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 that pathogens have "acquired", that is, resistance has evolved. When an organism is resistant to more than one drug, it is said to be multidrug-resistant. In a broad sense the immune system of an organism is a drug delivery system, albeit autonomous, and faces the same arms race problems as external drug delivery.
The development of antibiotic resistance in particular stems from the drugs targeting only specific bacterial proteins. Because the drug is so specific, any mutation in these proteins will interfere with or negate its destructive effect, resulting in antibiotic resistance.[2]
Bacteria are capable of not only altering the enzyme targeted by antibiotics, but also by the use of enzymes to modify the antibiotic itself and thus neutralise it. Examples of target-altering pathogens are Staphylococcus aureus, vancomycin-resistant enterococci and macrolide-resistant Streptococcus, while examples of antibiotic-modifying microbes are Pseudomonas aeruginosa and aminoglycoside-resistant Acinetobacter baumannii.[3]
In short, the lack of concerted effort by governments and the pharmaceutical industry, together with the innate capacity of microbes to develop resistance at a rate that outpaces development of new drugs, suggests that existing strategies for developing viable, long-term anti-microbial therapies are ultimately doomed to failure. Without alternative strategies, the acquisition of drug resistance by pathogenic microorganisms looms as possibly one of the most significant public health threats facing humanity in the 21st century.[4]
Resistance to chemicals is only one aspect of the problem, another being resistance to physical factors such as temperature, pressure, sound, radiation and magnetism, and not discussed in this article, but found at Physical factors affecting microbial life.
Contents
- 1 Introduction
- 2 Mechanisms
- 3 Metabolic price
- 4 Treatment
- 5 See also
- 6 References
- 7 External links
Introduction[edit]
Drug, 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 tumors where some cells may develop resistance to the drugs used in chemotherapy.[5] Chemotherapy causes fibroblasts near tumors to produce large amounts of the protein WNT16B. This protein stimulates the growth of cancer cells which are drug-resistant.[6] Malaria in 2012 has become a resurgent threat in South East Asia and sub-Saharan Africa, and drug-resistant strains of Plasmodium falciparum are posing massive problems for health authorities.[7] Leprosy has shown an increasing resistance to dapsone, and Leishmania to antimony.
A rapid 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.[8] A similar asexual method is used by fungi and is called "parasexuality". Examples of drug-resistant strains are to be found in microorganisms[9] such as bacteria and viruses, parasites both endo- and ecto-, plants, fungi, arthropods,[10] mammals,[11] birds,[12] reptiles,[13] fish, and amphibians.[13]
In the domestic environment, drug-resistant strains of organism may arise from seemingly safe activities such as the use of bleach,[14] tooth-brushing and mouthwashing,[15] the use of antibiotics, disinfectants and detergents, shampoos, and soaps, particularly antibacterial soaps,[16][17] hand-washing,[18] surface sprays, application of deodorants, sunblocks and any cosmetic or health-care product, insecticides, and dips.[19] The chemicals contained in these preparations, besides harming beneficial organisms, may intentionally or inadvertently target organisms that have the potential to develop resistance.[20]
"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[edit]
The four main mechanisms by which microorganisms exhibit resistance to antimicrobials are:
- Drug inactivation or modification: e.g., enzymatic deactivation of Penicillin G in some penicillin-resistant bacteria through the production of β-lactamases.
- Alteration of target site: e.g., alteration of PBP — the binding target site of penicillins — in MRSA and other penicillin-resistant bacteria.
- 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.
- Reduced drug accumulation: by decreasing drug permeability and/or increasing active efflux (pumping out) of the drugs across the cell surface.[21]
Metabolic price[edit]
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[22] in pathogens for which this concept is relevant (bacteria,[23] endoparasites, and tumor cells.) In viruses, an equivalent "cost" is genomic complexity.
Treatment[edit]
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.
There is research being done using antimicrobial peptides. In the future, there is a possibility that they might replace novel antibiotics.
See also[edit]
- Antibiotic resistance
- Carbapenem
- Fecal bacteriotherapy
- Mass drug administration
- Multidrug resistance
- Pharmacoepidemiology
- Primary drug resistance
- Small multidrug resistance protein
References[edit]
- ^ Drug Resistance at the US National Library of Medicine Medical Subject Headings (MeSH)
- ^ http://www.detectingdesign.com/antibioticresistance.html
- ^ Fisher, Jed F.; Mobashery, Shahriar (2010). "Enzymology of Bacterial Resistance". Comprehensive Natural Products II. Volume 8: Enzymes and Enzyme Mechanisms. Elsevier. pp. 443–201. doi:10.1016/B978-008045382-8.00161-1. ISBN 978-0-08-045382-8. edit
- ^ The Resistance Phenomenon in Microbes and Infectious Disease Vectors: Implications for Human Health and Strategies for Containment
- ^ http://www.merckmanuals.com/home/drugs/factors_affecting_response_to_drugs/tolerance_and_resistance_to_drugs.html
- ^ "Chemo 'Undermines Itself' Through Rogue Response",BBC News, 5 August 2012.
- ^ BBC News
- ^ 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. doi:10.1016/S0958-1669(03)00036-3. PMID 12849777.
- ^ http://www.tulane.edu/~wiser/protozoology/notes/drugs.html
- ^ http://horizon.documentation.ird.fr/exl-doc/pleins_textes/pleins_textes_5/b_fdi_12-13/15697.pdf
- ^ 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.
- ^ 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". Journal of Wildlife Management 46 (2): 453–457. doi:10.2307/3808656. JSTOR 3808656.
- ^ a b Reptile Channel
- ^ http://www.physorg.com/news145799281.html
- ^ http://www.healthstores.com/dentists/new_dental_products.htm
- ^ CBC News http://www.cbc.ca/marketplace/webextras/triclosan/antibacterial.html?triclosan .
- ^ http://health.howstuffworks.com/skin-care/cleansing/myths/antibacterial-soap-outlawed.htm
- ^ Weber, D. J.; Rutala, W. A. (2006). "Use of germicides in the home and the healthcare setting: Is there a relationship between germicide use and antibiotic resistance?". Infection Control and Hospital Epidemiology 27 (10): 1107–1119. doi:10.1086/507964. PMID 17006819. edit
- ^ Yoon, K. S.; Kwon, D. H.; Strycharz, J. P.; Hollingsworth, C. S.; Lee, S. H.; Clark, J. M. (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. PMID 19058634. edit
- ^ http://www.betterhealth.vic.gov.au/bhcv2/bhcarticles.nsf/pages/Antibacterial_cleaning_products
- ^ 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.
- ^ Gillespie, S. H.; McHugh, T. D. (1997). "The biological cost of antimicrobial resistance". Trends in Microbiology 5 (9): 337–339. doi:10.1016/S0966-842X(97)01101-3. PMID 9294886. edit
- ^ Wichelhaus TA, Böddinghaus B, Besier S, Schäfer V, Brade V, Ludwig A (2002). "Biological Cost of Rifampin Resistance from the Perspective of Staphylococcus aureus". Antimicrobial Agents and Chemotherapy 46 (11): 3381–5. doi:10.1128/AAC.46.11.3381-3385.2002. PMC 128759. PMID 12384339.
External links[edit]
- 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
- Battle of the Bugs: Fighting Antibiotic Resistance
- MDRIpred : A web server for predicting inhibitors against drug tolerant M. Tuberculosis, published in Chemistry Central Journal
- CancerDR: Cancer Drug Resistance Database. Scientific Reports 3, 1445
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Concepts in Pharmacology
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| Pharmacokinetics |
- ADME: Absorption
- Distribution
- Metabolism
- Excretion (Clearance)
- Loading dose
- Volume of distribution (Initial)
- Rate of infusion
- Compartment
- Bioequivalence
- Bioavailability
- Onset of action
- Biological half-life
- Plasma protein binding
- Therapeutic index (LD50/ED50)
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| Pharmacodynamics |
- Toxicity (Neurotoxicology)
- Dose–response relationship (Efficacy, Potency)
- Antimicrobial pharmacodynamics: Minimum inhibitory concentration/Bacteriostatic
- Minimum bactericidal concentration/Bactericide
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Agonism and
antagonism |
- Agonist: Inverse agonist
- Irreversible agonist
- Partial agonist
- Superagonist
- Physiological agonist
- Antagonist: Competitive antagonist
- Irreversible antagonist
- Physiological antagonist
- Other: Binding
- Affinity
- Binding selectivity
- Functional selectivity
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| Other |
- Drug tolerance: Tachyphylaxis
- Drug resistance: Antibiotic resistance
- Multiple drug resistance
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Drug discovery
strategies |
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Related
fields/subfields |
- Pharmacogenetics
- Pharmacogenomics
- Neuropsychopharmacology (Neuropharmacology, Psychopharmacology)
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