Multiple drug resistance

This article is about multiple drug resistance in microorganisms. For multiple drug resistance in tumor/cancer cells, see antineoplastic resistance.

Not to be confused with Multidrug tolerance.

Multiple drug resistance (MDR), multidrug resistance or multiresistance is antimicrobial resistance shown by a species of microorganism to at least one antimicrobial drug in three or more antimicrobial categories.^[1] Antimicrobial categories are classifications of antimicrobial agents based on their mode of action and specific to target organisms.^[1] The MDR types most threatening to public health are MDR bacteria that resist multiple antibiotics; other types include MDR viruses, parasites (resistant to multiple antifungal, antiviral, and antiparasitic drugs of a wide chemical variety).^[2]

Recognizing different degrees of MDR in bacteria, the terms extensively drug-resistant (XDR) and pandrug-resistant (PDR) have been introduced. Extensively drug-resistant (XDR) is the non-susceptibility of one bacteria species to all antimicrobial agents except in two or less antimicrobial categories. Within XDR, pandrug-resistant (PDR) is the non-susceptibility of bacteria to all antimicrobial agents in all antimicrobial categories.^[1] The definitions were published in 2011 in the journal Clinical Microbiology and Infection and are openly accessible.^[1]

Common multidrug-resistant organisms (MDROs)

Common multidrug-resistant organisms, typically bacteria, include:^[3]

• Vancomycin-Resistant Enterococci (VRE)
• Methicillin-resistant Staphylococcus aureus (MRSA)
• Extended-spectrum β-lactamase (ESBLs) producing Gram-negative bacteria
• Klebsiella pneumoniae carbapenemase (KPC) producing Gram-negatives
• Multidrug-resistant Gram negative rods (MDR GNR) MDRGN bacteria such as Enterobacter species, E.coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa
• Multi-drug-resistant tuberculosis

Overlapping with MDRGN, a group of Gram-positive and Gram-negative bacteria of particular recent importance have been dubbed as the ESKAPE group (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species).^[4]

Bacterial resistance to antibiotics

Main article: Antibiotic resistance

Various microorganisms have survived for thousands of years by their ability to adapt to antimicrobial agents. They do so via spontaneous mutation or by DNA transfer. This process enables some bacteria to oppose the action of certain antibiotics, rendering the antibiotics ineffective.^[5] These microorganisms employ several mechanisms in attaining multi-drug resistance:

• No longer relying on a glycoprotein cell wall^{[citation needed]}
• Enzymatic deactivation of antibiotics^[6]
• Decreased cell wall permeability to antibiotics^[7]
• Altered target sites of antibiotic^[8]
• Efflux mechanisms to remove antibiotics^[9]
• Increased mutation rate as a stress response^[10]

Many different bacteria now exhibit multi-drug resistance, including staphylococci, enterococci, gonococci, streptococci, salmonella, as well as numerous other Gram-negative bacteria and Mycobacterium tuberculosis. Antibiotic resistant bacteria are able to transfer copies of DNA that code for a mechanism of resistance to other bacteria even distantly related to them, which then are also able to pass on the resistance genes, resulting in generations of antibiotics resistant bacteria.^[11] This initial transfer of DNA is called horizontal gene transfer.^[12]

Bacterial resistance to bacteriophages

Phage-resistant bacteria variants have been observed in human studies. As for antibiotics, horizontal transfer of phage resistance can be acquired by plasmid acquisition.^[13]

Antifungal resistance

Yeasts such as Candida species can become resistant under long-term treatment with azole preparations, requiring treatment with a different drug class. Lomentospora prolificans infections are often fatal because of their resistance to multiple antifungal agents.^[14]

Antiviral resistance

HIV is the prime example of MDR against antivirals, as it mutates rapidly under monotherapy. Influenza virus has become increasingly MDR; first to amantadines, then to neuraminidase inhibitors such as oseltamivir, (2008-2009: 98.5% of Influenza A tested resistant), also more commonly in people with weak immune systems. Cytomegalovirus can become resistant to ganciclovir and foscarnet under treatment, especially in immunosuppressed patients. Herpes simplex virus rarely becomes resistant to acyclovir preparations, mostly in the form of cross-resistance to famciclovir and valacyclovir, usually in immunosuppressed patients.^[15]

Antiparasitic resistance

The prime example for MDR against antiparasitic drugs is malaria. Plasmodium vivax has become chloroquine and sulfadoxine-pyrimethamine resistant a few decades ago, and as of 2012 artemisinin-resistant Plasmodium falciparum has emerged in western Cambodia and western Thailand.^[16]Toxoplasma gondii can also become resistant to artemisinin, as well as atovaquone and sulfadiazine, but is not usually MDR^[17]Antihelminthic resistance is mainly reported in the veterinary literature, for example in connection with the practice of livestock drenching^[18] and has been recent focus of FDA regulation.

Preventing the emergence of antimicrobial resistance

To limit the development of antimicrobial resistance, it has been suggested to:^{[citation needed]}

• Use the appropriate antimicrobial for an infection; e.g. no antibiotics for viral infections
• Identify the causative organism whenever possible
• Select an antimicrobial which targets the specific organism, rather than relying on a broad-spectrum antimicrobial
• Complete an appropriate duration of antimicrobial treatment (not too short and not too long)
• Use the correct dose for eradication; subtherapeutic dosing is associated with resistance, as demonstrated in food animals.
• More thorough education of and by prescribers on their actions' implications globally.

The medical community relies on education of its prescribers, and self-regulation in the form of appeals to voluntary antimicrobial stewardship, which at hospitals may take the form of an antimicrobial stewardship program. It has been argued that depending on the cultural context government can aid in educating the public on the importance of restrictive use of antibiotics for human clinical use, but unlike narcotics, there is no regulation of its use anywhere in the world at this time. Antibiotic use has been restricted or regulated for treating animals raised for human consumption with success, in Denmark for example.^[19]

Infection prevention is the most efficient strategy of prevention of an infection with a MDR organism within a hospital, because there are few alternatives to antibiotics in the case of an extensively resistant or panresistant infection; if an infection is localized, removal or excision can be attempted (with MDR-TB the lung for example), but in the case of a systemic infection only generic measures like boosting the immune system with immunoglobulins may be possible. The use of bacteriophages (viruses which kill bacteria) is a developing area of possible therapeutic treatments.^[20]

It is necessary to develop new antibiotics over time since the selection of resistant bacteria cannot be prevented completely. This means with every application of a specific antibiotic, the survival of a few bacteria which already got a resistance gene against the substance is promoted, and the concerning bacterial population amplifies. Therefore, the resistance gene is farther distributed in the organism and the environment, and a higher percentage of bacteria means they no longer respond to a therapy with this specific antibiotic. In addition to developing new antibiotics, new strategies entirely must be implemented in order to keep the public safe from the event of total resistance. New strategies are being tested such as UV light treatments and bacteriophage utilization, however more resources must be dedicated to this cause.

See also

• Drug resistance
• MDRGN bacteria
• Xenobiotic metabolism
• NDM1 enzymatic resistance
• Herbicide resistance
• P-glycoprotein

References

1. A.-P. Magiorakos, A. Srinivasan, R. B. Carey, Y. Carmeli, M. E. Falagas, C. G. Giske, S. Harbarth, J. F. Hinndler et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria... 6 December 2017 at the Wayback Machine. Clinical Microbiology and Infection, Vol 8, Iss. 3 first published 27 July 2011 [via Wiley Online Library]. Retrieved 16 August 2014.
2. Drug+Resistance,+Multiple at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
3. Gall E, Long A, Hall KK (2020). "Infections Due to Other Multidrug-Resistant Organisms". Making Healthcare Safer III: A Critical Analysis of Existing and Emerging Patient Safety Practices. Rockville (MD): Agency for Healthcare Research and Quality (US). PMID 32255576. from the original on 18 October 2022. Retrieved 15 December 2023.
4. Boucher, HW, Talbot GH, Bradley JS, Edwards JE, Gilvert D, Rice LB, Schedul M., Spellberg B., Bartlett J. (1 January 2009). "Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America". Clinical Infectious Diseases. 48 (1): 1–12. doi:10.1086/595011. PMID 19035777.{{cite journal}}: CS1 maint: multiple names: authors list (link)
5. Bennett PM (March 2008). "Plasmid encoded antibiotic resistance: acquisition and transfer of antibiotic resistance genes in bacteria". Br. J. Pharmacol. 153 (Suppl 1): S347–57. doi:10.1038/sj.bjp.0707607. PMC 2268074. PMID 18193080.
6. Reygaert WC (2018). "An overview of the antimicrobial resistance mechanisms of bacteria". AIMS Microbiology. 4 (3): 482–501. doi:10.3934/microbiol.2018.3.482. ISSN 2471-1888. PMC 6604941. PMID 31294229.
7. Peterson E, Kaur P (2018). "Antibiotic Resistance Mechanisms in Bacteria: Relationships Between Resistance Determinants of Antibiotic Producers, Environmental Bacteria, and Clinical Pathogens". Frontiers in Microbiology. 9: 2928. doi:10.3389/fmicb.2018.02928. ISSN 1664-302X. PMC 6283892. PMID 30555448.
8. Periasamy H, Joshi P, Palwe S, Shrivastava R, Bhagwat S, Patel M (10 February 2020). "High prevalence of Escherichia coli clinical isolates in India harbouring four amino acid inserts in PBP3 adversely impacting activity of aztreonam/avibactam". Journal of Antimicrobial Chemotherapy. 75 (6): 1650–1651. doi:10.1093/jac/dkaa021. ISSN 0305-7453. PMID 32040179. from the original on 24 February 2024. Retrieved 6 May 2023.
9. Li XZ, Nikaido H (August 2009). "Efflux-mediated drug resistance in bacteria: an update". Drugs. 69 (12): 1555–623. doi:10.2165/11317030-000000000-00000. PMC 2847397. PMID 19678712.
10. Stix G (April 2006). "An antibiotic resistance fighter". Sci. Am. 294 (4): 80–3. Bibcode:2006SciAm.294d..80S. doi:10.1038/scientificamerican0406-80. PMID 16596883.
11. Hussain, T. Pakistan at the verge of potential epidemics by multi-drug resistant pathogenic bacteria (2015). Adv. Life Sci. 2(2). pp: 46-47
12. Tao S, Chen H, Li N, Wang T, Liang W (2022). "The Spread of Antibiotic Resistance Genes In Vivo Model". Canadian Journal of Infectious Diseases and Medical Microbiology. 2022: e3348695. doi:10.1155/2022/3348695. ISSN 1712-9532. PMC 9314185. PMID 35898691.
13. Oechslin F (30 June 2018). "Resistance Development to Bacteriophages Occurring during Bacteriophage Therapy". Viruses. 10 (7): 351. doi:10.3390/v10070351. PMC 6070868. PMID 29966329.
14. Howden BP, Slavin MA, Schwarer AP, Mijch AM (February 2003). "Successful control of disseminated Scedosporium prolificans infection with a combination of voriconazole and terbinafine". Eur. J. Clin. Microbiol. Infect. Dis. 22 (2): 111–3. doi:10.1007/s10096-002-0877-z. PMID 12627286. S2CID 29095136.
15. Levin MJ, Bacon TH, Leary JJ (2004). "Resistance of Herpes Simplex Virus Infections to Nucleoside Analogues in HIV-Infected Patients". Clinical Infectious Diseases. 39 (s5): S248–S257. doi:10.1086/422364. ISSN 1058-4838. PMID 15494896.
16. Dondorp, A., Nosten, F., Yi, P., Das, D., Phyo, A., & Tarning, J. et al. (2009). Artemisinin Resistance in Plasmodium falciparum Malaria. New England Journal Of Medicine, 361, 455-467.
17. Doliwa C, Escotte-Binet S, Aubert D, Velard F, Schmid A, Geers R, Villena I. Induction of sulfadiazine resistance in vitro in Toxoplasma gondii.Exp Parasitol. 2013 Feb;133(2):131-6.
18. Laurenson YC, Bishop SC, Forbes AB, Kyriazakis I.Modelling the short- and long-term impacts of drenching frequency and targeted selective treatment on the performance of grazing lambs and the emergence of antihelmintic resistance.Parasitology. 2013 Feb 1:1-12.
19. Levy S (2014). "Reduced Antibiotic Use in Livestock: How Denmark Tackled Resistance". Environmental Health Perspectives. 122 (6): A160-5. doi:10.1289/ehp.122-A160. ISSN 0091-6765. PMC 4050507. PMID 24892505.
20. Schooley RT, Biswas B, Gill JJ, Hernandez-Morales A, Lancaster J, Lessor L, Barr JJ, Reed SL, Rohwer F, Benler S, Segall AM, Taplitz R, Smith DM, Kerr K, Kumaraswamy M, Nizet V, Lin L, McCauley MD, Strathdee SA, Benson CA, Pope RK, Leroux BM, Picel AC, Mateczun AJ, Cilwa KE, Regeimbal JM, Estrella LA, Wolfe DM, Henry MS, Quinones J, Salka S, Bishop-Lilly KA, Young R, Hamilton T (14 August 2017). "Development and Use of Personalized Bacteriophage-Based Therapeutic Cocktails To Treat a Patient with a Disseminated Resistant Acinetobacter baumannii Infection". Antimicrobial Agents and Chemotherapy. 61 (10). American Society for Microbiology: e00954-17. doi:10.1128/aac.00954-17. ISSN 0066-4804. PMC 5610518. PMID 28807909.

Further reading

• Greene HL, Noble JH (2001). Textbook of primary care medicine. St. Louis: Mosby. ISBN 978-0-323-00828-0.

External links

• BURDEN of Resistance and Disease in European Nations - An EU project to estimate the financial burden of antibiotic resistance in European Hospitals
• European Centre of Disease Prevention and Control and (ECDC): Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: An international expert proposal for interim standard definitions for acquired resistance Disease Programmes Unit
• State of Connecticut Department of Public Health MDRO information MultidrugResistant Organisms MDROs What Are They