Editing Antimicrobial resistance (section)

==Mechanisms and organisms==

===Bacteria===
{{Further|List of antibiotic resistant bacteria}}[[File:mecA Resistance.svg|thumb|Diagram depicting antibiotic resistance through alteration of the antibiotic's target site, modeled after MRSA's resistance to penicillin. Beta-lactam antibiotics permanently inactivate [[Penicillin-binding protein|PBP enzymes]], which are essential for bacterial life, by permanently binding to their active sites. [[Methicillin-resistant Staphylococcus aureus|MRSA]], however, expresses a PBP that does not allow the antibiotic into its active site.|alt=Diagram depicting antibiotic resistance through alteration of the antibiotic's target site]]

The five main mechanisms by which bacteria exhibit resistance to antibiotics are:
# Drug inactivation or modification: for example, enzymatic deactivation of [[Penicillin|penicillin G]] in some penicillin-resistant bacteria through the production of [[Beta-lactamases|β-lactamases]]. Drugs may also be chemically modified through the addition of [[functional group]]s by [[transferase]] enzymes; for example, [[acetylation]], [[phosphorylation]], or [[adenylation]] are common resistance mechanisms to [[aminoglycoside]]s. Acetylation is the most widely used mechanism and can affect a number of [[drug class]]es.<ref name="reygaert_2018">{{cite journal | vauthors = Reygaert WC | title = An overview of the antimicrobial resistance mechanisms of bacteria | journal = AIMS Microbiology | volume = 4 | issue = 3 | pages = 482–501 | date = 2018 | pmid = 31294229 | pmc = 6604941 | doi = 10.3934/microbiol.2018.3.482 }}</ref><ref name="baylay_2019">{{cite book | vauthors = Baylay AJ, Piddock LJ, Webber MA |title=Bacterial Resistance to Antibiotics – from Molecules to Man |chapter=Molecular Mechanisms of Antibiotic Resistance – Part I |date=14 March 2019 |pages=1–26 |publisher=Wiley |doi=10.1002/9781119593522.ch1|isbn=978-1-119-94077-7 |s2cid=202806156 }}</ref>{{rp|6–8}}
# Alteration of target- or binding site: for example, alteration of [[Penicillin binding protein|PBP]]—the binding target site of penicillins—in [[Methicillin-resistant Staphylococcus aureus|MRSA]] and other penicillin-resistant bacteria. Another protective mechanism found among bacterial species is ribosomal protection proteins. These proteins protect the bacterial cell from antibiotics that target the cell's ribosomes to inhibit protein synthesis. The mechanism involves the binding of the ribosomal protection proteins to the ribosomes of the bacterial cell, which in turn changes its conformational shape. This allows the ribosomes to continue synthesizing proteins essential to the cell while preventing antibiotics from binding to the ribosome to inhibit protein synthesis.<ref>{{cite journal | vauthors = Connell SR, Tracz DM, Nierhaus KH, Taylor DE | title = Ribosomal protection proteins and their mechanism of tetracycline resistance | journal = Antimicrobial Agents and Chemotherapy | volume = 47 | issue = 12 | pages = 3675–81 | date = December 2003 | pmid = 14638464 | pmc = 296194 | doi = 10.1128/AAC.47.12.3675-3681.2003 }}</ref>
# Alteration of metabolic pathway: for example, some [[sulfa drugs|sulfonamide]]-resistant bacteria do not require [[para-aminobenzoic acid]] (PABA), an important precursor for the synthesis of [[folic acid]] and [[nucleic acid]]s in bacteria inhibited by sulfonamides, instead, like mammalian cells, they turn to using preformed folic acid.<ref>{{cite journal | vauthors = Henry RJ | title = The Mode of Action of Sulfonamides | journal = Bacteriological Reviews | volume = 7 | issue = 4 | pages = 175–262 | date = December 1943 | pmid = 16350088 | pmc = 440870 | doi = 10.1128/MMBR.7.4.175-262.1943 }}</ref>
# Reduced drug accumulation: by decreasing drug [[Semipermeable membrane|permeability]] or increasing active [[efflux (microbiology)|efflux]] (pumping out) of the drugs across the cell surface.<ref>{{cite journal | vauthors = Li XZ, Nikaido H | title = Efflux-mediated drug resistance in bacteria: an update | journal = Drugs | volume = 69 | issue = 12 | pages = 1555–623 | date = August 2009 | pmid = 19678712 | pmc = 2847397 | doi = 10.2165/11317030-000000000-00000 }}</ref> These [[multidrug efflux pumps]] within the cellular membrane of certain bacterial species are used to pump antibiotics out of the cell before they are able to do any damage. They are often activated by a specific substrate associated with an antibiotic,<ref>{{cite journal | vauthors = Aminov RI, Mackie RI | title = Evolution and ecology of antibiotic resistance genes | journal = FEMS Microbiology Letters | volume = 271 | issue = 2 | pages = 147–61 | date = June 2007 | pmid = 17490428 | doi = 10.1111/j.1574-6968.2007.00757.x | doi-access = free }}</ref> as in [[fluoroquinolone]] resistance.<ref>{{cite journal | vauthors = Morita Y, Kodama K, Shiota S, Mine T, Kataoka A, Mizushima T, Tsuchiya T | title = NorM, a putative multidrug efflux protein, of Vibrio parahaemolyticus and its homolog in Escherichia coli | journal = Antimicrobial Agents and Chemotherapy | volume = 42 | issue = 7 | pages = 1778–82 | date = July 1998 | pmid = 9661020 | pmc = 105682 | doi = 10.1128/AAC.42.7.1778 }}</ref>
# Ribosome splitting and recycling: for example, drug-mediated stalling of the ribosome by [[lincomycin]] and [[erythromycin]] unstalled by a heat shock protein found in ''Listeria monocytogenes'', which is a homologue of HflX from other bacteria. Liberation of the ribosome from the drug allows further translation and consequent resistance to the drug.<ref>{{cite journal | vauthors = Duval M, Dar D, Carvalho F, Rocha EP, Sorek R, Cossart P | title = HflXr, a homolog of a ribosome-splitting factor, mediates antibiotic resistance | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 115 | issue = 52 | pages = 13359–13364 | date = December 2018 | pmid = 30545912 | pmc = 6310831 | doi = 10.1073/pnas.1810555115 | bibcode = 2018PNAS..11513359D | doi-access = free }}</ref>
[[File:Antibiotic resistance mechanisms.jpg|thumb|300x300px|A number of mechanisms used by common antibiotics to deal with bacteria and ways by which bacteria become resistant to them|alt=Infographic showing mechanisms for antibiotic resistance]]

There are several different types of germs that have developed a resistance over time.

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="Murray_2022">{{cite journal | vauthors = Murray CJ, Ikuta KS, Sharara F, Swetschinski L, Robles Aguilar G, Gray A, Han 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>

Penicillinase-producing ''Neisseria gonorrhoeae'' developed a resistance to penicillin in 1976. Another example is Azithromycin-resistant ''Neisseria gonorrhoeae'', which developed a resistance to azithromycin in 2011.<ref>{{cite web|title=About Antibiotic Resistance|url=https://www.cdc.gov/drugresistance/about.html|website=CDC|date=13 March 2020|access-date=8 September 2017|archive-date=1 October 2017|archive-url=https://web.archive.org/web/20171001044758/https://www.cdc.gov/drugresistance/about.html|url-status=live}}</ref>

In [[gram-negative bacteria]], plasmid-mediated resistance genes produce proteins that can bind to [[DNA gyrase]], protecting it from the action of quinolones. Finally, mutations at key sites in DNA gyrase or [[topoisomerase IV]] can decrease their binding affinity to quinolones, decreasing the drug's effectiveness.<ref>{{cite journal | vauthors = Robicsek A, Jacoby GA, Hooper DC | title = The worldwide emergence of plasmid-mediated quinolone resistance | journal = The Lancet. Infectious Diseases | volume = 6 | issue = 10 | pages = 629–40 | date = October 2006 | pmid = 17008172 | doi = 10.1016/S1473-3099(06)70599-0 }}</ref>

Some bacteria are naturally resistant to certain antibiotics; for example, gram-negative bacteria are resistant to most [[β-lactam antibiotic]]s due to the presence of [[Beta-lactamases|β-lactamase]]. Antibiotic resistance can also be acquired as a result of either genetic mutation or [[horizontal gene transfer]].<ref>{{cite journal|vauthors=Ochiai K, Yamanaka T, Kimura K, Sawada O, O|year=1959|title=Inheritance of drug resistance (and its transfer) between Shigella strains and Between Shigella and E.coli strains|journal=Hihon Iji Shimpor|language=ja|volume=34|page=1861}}</ref> Although mutations are rare, with spontaneous mutations in the [[pathogen]] [[genome]] occurring at a rate of about 1 in 10<sup>5</sup> to 1 in 10<sup>8</sup> per chromosomal replication,<ref>{{cite book |vauthors=Watford S, Warrington SJ |chapter=Bacterial DNA Mutations |date=2018 |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK459274/ |title=StatPearls |publisher=StatPearls Publishing |pmid=29083710 |access-date=21 January 2019 |archive-date=8 March 2021 |archive-url=https://web.archive.org/web/20210308150820/https://www.ncbi.nlm.nih.gov/books/NBK459274/ |url-status=live }}</ref> the fact that bacteria reproduce at a high rate allows for the effect to be significant. Given that lifespans and production of new generations can be on a timescale of mere hours, a new (de novo) mutation in a parent cell can quickly become an [[heredity|inherited]] mutation of widespread prevalence, resulting in the [[microevolution]] of a fully resistant colony. However, chromosomal mutations also confer a cost of fitness. For example, a ribosomal mutation may protect a bacterial cell by changing the binding site of an antibiotic but may result in slower growth rate.<ref>{{cite journal | vauthors = Levin BR, Perrot V, Walker N | title = Compensatory mutations, antibiotic resistance and the population genetics of adaptive evolution in bacteria | journal = Genetics | volume = 154 | issue = 3 | pages = 985–97 | date = March 2000 | doi = 10.1093/genetics/154.3.985 | pmid = 10757748 | pmc = 1460977 | url = http://www.genetics.org/cgi/pmidlookup?view=long&pmid=10757748 | access-date = 4 March 2017 | archive-date = 18 January 2023 | archive-url = https://web.archive.org/web/20230118003230/https://academic.oup.com/genetics | url-status = live }}</ref> Moreover, some adaptive mutations can propagate not only through inheritance but also through [[horizontal gene transfer]]. The most common mechanism of horizontal gene transfer is the transferring of [[Plasmid-mediated resistance|plasmids]] carrying antibiotic resistance genes between bacteria of the same or different species via [[Bacterial conjugation|conjugation]]. However, bacteria can also acquire resistance through [[Transformation (genetics)|transformation]], as in ''Streptococcus pneumoniae'' uptaking of naked fragments of extracellular DNA that contain antibiotic resistance genes to streptomycin,<ref>{{cite journal | vauthors = Hotchkiss RD | title = Transfer of penicillin resistance in pneumococci by the desoxyribonucleate derived from resistant cultures | journal = Cold Spring Harbor Symposia on Quantitative Biology | volume = 16 | pages = 457–61 | date = 1951 | pmid = 14942755 | doi = 10.1101/SQB.1951.016.01.032 }}</ref> through [[Transduction (genetics)|transduction]], as in the bacteriophage-mediated transfer of tetracycline resistance genes between strains of ''S. pyogenes'',<ref>{{cite journal | vauthors = Ubukata K, Konno M, Fujii R | title = Transduction of drug resistance to tetracycline, chloramphenicol, macrolides, lincomycin and clindamycin with phages induced from Streptococcus pyogenes | journal = The Journal of Antibiotics | volume = 28 | issue = 9 | pages = 681–8 | date = September 1975 | pmid = 1102514 | doi = 10.7164/antibiotics.28.681 | doi-access = free }}</ref> or through [[gene transfer agent]]s, which are particles produced by the host cell that resemble bacteriophage structures and are capable of transferring DNA.<ref>{{cite journal | vauthors = von Wintersdorff CJ, Penders J, van Niekerk JM, Mills ND, Majumder S, van Alphen LB, Savelkoul PH, Wolffs PF | title = Dissemination of Antimicrobial Resistance in Microbial Ecosystems through Horizontal Gene Transfer | journal = Frontiers in Microbiology | volume = 7 | pages = 173 | date = 19 February 2016 | pmid = 26925045 | pmc = 4759269 | doi = 10.3389/fmicb.2016.00173 | doi-access = free }}</ref>

Antibiotic resistance can be introduced artificially into a microorganism through laboratory protocols, sometimes used as a [[selectable marker]] to examine the mechanisms of gene transfer or to identify individuals that absorbed a piece of DNA that included the resistance gene and another gene of interest.<ref>{{cite journal | vauthors = Chan CX, Beiko RG, Ragan MA | title = Lateral transfer of genes and gene fragments in Staphylococcus extends beyond mobile elements | journal = Journal of Bacteriology | volume = 193 | issue = 15 | pages = 3964–77 | date = August 2011 | pmid = 21622749 | pmc = 3147504 | doi = 10.1128/JB.01524-10 }}</ref>

Recent findings show no necessity of large populations of bacteria for the appearance of antibiotic resistance. Small populations of ''[[Escherichia coli]]'' in an antibiotic gradient can become resistant. Any heterogeneous environment with respect to nutrient and antibiotic gradients may facilitate antibiotic resistance in small bacterial populations. Researchers hypothesize that the mechanism of resistance evolution is based on four SNP mutations in the genome of ''E. coli'' produced by the gradient of antibiotic.<ref>{{cite journal | vauthors = Johansen TB, Scheffer L, Jensen VK, Bohlin J, Feruglio SL | title = Whole-genome sequencing and antimicrobial resistance in Brucella melitensis from a Norwegian perspective | journal = Scientific Reports | volume = 8 | issue = 1 | pages = 8538 | date = June 2018 | pmid = 29867163 | pmc = 5986768 | doi = 10.1038/s41598-018-26906-3 | bibcode = 2018NatSR...8.8538J }}</ref>

In one study, which has implications for space microbiology, a non-pathogenic strain ''E. coli'' MG1655 was exposed to trace levels of the broad spectrum antibiotic [[chloramphenicol]], under simulated microgravity (LSMMG, or Low Shear Modeled Microgravity) over 1000 generations. The adapted strain acquired resistance to not only chloramphenicol, but also cross-resistance to other antibiotics;<ref>{{cite journal | vauthors = Tirumalai MR, Karouia F, Tran Q, Stepanov VG, Bruce RJ, Ott M, Pierson DL, Fox GE| title = Evaluation of acquired antibiotic resistance in ''Escherichia coli'' exposed to long-term low-shear modeled microgravity and background antibiotic exposure| journal = mBio | volume =10 |issue= e02637-18| date = January 2019 | pmid = 30647159 | pmc = 6336426  | doi = 10.1128/mBio.02637-18}}</ref> this was in contrast to the observation on the same strain, which was adapted to over 1000 generations under LSMMG, but without any antibiotic exposure; the strain in this case did not acquire any such resistance.<ref>{{cite journal | vauthors = Tirumalai MR, Karouia F, Tran Q, Stepanov VG, Bruce RJ, Ott M, Pierson DL, Fox GE| title = The adaptation of ''Escherichia coli'' cells grown in simulated microgravity for an extended period is both phenotypic and genomic.| journal = npj Microgravity | volume =3 |issue= 15| date = May 2017 | page = 15| pmid = 28649637 | pmc = 5460176 | doi = 10.1038/s41526-017-0020-1}}</ref> Thus, irrespective of where they are used, the use of an antibiotic would likely result in persistent resistance to that antibiotic, as well as cross-resistance to other antimicrobials.

In recent years, the emergence and spread of [[Beta-lactamases|β-lactamases]] called [[carbapenemase]]s has become a major health crisis.<ref>{{cite journal | vauthors = Ghaith DM, Mohamed ZK, Farahat MG, Aboulkasem Shahin W, Mohamed HO | title = Colonization of intestinal microbiota with carbapenemase-producing Enterobacteriaceae in paediatric intensive care units in Cairo, Egypt | journal = Arab Journal of Gastroenterology | volume = 20 | issue = 1 | pages = 19–22 | date = March 2019 | pmid = 30733176 | doi = 10.1016/j.ajg.2019.01.002 | s2cid = 73444389 | url = https://zenodo.org/record/6349599 | access-date = 30 May 2022 | archive-date = 27 November 2022 | archive-url = https://web.archive.org/web/20221127085649/https://zenodo.org/record/6349599 | url-status = live }}</ref><ref>{{cite journal | vauthors = Diene SM, Rolain JM | title = Carbapenemase genes and genetic platforms in Gram-negative bacilli: Enterobacteriaceae, Pseudomonas and Acinetobacter species | journal = Clinical Microbiology and Infection | volume = 20 | issue = 9 | pages = 831–8 | date = September 2014 | pmid = 24766097 | doi = 10.1111/1469-0691.12655 | doi-access = free }}</ref> One such carbapenemase is [[New Delhi metallo-beta-lactamase 1]] (NDM-1),<ref name="Kumarasamy">{{cite journal | vauthors = Kumarasamy KK, Toleman MA, Walsh TR, Bagaria J, Butt F, Balakrishnan R, Chaudhary U, Doumith M, Giske CG, Irfan S, Krishnan P, Kumar AV, Maharjan S, Mushtaq S, Noorie T, Paterson DL, Pearson A, Perry C, Pike R, Rao B, Ray U, Sarma JB, Sharma M, Sheridan E, Thirunarayan MA, Turton J, Upadhyay S, Warner M, Welfare W, Livermore DM, Woodford N | title = Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study | journal = The Lancet. Infectious Diseases | volume = 10 | issue = 9 | pages = 597–602 | date = September 2010 | pmid = 20705517 | pmc = 2933358 | doi = 10.1016/S1473-3099(10)70143-2 }}</ref> an [[enzyme]] that makes [[bacteria]] [[Antibiotic resistance|resistant]] to a broad range of [[beta-lactam antibiotic]]s. The most common bacteria that make this enzyme are gram-negative such as ''E. coli'' and ''[[Klebsiella pneumoniae]]'', but the gene for NDM-1 can spread from one strain of bacteria to another by [[horizontal gene transfer]].<ref>{{cite journal | vauthors = Hudson CM, Bent ZW, Meagher RJ, Williams KP | title = Resistance determinants and mobile genetic elements of an NDM-1-encoding Klebsiella pneumoniae strain | journal = PLOS ONE | volume = 9 | issue = 6 | pages = e99209 | date = 7 June 2014 | pmid = 24905728 | pmc = 4048246 | doi = 10.1371/journal.pone.0099209 | bibcode = 2014PLoSO...999209H | doi-access = free }}</ref>

===Viruses===
Specific [[antiviral drug]]s are used to treat some viral infections. These drugs prevent viruses from reproducing by inhibiting essential stages of the virus's replication cycle in infected cells. Antivirals are used to treat [[HIV]], [[hepatitis B]], [[hepatitis C]], [[influenza]], [[herpesviridae|herpes viruses]] including [[varicella zoster virus]], [[cytomegalovirus]] and [[Epstein–Barr virus]]. With each virus, some strains have become resistant to the administered drugs.<ref>{{cite journal | vauthors = Lou Z, Sun Y, Rao Z | title = Current progress in antiviral strategies | journal = Trends in Pharmacological Sciences | volume = 35 | issue = 2 | pages = 86–102 | date = February 2014 | pmid = 24439476 | pmc = 7112804 | doi = 10.1016/j.tips.2013.11.006 }}</ref>

Antiviral drugs typically target key components of viral reproduction; for example, [[oseltamivir]] targets influenza [[neuraminidase]], while guanosine analogs inhibit viral DNA polymerase. Resistance to antivirals is thus acquired through mutations in the genes that encode the protein targets of the drugs.

Resistance to HIV antivirals is problematic, and even multi-drug resistant strains have evolved.<ref>{{cite journal | vauthors = Pennings PS | title = HIV Drug Resistance: Problems and Perspectives | journal = Infectious Disease Reports | volume = 5 | issue = Suppl 1 | pages = e5 | date = June 2013 | pmid = 24470969 | pmc = 3892620 | doi = 10.4081/idr.2013.s1.e5 }}</ref> One source of resistance is that many current HIV drugs, including NRTIs and NNRTIs, target [[reverse transcriptase]]; however, HIV-1 reverse transcriptase is highly error prone and thus mutations conferring resistance arise rapidly.<ref>{{cite journal | vauthors = Das K, Arnold E | title = HIV-1 reverse transcriptase and antiviral drug resistance. Part 1 | journal = Current Opinion in Virology | volume = 3 | issue = 2 | pages = 111–8 | date = April 2013 | pmid = 23602471 | pmc = 4097814 | doi = 10.1016/j.coviro.2013.03.012 }}</ref> Resistant strains of the HIV virus emerge rapidly if only one antiviral drug is used.<ref>{{cite journal | vauthors = Ton Q, Frenkel L | title = HIV drug resistance in mothers and infants following use of antiretrovirals to prevent mother-to-child transmission | journal = Current HIV Research | volume = 11 | issue = 2 | pages = 126–36 | date = March 2013 | pmid = 23432488 | doi = 10.2174/1570162x11311020005 }}</ref> Using three or more drugs together, termed [[combination therapy]], has helped to control this problem, but new drugs are needed because of the continuing emergence of drug-resistant HIV strains.<ref>{{cite journal | vauthors = Ebrahim O, Mazanderani AH | title = Recent developments in hiv treatment and their dissemination in poor countries | journal = Infectious Disease Reports | volume = 5 | issue = Suppl 1 | pages = e2 | date = June 2013 | pmid = 24470966 | pmc = 3892621 | doi = 10.4081/idr.2013.s1.e2 }}</ref>

===Fungi===
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="Fisher_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="Fisher_2022" />

In the USA [[fluconazole]]-resistant Candida species and azole resistance in Aspergillus fumigatus have been highlighted as a growing threat.<ref name="CDC2013" />

More than 20 species of ''Candida'' can cause [[candidiasis]] infection, the most common of which is ''[[Candida albicans]]''. ''Candida'' yeasts normally inhabit the skin and mucous membranes without causing infection. However, overgrowth of ''Candida'' can lead to candidiasis. Some ''Candida'' species (e.g. ''[[Candida glabrata]])'' are becoming resistant to first-line and second-line [[Antifungal|antifungal agents]] such as [[echinocandin]]s and [[Azole#Use as anti-fungal agents|azoles]].<ref name="CDC2013" />

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 |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="Fisher_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="Fisher_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="Fisher_2022" />

===Parasites===

The [[protozoa]]n parasites that cause the diseases [[malaria]], [[trypanosomiasis]], [[toxoplasmosis]], [[cryptosporidiosis]] and [[leishmaniasis]] are important human pathogens.<ref name="pmid25057459">{{cite journal | vauthors = Andrews KT, Fisher G, Skinner-Adams TS | title = Drug repurposing and human parasitic protozoan diseases | journal = International Journal for Parasitology: Drugs and Drug Resistance | volume = 4 | issue = 2 | pages = 95–111 | date = August 2014 | pmid = 25057459 | pmc = 4095053 | doi = 10.1016/j.ijpddr.2014.02.002 }}</ref>

Malarial parasites that are resistant to the drugs that are currently available to infections are common and this has led to increased efforts to develop new drugs.<ref>{{cite journal | vauthors = Visser BJ, van Vugt M, Grobusch MP | title = Malaria: an update on current chemotherapy | journal = Expert Opinion on Pharmacotherapy | volume = 15 | issue = 15 | pages = 2219–54 | date = October 2014 | pmid = 25110058 | doi = 10.1517/14656566.2014.944499 | s2cid = 34991324 }}</ref> Resistance to recently developed drugs such as [[artemisinin]] has also been reported. The problem of drug resistance in malaria has driven efforts to develop vaccines.<ref>{{cite journal | vauthors = Chia WN, Goh YS, Rénia L | title = Novel approaches to identify protective malaria vaccine candidates | journal = Frontiers in Microbiology | volume = 5 | pages = 586 | year = 2014 | pmid = 25452745 | pmc = 4233905 | doi = 10.3389/fmicb.2014.00586 | doi-access = free }}</ref>

[[Trypanosoma|Trypanosomes]] are parasitic protozoa that cause [[African trypanosomiasis]] and [[Chagas disease]] (American trypanosomiasis).<ref>{{cite journal | vauthors = Franco JR, Simarro PP, Diarra A, Jannin JG | title = Epidemiology of human African trypanosomiasis | journal = Clinical Epidemiology | volume = 6 | pages = 257–75 | year = 2014 | pmid = 25125985 | pmc = 4130665 | doi = 10.2147/CLEP.S39728 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Herrera L | title = Trypanosoma cruzi, the Causal Agent of Chagas Disease: Boundaries between Wild and Domestic Cycles in Venezuela | journal = Frontiers in Public Health | volume = 2 | pages = 259 | date = 2014 | pmid = 25506587 | pmc = 4246568 | doi = 10.3389/fpubh.2014.00259 | doi-access = free }}</ref> There are no vaccines to prevent these infections so drugs such as [[pentamidine]] and [[suramin]], [[benznidazole]] and [[nifurtimox]] are used to treat infections. These drugs are effective but infections caused by resistant parasites have been reported.<ref name="pmid25057459" />

[[Leishmaniasis]] is caused by protozoa and is an important public health problem worldwide, especially in sub-tropical and tropical countries. Drug resistance has "become a major concern".<ref>{{cite journal | vauthors = Mansueto P, Seidita A, Vitale G, Cascio A | title = Leishmaniasis in travelers: a literature review | journal = Travel Medicine and Infectious Disease | volume = 12 | issue = 6 Pt A | pages = 563–81 | year = 2014 | pmid = 25287721 | doi = 10.1016/j.tmaid.2014.09.007 | url = https://iris.unipa.it/bitstream/10447/101959/4/Travel%20Medicine%20and%20Infectious%20Disease%202014%2012%20563-581.pdf | hdl = 10447/101959 | hdl-access = free | access-date = 23 October 2017 | archive-date = 12 October 2022 | archive-url = https://web.archive.org/web/20221012000116/https://iris.unipa.it/bitstream/10447/101959/4/Travel%20Medicine%20and%20Infectious%20Disease%202014%2012%20563-581.pdf | url-status = live }}</ref>

===Global and genomic data===
[[File:The global resistome based on sewage-based monitoring.webp|thumb|The global 'resistome' based on sewage-based monitoring<ref name="10.1038/s41467-022-34312-7"/>]]
[[File:Gene-sharing network between bacterial genera.webp|thumb|200px|Gene-sharing network between bacterial genera<ref name="10.1038/s41467-022-34312-7"/>]]
In 2022, genomic epidemiologists reported results from a [[global health|global]] survey of antimicrobial resistance via genomic [[wastewater-based epidemiology]], finding large regional variations, providing maps, and suggesting resistance genes are also [[Horizontal gene transfer|passed on]] between microbial species that are not closely related.<ref>{{cite news |title=Antibiotika-Resistenzen verbreiten sich offenbar anders als gedacht |url=https://www.deutschlandfunknova.de/nachrichten/bakterien-antibiotika-resistenzen-verbreiten-sich-offenbar-anders-als-gedacht |access-date=17 January 2023 |work=[[Deutschlandfunk Nova]] |language=de |archive-date=17 January 2023 |archive-url=https://web.archive.org/web/20230117125129/https://www.deutschlandfunknova.de/nachrichten/bakterien-antibiotika-resistenzen-verbreiten-sich-offenbar-anders-als-gedacht |url-status=live }}</ref><ref name="10.1038/s41467-022-34312-7">{{cite journal | vauthors = Munk P, Brinch C, Møller FD, Petersen TN, Hendriksen RS, Seyfarth AM, Kjeldgaard JS, Svendsen CA, van Bunnik B, Berglund F, Larsson DG, Koopmans M, Woolhouse M, Aarestrup FM | title = Genomic analysis of sewage from 101 countries reveals global landscape of antimicrobial resistance | journal = Nature Communications | volume = 13 | issue = 1 | pages = 7251 | date = December 2022 | pmid = 36456547 | pmc = 9715550 | doi = 10.1038/s41467-022-34312-7 | doi-access = free | bibcode = 2022NatCo..13.7251M }}</ref> The [[WHO]] provides the Global Antimicrobial Resistance and Use Surveillance System (GLASS) reports which summarize annual (e.g. 2020's) data on international AMR, also including an interactive dashboard.<ref>{{cite news |title=Superbugs on the rise: WHO report signals increase in antibiotic resistance |url=https://medicalxpress.com/news/2022-12-superbugs-antibiotic-resistance.html |access-date=18 January 2023 |work=World Health Organization via medicalxpress.com|archive-date=2 February 2023 |archive-url=https://web.archive.org/web/20230202015448/https://medicalxpress.com/news/2022-12-superbugs-antibiotic-resistance.html |url-status=live }}</ref><ref>{{cite web |title=Global antimicrobial resistance and use surveillance system (GLASS) report: 2022 |url=https://www.who.int/publications/i/item/9789240062702 |website=who.int |access-date=18 January 2023|archive-date=21 January 2023 |archive-url=https://web.archive.org/web/20230121073827/https://www.who.int/publications/i/item/9789240062702 |url-status=live }}</ref>