Drug resistance

Drug resistance is the reduction in effectiveness of a drug such as an antimicrobial or an antineoplastic^[1] in curing a disease or condition. When the drug is not intended to kill or inhibit a pathogen, then the term is equivalent to dosage failure or drug tolerance. More commonly, the term is used in the context of resistance acquired by pathogens. When an organism is resistant to more than one drug, it is said to be multidrug-resistant.

Introduction

Drug or toxin or chemical resistance is a consequence of evolution and is a response to pressures imposed on any living organism. Individual organisms vary in their sensitivity to the drug used and some with greater fitness may be capable of surviving drug treatment. Drug-resistant traits are accordingly inherited by subsequent offspring, resulting in a population that is more drug-resistant. Unless the drug used makes sexual reproduction or cell-division or horizontal gene transfer impossible in the entire target population, resistance to the drug will inevitably follow. This can be seen in cancerous tumours where some cells may develop resistance to the drugs used in chemotherapy.^[2] A quicker process of sharing resistance exists among single-celled organisms, and is termed horizontal gene transfer in which there is a direct exchange of genes, particularly in the biofilm state.^[3] A similar asexual method is used by fungi and is termed parasexuality. Examples of drug-resistant strains are to be found in microorganisms^[4] such as bacteria and viruses, parasites both endo- and ecto-, plants, fungi, arthropods,^[5] mammals,^[6] birds,^[7] reptiles,^[8] fish and amphibians.^[8]

In the domestic environment, drug-resistant strains of organism may arise from seemingly safe activities such as the use of bleach,^[9] tooth-brushing and mouthwashing,^[10] the use of antibiotics, disinfectants and detergents, shampoos and soaps, particularly antibacterial soaps,^[11][12] hand-washing,^[13] surface sprays, application of deodorants, sunblocks and any cosmetic or health-care product, insecticides and dips.^[14] The chemicals contained in these preparations, besides harming beneficial organisms, may intentionally or inadvertently target organisms that have the potential to develop resistance and thereby become increasingly problematic.^[15]

"Drug resistance develops naturally, but careless practices in drug supply and use are hastening it unnecessarily." - Center for Global Development

"The overuse of antibacterial cleaning products in the home may be producing strains of multi-antibiotic-resistant bacteria." - Better Health Channel - Australian Government

"The use and misuse of antimicrobials in human medicine and animal husbandry over the past 70 years has led to a relentless rise in the number and types of microorganisms resistant to these medicines - leading to death, increased suffering and disability, and higher healthcare costs." - World Health Organisation 2010

"Deaths from acute respiratory infections, diarrhoeal diseases, measles, AIDS, malaria and tuberculosis account for more than 85% of the mortality from infection worldwide. Resistance to first-line drugs in most of the pathogens causing these diseases ranges from zero to almost 100%. In some instances resistance to second- and thirdline agents is seriously compromising treatment outcome. Added to this is the significant global burden of resistant hospital-acquired infections, the emerging problems of antiviral resistance and the increasing problems of drug resistance in the neglected parasitic diseases of poor and marginalized populations." - WHO Global Strategy for Containment of Antimicrobial Resistance 2010

Mechanisms

The four main mechanisms by which microorganisms exhibit resistance to antimicrobials are:

1. Drug inactivation or modification: e.g., enzymatic deactivation of Penicillin G in some penicillin-resistant bacteria through the production of β-lactamases.
2. Alteration of target site: e.g., alteration of PBP — the binding target site of penicillins — in MRSA and other penicillin-resistant bacteria.
3. Alteration of metabolic pathway: e.g., some sulfonamide-resistant bacteria do not require para-aminobenzoic acid (PABA), an important precursor for the synthesis of folic acid and nucleic acids in bacteria inhibited by sulfonamides. Instead, like mammalian cells, they turn to utilizing preformed folic acid.
4. Reduced drug accumulation: by decreasing drug permeability and/or increasing active efflux (pumping out) of the drugs across the cell surface.^[16]

Metabolic price

Biological cost or metabolic price is a measure of the increased energy metabolism required to achieve a function.

Drug resistance has a high metabolic price,^[17] in pathogens for which this concept is relevant (bacteria,^[18] endoparasites, and tumor cells.) In viruses, an equivalent "cost" is genomic complexity.

Treatment

The chances of drug resistance can sometimes be minimised by using multiple drugs simultaneously. This works because individual mutations can be independent and may tackle only one drug at a time; if the individuals are still killed by the other drugs, then the mutations cannot persist. This was used successfully in tuberculosis. However, cross resistance where mutations confer resistance to two or more treatments can be problematic.

For antibiotic resistance, which represents a widespread problem nowadays, destroying the resistant bacteria can be achieved by phage therapy, in which specific bacteriophage (virus that kill bacteria) are being used.

See also

• multidrug resistance
• antibiotic resistance
• mass drug administration
• pharmacoepidemiology

References

1. ^ MeSH Drug+Resistance
2. ^ http://www.merckmanuals.com/home/drugs/factors_affecting_response_to_drugs/tolerance_and_resistance_to_drugs.html
3. ^ Molin, S; Tolker-Nielsen, T (2003). "Gene transfer occurs with enhanced efficiency in biofilms and induces enhanced stabilisation of the biofilm structure". Current opinion in biotechnology 14 (3): 255–61. PMID 12849777. 
4. ^ http://www.tulane.edu/~wiser/protozoology/notes/drugs.html
5. ^ http://horizon.documentation.ird.fr/exl-doc/pleins_textes/pleins_textes_5/b_fdi_12-13/15697.pdf
6. ^ Lund, M (1972). "Rodent resistance to the anticoagulant rodenticides, with particular reference to Denmark". Bulletin of the World Health Organization 47 (5): 611–8. PMC 2480843. PMID 4540680. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2480843. 
7. ^ Shefte, N.; Bruggers, R. L.; Schafer, E. W. (1982). "Repellency and Toxicity of Three Bird Control Chemicals to Four Species of African Grain-Eating Birds". The Journal of Wildlife Management 46 (2): 453–457. doi:10.2307/3808656. JSTOR 3808656. 
8. ^ ^{a b} Reptile Channel
9. ^ http://www.physorg.com/news145799281.html
10. ^ http://www.healthstores.com/dentists/new_dental_products.htm
11. ^ CBC News. http://www.cbc.ca/marketplace/webextras/triclosan/antibacterial.html?triclosan. 
12. ^ http://health.howstuffworks.com/skin-care/cleansing/myths/antibacterial-soap-outlawed.htm
13. ^ http://www.journals.uchicago.edu/doi/abs/10.1086/507964
14. ^ Kyong Sup Yoon, Deok Ho Kwon, Joseph P. Strycharz, Craig S. Hollingsworth, Si Hyeock Lee, J. Marshall Clark (2008). Biochemical and Molecular Analysis of Deltamethrin Resistance in the Common Bed Bug (Hemiptera: Cimicidae) Journal of Medical Entomology, 45 (6), 1092-1101 DOI: 10.1603/0022-2585(2008)45[1092:BAMAOD]2.0.CO;2
15. ^ http://www.betterhealth.vic.gov.au/bhcv2/bhcarticles.nsf/pages/Antibacterial_cleaning_products
16. ^ Li, X, Nikadio H (2009). "Efflux-Mediated Drug Resistance in Bacteria: an Update". Drug 69 (12): 1555–623. doi:10.2165/11317030-000000000-00000. PMC 2847397. PMID 19678712. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2847397. 
17. ^ The biological cost of antimicrobial resistance Stephen H. Gillespie*, and Timothy D. McHugh
18. ^ Wichelhaus TA, Böddinghaus B, Besier S, Schäfer V, Brade V, Ludwig A (2002). "Biological Cost of Rifampin Resistance from the Perspective of Staphylococcus aureus". Antimicrob. Agents Chemother. 46 (11): 3381–5. doi:10.1128/AAC.46.11.3381-3385.2002. PMC 128759. PMID 12384339. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=128759. 

External links

• BURDEN of Resistance and Disease in European Nations—An EU project to estimate the financial burden of antibiotic resistance in European hospitals
• Merck - Tolerance and Resistance
• Cosmetics Database
• HCMV drug resistance mutations tool
• Combating Drug Resistance - An informative article on multidrug resistance