifungal resistance to external pressures. Antifungal resistance is a [[One Health]] concern, driven by multiple extrinsic factors, including extensive fungicidal use, overuse of clinical antifungals, [[environmental change]] and host factors.<ref name=":11Fisher_2022" />

The emergence of ''Candida auris'' as a potential human pathogen that sometimes exhibits multi-class antifungal drug resistance is concerning and has been associated with several outbreaks globally. The WHO has released a priority fungal pathogen list, including pathogens with antifungal resistance.<ref name="WHO">{{cite book |url=https://www.who.int/publications/i/item/9789240060241 |title=WHO fungal priority pathogens list to guide research, development and public health action |date=25 October 2022 |publisher=World Health Organization |editor=World Health Organization |isbn=978-92-4-006024-1 |language=En |format=PDF |access-date=27 October 2022 |archive-url=https://web.archive.org/web/20221026235331/https://www.who.int/publications/i/item/9789240060241 |archive-date=26 October 2022 |url-status=live}}</ref>

The identification of antifungal resistance is undermined by limited classical diagnosis of infection, where a culture is lacking, preventing susceptibility testing.<ref name=":11Fisher_2022" /> National and international surveillance schemes for fungal disease and antifungal resistance are limited, hampering the understanding of the disease burden and associated resistance.<ref name=":11Fisher_2022" /> The application of molecular testing to identify genetic markers associating with resistance may improve the identification of antifungal resistance, but the diversity of mutations associated with resistance is increasing across the fungal species causing infection. In addition, a number of resistance mechanisms depend on up-regulation of selected genes (for instance reflux pumps) rather than defined mutations that are amenable to molecular detection.

Due to the limited number of antifungals in clinical use and the increasing global incidence of antifungal resistance, using the existing antifungals in combination might be beneficial in some cases but further research is needed. Similarly, other approaches that might help to combat the emergence of antifungal resistance could rely on the development of host-directed therapies such as [[immunotherapy]] or vaccines.<ref name=":11Fisher_2022" />

The 1950s to 1970s represented the golden age of antibiotic discovery, where countless new classes of antibiotics were discovered to treat previously incurable diseases such as tuberculosis and syphilis.<ref>{{cite journal | vauthors = Aminov RI | title = A brief history of the antibiotic era: lessons learned and challenges for the future | language = en | journal = Frontiers in Microbiology | volume = 1 | pages = 134 | date = 2010 | pmid = 21687759 | pmc = 3109405 | doi = 10.3389/fmicb.2010.00134 | doi-access = free }}</ref> However, since that time the discovery of new classes of antibiotics has been almost nonexistent, and represents a situation that is especially problematic considering the resiliency of bacteria<ref>{{cite journal | vauthors = Carvalho G, Forestier C, Mathias JD | title = Antibiotic resilience: a necessary concept to complement antibiotic resistance? | journal = Proceedings. Biological Sciences | volume = 286 | issue = 1916 | pages = 20192408 | date = December 2019 | pmid = 31795866 | pmc = 6939251 | doi = 10.1098/rspb.2019.2408 }}</ref> shown over time and the continued misuse and overuse of antibiotics in treatment.<ref name="worldcat.org">{{cite book|title=Antimicrobial resistance : global report on surveillance| authorpublisher = World Health Organization|isbn=978-92-4-156474-8|location=Geneva, Switzerland|oclc=880847527 |year=2014}}</ref>

[[Antibiotic sensitivity|Antimicrobial susceptibility testing]] (AST) can facilitate a [[precision medicine]] approach to treatment by helping clinicians to prescribe more effective and targeted antimicrobial therapy.<ref>{{cite news |date=20 November 2018 |title=Diagnostics Are Helping Counter Antimicrobial Resistance, But More Work Is Needed |work=MDDI Online |url=https://www.mddionline.com/diagnostics-are-helping-counter-antimicrobial-resistance-more-work-needed |access-date=2 December 2018 |archive-date=2 December 2018 |archive-url=https://web.archive.org/web/20181202202615/https://www.mddionline.com/diagnostics-are-helping-counter-antimicrobial-resistance-more-work-needed |url-status=dead }}</ref> At the same time with traditional phenotypic AST it can take 12 to 48 hours to obtain a result due to the time taken for organisms to grow on/in culture media.<ref name=":6van_Belkum_2019">{{cite journal |display-authors=6 |vauthors=van Belkum A, Bachmann TT, Lüdke G, Lisby JG, Kahlmeter G, Mohess A, Becker K, Hays JP, Woodford N, Mitsakakis K, Moran-Gilad J, Vila J, Peter H, Rex JH, Dunne WM |date=January 2019 |title=Developmental roadmap for antimicrobial susceptibility testing systems |journal=Nature Reviews. Microbiology |volume=17 |issue=1 |pages=51–62 |doi=10.1038/s41579-018-0098-9 |pmc=7138758 |pmid=30333569 |doi-access=free |hdl=2445/132505}}</ref> Rapid testing, possible from [[molecular diagnostics]] innovations, is defined as "being feasible within an 8-h working shift".<ref name=":6van_Belkum_2019" /> There are several commercial Food and Drug Administration-approved assays available which can detect AMR genes from a variety of specimen types. Progress has been slow due to a range of reasons including cost and regulation.<ref>{{cite journal |vauthors= |date=October 2018 |title=Progress on antibiotic resistance |journal=Nature |volume=562 |issue=7727 |pages=307 |bibcode=2018Natur.562Q.307. |doi=10.1038/d41586-018-07031-7 |pmid=30333595 |doi-access=free}}</ref> Genotypic AMR characterisation methods are, however, being increasingly used in combination with machine learning algorithms in research to help better predict phenotypic AMR from organism genotype.<ref>{{cite journal |display-authors=6 |vauthors=Kim JI, Maguire F, Tsang KK, Gouliouris T, Peacock SJ, McAllister TA, McArthur AG, Beiko RG |date=September 2022 |title=Machine Learning for Antimicrobial Resistance Prediction: Current Practice, Limitations, and Clinical Perspective |journal=Clinical Microbiology Reviews |volume=35 |issue=3 |pages=e0017921 |doi=10.1128/cmr.00179-21 |pmc=9491192 |pmid=35612324 }}</ref><ref>{{cite journal |vauthors=Banerjee R, Patel R |date=February 2023 |title=Molecular diagnostics for genotypic detection of antibiotic resistance: current landscape and future directions |journal=JAC-antimicrobial Resistance |volume=5 |issue=1 |pages=dlad018 |doi=10.1093/jacamr/dlad018 |pmc=9937039 |pmid=36816746}}</ref>

Optical techniques such as phase contrast microscopy in combination with single-cell analysis are another powerful method to monitor bacterial growth. In 2017, scientists from Uppsala University in Sweden published a method<ref>{{cite journal |vauthors=Baltekin Ö, Boucharin A, Tano E, Andersson DI, Elf J |date=August 2017 |title=Antibiotic susceptibility testing in less than 30 min using direct single-cell imaging |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=114 |issue=34 |pages=9170–9175 |bibcode=2017PNAS..114.9170B |doi=10.1073/pnas.1708558114 |pmc=5576829 |pmid=28790187 |doi-access=free}}</ref> that applies principles of [[microfluidics]] and cell tracking, to monitor bacterial response to antibiotics in less than 30 minutes overall manipulation time. This invention was awarded the 8M£ [https://amr.longitudeprize.org/ Longitude Prize on AMR] in 2024. Recently, this platform has been advanced by coupling microfluidic chip with [[Optical tweezers|optical tweezing]]<ref>{{cite journal |vauthors=Luro S, Potvin-Trottier L, Okumus B, Paulsson J |date=January 2020 |title=Isolating live cells after high-throughput, long-term, time-lapse microscopy |journal=Nature Methods |volume=17 |issue=1 |pages=93–100 |doi=10.1038/s41592-019-0620-7 |pmc=7525750 |pmid=31768062}}</ref> in order to isolate bacteria with altered phenotype directly from the analytical matrix.

Rapid diagnostic methods have also been trialled as antimicrobial stewardship interventions to influence the healthcare drivers of AMR. Serum [[procalcitonin]] measurement has been shown to reduce mortality rate, antimicrobial consumption and antimicrobial-related side-effects in patients with respiratory infections, but impact on AMR has not yet been demonstrated.<ref>{{cite journal |display-authors=6 |vauthors=Schuetz P, Wirz Y, Sager R, Christ-Crain M, Stolz D, Tamm M, Bouadma L, Luyt CE, Wolff M, Chastre J, Tubach F, Kristoffersen KB, Burkhardt O, Welte T, Schroeder S, Nobre V, Wei L, Bucher HC, Bhatnagar N, Annane D, Reinhart K, Branche A, Damas P, Nijsten M, de Lange DW, Deliberato RO, Lima SS, Maravić-Stojković V, Verduri A, Cao B, Shehabi Y, Beishuizen A, Jensen JS, Corti C, Van Oers JA, Falsey AR, de Jong E, Oliveira CF, Beghe B, Briel M, Mueller B |date=October 2017 |title=Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections |journal=The Cochrane Database of Systematic Reviews |volume=10 |issue=10 |pages=CD007498 |doi=10.1002/14651858.CD007498.pub3 |pmc=6485408 |pmid=29025194 |collaboration=Cochrane Acute Respiratory Infections Group}}</ref> Similarly, point of care serum testing of the inflammatory biomarker [[C-reactive protein]] has been shown to influence antimicrobial prescribing rates in this patient cohort, but further research is required to demonstrate an effect on rates of AMR.<ref>{{cite journal |vauthors=Smedemark SA, Aabenhus R, Llor C, Fournaise A, Olsen O, Jørgensen KJ |date=October 2022 |title=Biomarkers as point-of-care tests to guide prescription of antibiotics in people with acute respiratory infections in primary care |journal=The Cochrane Database of Systematic Reviews |volume=2022 |issue=10 |pages=CD010130 |doi=10.1002/14651858.CD010130.pub3 |pmc=9575154 |pmid=36250577 |collaboration=Cochrane Acute Respiratory Infections Group}}</ref> Clinical investigation to rule out bacterial infections are often done for patients with pediatric acute respiratory infections. Currently it is unclear if rapid viral testing affects antibiotic use in children.<ref>{{cite journal |vauthors=Doan Q, Enarson P, Kissoon N, Klassen TP, Johnson DW |date=September 2014 |title=Rapid viral diagnosis for acute febrile respiratory illness in children in the Emergency Department |journal=The Cochrane Database of Systematic Reviews |volume=92014 |issue=9 |pages=CD006452 |doi=10.1002/14651858.CD006452.pub4 |pmc=6718218 |pmid=25222468}}</ref>

Two registrational trials have evaluated vaccine candidates in active immunization strategies against ''S. aureus'' infection. In a phase II trial, a bivalent vaccine of capsular proteins 5 & 8 was tested in 1804 hemodialysis patients with a primary fistula or synthetic graft vascular access. After 40 weeks following vaccination a protective effect was seen against ''S. aureus'' bacteremia, but not at 54 weeks following vaccination.<ref>{{cite journal | vauthors = Shinefield H, Black S, Fattom A, Horwith G, Rasgon S, Ordonez J, Yeoh H, Law D, Robbins JB, Schneerson R, Muenz L, Fuller S, Johnson J, Fireman B, Alcorn H, Naso R | display-authors = 6 | title = Use of a Staphylococcus aureus conjugate vaccine in patients receiving hemodialysis | journal = The New England Journal of Medicine | volume = 346 | issue = 7 | pages = 491–6 | date = February 2002 | pmid = 11844850 | doi = 10.1056/NEJMoa011297 | doi-access = free }}</ref> Based on these results, a second trial was conducted which failed to show efficacy.<ref name=":7Fowler_2014">{{cite journal | vauthors = Fowler VG, Proctor RA | title = Where does a Staphylococcus aureus vaccine stand? | journal = Clinical Microbiology and Infection | volume = 20 | issue = 5 | pages = 66–75 | date = May 2014 | pmid = 24476315 | pmc = 4067250 | doi = 10.1111/1469-0691.12570 }}</ref>

Numerous investigators have suggested that a multiple-antigen vaccine would be more effective, but a lack of biomarkers defining human protective immunity keep these proposals in the logical, but strictly hypothetical arena.<ref name=":7Fowler_2014" />

During the last decades, [[Copper nanoparticle|copper]] and [[Silver nanoparticle|silver]] [[nanomaterials]] have demonstrated appealing features for the development of a new family of antimicrobial agents.<ref>{{cite journal | vauthors = Ermini ML, Voliani V | title = Antimicrobial Nano-Agents: The Copper Age | journal = ACS Nano | volume = 15 | issue = 4 | pages = 6008–6029 | date = April 2021 | pmid = 33792292 | pmc = 8155324 | doi = 10.1021/acsnano.0c10756 | doi-access = free }}</ref> Nanoparticles (1-100 nm) show unique properties and promise as antimicrobial agents against resistant bacteria. [[Silver nanoparticle|Silver (AgNPs)]] and gold nanoparticles (AuNPs) are extensively studied, disrupting bacterial cell membranes and interfering with protein synthesis. Zinc oxide (ZnO NPs), copper (CuNPs), and silica (SiNPs) nanoparticles also exhibit antimicrobial properties. However, high synthesis costs, potential toxicity, and instability pose challenges. To overcome these, biological synthesis methods and combination therapies with other antimicrobials are explored. Enhanced biocompatibility and targeting are also under investigation to improve efficacy.<ref name="Singh_2024" />

One of the key tools identified by the WHO and others for the fight against rising antimicrobial resistance is improved surveillance of the spread and movement of AMR genes through different communities and regions. Recent advances in high-throughput [[DNA sequencing]] as a result of the [[Human Genome Project]] have resulted in the ability to determine the individual microbial genes in a sample.<ref name=":14Kim_2021">{{cite journal | vauthors = Kim DW, Cha CJ | title = Antibiotic resistome from the One-Health perspective: understanding and controlling antimicrobial resistance transmission | journal = Experimental & Molecular Medicine | volume = 53 | issue = 3 | pages = 301–309 | date = March 2021 | pmid = 33642573 | pmc = 8080597 | doi = 10.1038/s12276-021-00569-z }}</ref> Along with the availability of databases of known antimicrobial resistance genes, such as the Comprehensive Antimicrobial Resistance Database (CARD)<ref>{{cite journal | vauthors = Alcock BP, Huynh W, Chalil R, Smith KW, Raphenya AR, Wlodarski MA, Edalatmand A, Petkau A, Syed SA, Tsang KK, Baker SJ, Dave M, McCarthy MC, Mukiri KM, Nasir JA, Golbon B, Imtiaz H, Jiang X, Kaur K, Kwong M, Liang ZC, Niu KC, Shan P, Yang JY, Gray KL, Hoad GR, Jia B, Bhando T, Carfrae LA, Farha MA, French S, Gordzevich R, Rachwalski K, Tu MM, Bordeleau E, Dooley D, Griffiths E, Zubyk HL, Brown ED, Maguire F, Beiko RG, Hsiao WW, Brinkman FS, Van Domselaar G, McArthur AG | display-authors = 6 | title = CARD 2023: expanded curation, support for machine learning, and resistome prediction at the Comprehensive Antibiotic Resistance Database | journal = Nucleic Acids Research | volume = 51 | issue = D1 | pages = D690–D699 | date = January 2023 | pmid = 36263822 | pmc = 9825576 | doi = 10.1093/nar/gkac920 }}</ref><ref>{{cite web |title=The Comprehensive Antibiotic Resistance Database |url=https://card.mcmaster.ca/ |access-date=2023-03-28 |website=card.mcmaster.ca |archive-date=28 March 2023 |archive-url=https://web.archive.org/web/20230328115250/https://card.mcmaster.ca/ |url-status=live }}</ref> and [[ResFinder]],<ref>{{cite journal | vauthors = Florensa AF, Kaas RS, Clausen PT, Aytan-Aktug D, Aarestrup FM | title = ResFinder - an open online resource for identification of antimicrobial resistance genes in next-generation sequencing data and prediction of phenotypes from genotypes | journal = Microbial Genomics | volume = 8 | issue = 1 | date = January 2022 | pmid = 35072601 | pmc = 8914360 | doi = 10.1099/mgen.0.000748 | doi-access = free }}</ref><ref>{{cite web |title=ResFinder 4.1 |url=https://cge.food.dtu.dk/services/ResFinder/ |access-date=2023-03-28 |website=cge.food.dtu.dk |archive-date=28 March 2023 |archive-url=https://web.archive.org/web/20230328115302/https://cge.food.dtu.dk/services/ResFinder/ |url-status=live }}</ref> this allows the identification of all the antimicrobial resistance genes within the sample - the so-called "[[resistome]]". In doing so, a profile of these genes within a community or environment can be determined, providing insights into how antimicrobial resistance is spreading through a population and allowing for the identification of resistance that is of concern.<ref name=":14Kim_2021" />

Phage therapy relies on the use of naturally occurring bacteriophages to infect and lyse bacteria at the site of infection in a host. Due to current advances in genetics and biotechnology these bacteriophages can possibly be manufactured to treat specific infections.<ref name=":2a">{{cite journal | vauthors = Lin DM, Koskella B, Lin HC | title = Phage therapy: An alternative to antibiotics in the age of multi-drug resistance | journal = World Journal of Gastrointestinal Pharmacology and Therapeutics | volume = 8 | issue = 3 | pages = 162–173 | date = August 2017 | pmid = 28828194 | pmc = 5547374 | doi = 10.4292/wjgpt.v8.i3.162 | df = dmy-all | doi-access = free }}</ref> Phages can be bioengineered to target multidrug-resistant bacterial infections, and their use involves the added benefit of preventing the elimination of beneficial bacteria in the human body.<ref name=":2Rather_2017" /> Phages destroy bacterial cell walls and membrane through the use of lytic proteins which kill bacteria by making many holes from the inside out.<ref name=":3Salmond_2015">{{cite journal | vauthors = Salmond GP, Fineran PC | title = A century of the phage: past, present and future | journal = Nature Reviews. Microbiology | volume = 13 | issue = 12 | pages = 777–86 | date = December 2015 | pmid = 26548913 | doi = 10.1038/nrmicro3564 | s2cid = 8635034 }}</ref> Bacteriophages can even possess the ability to digest the [[biofilm]] that many bacteria develop that protect them from antibiotics in order to effectively infect and kill bacteria. Bioengineering can play a role in creating successful bacteriophages.<ref name=":3Salmond_2015" />

* {{cite journal | vauthors = Arias CA, Murray BE | title = Antibiotic-resistant bugs in the 21st century-- – a clinical super-challenge | journal = The New England Journal of Medicine | volume = 360 | issue = 5 | pages = 439–43439–443 | date = January 2009 | pmid = 19179312 | doi = 10.1056/NEJMp0804651 | s2cid = 205104375 | doi-access = free }}

* {{cite journal | vauthors = Goossens H, Ferech M, Vander Stichele R, Elseviers M | title = Outpatient antibiotic use in Europe and association with resistance: a cross-national database study | journal = Lancet | volume = 365 | issue = 9459 | pages = 579–87579–587 | year = 2005 | pmid = 15708101 | doi = 10.1016/S0140-6736(05)17907-0 | series = Group Esac Project | others = Esac Project | s2cid = 23782228 }}

* {{cite journal | vauthors = Hawkey PM, Jones AM | title = The changing epidemiology of resistance | journal = The Journal of Antimicrobial Chemotherapy | volume = 64 | issue = Suppl 1 | pages = i3-10i3–10 | date = September 2009 | pmid = 19675017 | doi = 10.1093/jac/dkp256 | url = https://academic.oup.com/jac/article-pdf/64/suppl_1/i3/2249203/dkp256.pdf | doi-access = free | access-date = 20 April 2018 | archive-date = 18 January 2023 | archive-url = https://web.archive.org/web/20230118003238/https://watermark.silverchair.com/dkp256.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAAsgwggLEBgkqhkiG9w0BBwagggK1MIICsQIBADCCAqoGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMrh5H15d5E_vifnSvAgEQgIICe1toK2QGW3X7MGftkgsKdqGAsi5Stuucpzad_13uwNVwyhYaFSRpCtYtNrutOJQk2LXtZvV53QFumcPSj3SQ2MwmCl-YZngTUFQ6mwUKfWwiiuM00V8IRCHdAt9TMgNU0XWMcpdB2rALKbYl_KoVlp4mpRCWcpt7gz-IpHAY72I5cTXL103IQ6mbrQXL5sA9Gf-Fl8Y_ZjeH0WqK5VEaNfnnNMosQCMrYiJw-_0Zbm3LmKs3rL21ZD1TmpNUC2Rn0W9scSKvVTNU8Lc866_pAmGXgjrgkJgNbDT5WfDQIznPNHCwqxTq4UEPrvLNxV9HobNcShURuxCP21myKWmuyuINZUar_44cQvZ2FHz84DVff7T0PFqbLIjgWDIndDBFC8l1A1EXRE5pRM9uZDM5qvycWnQd9hVB9rse_RyHQq8Fal_G1qljMM5rlB684Yk09Hp1TDGqej1pcplmulu-BI7xEQ-lqmDdLsZ-yXRaULp1wIFvweA7nM9suYlSqY2ZWuX-9pm9C7j18xU7mzoFGahvVwiAQgug5EfG2lzvFs5yEUIsf5trd-M1xpz0DXG1EfYGjo321biAjgU3eI4eITfFdZzEl7tWJNq78askbkReHGaQDNIrKErGKD7tUB8Xi2htQGJzSE8okx5ijWEbUnLxfQK4T1qnCXgq5rpXeIJId1XV4LUpv5OpV-QWhSGBw9N4BNh5u2r9nitztPSbzl9FBt3RlFAW0DqvgziSxxjOKHXMmnP5w6eu6ARpGgZWATN4FEcKgoACf2Ro1LZQ0xW59oWp6fqmrc7UpwspWKfZeeyPT9fX6CCnr6eJ-YeXuOHTl873lY-sfNyl | url-status = live }}

* {{cite journal | vauthors = Soulsby EJ | title = Resistance to antimicrobials in humans and animals | journal = BMJ | volume = 331 | issue = 7527 | pages = 1219–201219–1220 | date = November 2005 | pmid = 16308360 | pmc = 1289307 | doi = 10.1136/bmj.331.7527.1219 }}

* [https://pharmaxchange.info/2011/02/animation-of-antimicrobial-resistance/ Animation of Antibiotic Resistance] {{Webarchive|url=https://web.archive.org/web/20220928132102/https://pharmaxchange.info/2011/02/animation-of-antimicrobial-resistance/ |date=28 September 2022 }}