Multiple drug resistance
Multiple drug resistance (MDR), multi-drug resistance or multiresistance is a condition enabling disease-causing microrganisms (bacteria, viruses, fungi or parasites) to resist distinct antimicrobials, first and foremost antibiotics,but also antifungal drugs, antiviral medications, antiparasitic drugs, chemicals of a wide variety of structure and function targeted at eradicating the organism. Recognizing different degrees of MDR, the terms extensively-drug resistant (XDR) and pandrug-resistant (PDR) have been introduced. The definitions were published in 2011 in a journal called "Clinical Microbiology and Infection" and are openly accessible This article discusses multi-drug resistance of bacteria, fungi, viruses and parasites, not that of tumor cells, which are discussed in the section of antineoplastic resistance.
Common multi-drug-resistant organisms (MDROs)
are usually bacteria:
- 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
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 baumanii, Pseudomonas aeruginosa and Enterobacter species)
Bacterial resistance to antibiotics
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. These microorganisms employ several mechanisms in attaining multi-drug resistance:
- No longer relying on a glycoprotein cell wall
- Enzymatic deactivation of antibiotics
- Decreased cell wall permeability to antibiotics
- Altered target sites of antibiotic
- Efflux mechanisms to remove antibiotics
- Increased mutation rate as a stress response
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. Some resistant bacteria are able to transfer copies of DNA that code for a mechanism of resistance to other nearby species of bacteria, thereby conferring resistance to their neighbors, which then are also able to pass on the resistant gene. This process is called horizontal gene transfer.
Yeasts such as Candida species can become resistant under long term treatment with azole preparations, requiring treatment with a different drug class. Scedosporium prolificans infections are almost uniformly fatal because of their resistance to multiple antifungal agents.
HIV is the prime example of MDR against antivirals, as it mutates rapidly under monotherapy. Influenza virus has become increasingly MDR; first to amantadenes, then to neuraminidase inhibitors such as oseltamivir, (2008-2009: 98.5% of Influenza A tested resistant), also more commonly in immunoincompetent people 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.
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. Toxoplasma gondii can also become resistant to artemisinin, as well as atovaquone and sulfadiazine, but is not usually MDR Antihelminthic resistance is mainly reported in the veterinary literature, for example in connection with the practice of livestock drenching 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:
- 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.
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.
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) has no clinical application at the present time.
- Drug Resistance, Multiple at the US National Library of Medicine Medical Subject Headings (MeSH)
- 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.... Clinical Microbiology and Infection, Vol 8, Iss. 3 first published 27 July 2011 [via Wiley Online Library]. Retrieved 16 August 2014.
- Boucher, HW, Talbot GH, Bradley JS, Edwards JE, Gilvert D, Rice LB, Schedul M., Spellberg B., Bartlett J. "Bad buds, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America". Clinical Infectious Diseases. 2009 Jan 1;48(1):1-12. doi:10.1086/595011.
- 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.
- 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.
- Stix G (April 2006). "An antibiotic resistance fighter". Sci. Am. 294 (4): 80–3. doi:10.1038/scientificamerican0406-80. PMID 16596883.
- 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.
- 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.
- 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.
- Greene HL, Noble JH (2001). Textbook of primary care medicine. St. Louis: Mosby. ISBN 0-323-00828-3.
- 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 http://www.ecdc.europa.eu/en/activities/diseaseprogrammes/ARHAI/Pages/public_consultation_clinical_microbiology_infection_article.aspx
- State of Connecticut Department of Public Health MDRO information http://www.ct.gov/dph/cwp/view.asp?a=3136&q=424162
APUA or Alliance for the Prudent Use of Antibiotics http://www.tufts.edu/med/apua/about_issue/multi_drug.shtml