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"What doesn't kill them makes them stronger". Drug resistance is the reduced effectiveness of a particular drug to a particular disease. Drug resistance comes in various forms with the most common of resistance occurring in microbial infections and in cancers. This essay will highlight upon the causes of resistance to antimicrobial drugs and anticancer drugs, in particular chemotherapeutic agents. Some examples of conditions where drug resistance occurs is in: HIV virus, staphylococcal infections, tuberculosis, influenza, gonorrhoea, Candida infection and malaria. In cancer therapy, chemotherapeutic agents are the most common group of drugs to which resistance occurs. (1)
Resistance to the use of a particular drug primarily occurs as a result of a change or evolution of a particular organism or cell. In the case of antimicrobial resistance it would be the evolution of bacteria, and in the case of anticancer resistance, it would be the evolution of cancerous cells that become resistance towards a particular drug. The extent to which resistance occurs varies widely in many individuals and is specific in various organisms.
With reference to drug resistance towards antimicrobial agents, the resistance is based on a number of factors grouped into two categories. These are Natural pressures and pressures made according to the way in which they are used in public healthcare (societal pressures). Natural pressures are the primary cause of resistance development and the causes are related to the properties of the organisms. Some natural pressures include - selective pressures, mutations and gene transfer. Societal pressures which are usually secondary causes include: the excessive use of antimicrobials, the insufficient control on drug prescribing, inadequate compliance with treatment regimens, prescribing incorrect doses, the lack of the control of infections, and the increase in ease of human travelling (2). This essay concentrates in particular to drug resistance in both antimicrobial and anticancer agents.
The resistance to antimicrobials had been since the discovery of the first antibiotics. In 1928 a Scottish scientist - Sir Alexander flemming was working with the staphylococcus bacteria and noticed by chance the inhibition of the staphylococci bacterial growth on an agar plate which was assumed to be contaminated by a type of mould growing on a lab plate. This substance was later isolated by Chain and Floery and was named as penicillin and was an antibiotic, it came into use in 1946 and now it is a widely antibiotic and has many derivatives. (3) Over the decades there has been the discovery and development of many antimicrobial agents, but due to the evolution of microbes and disease, many have lost their effectiveness. This proves to be a great problem in healthcare.
Microbes are living organisms, their aim like any other organism is to reproduce and thrive, microbes are very good at this due to their ability to grow fast and reproduce very quickly and efficiently effectively increase their population number within a small amount of time in a certain environment. Microbes include - bacteria (e.g. staph), viruses (e.g. influenza), fungi (e.g. Candida Alba) and parasites with the most known one being malaria. (4) In human medicine antimicrobials act towards killing microbes and inhibiting the proliferation of microbes. Antimicrobial drug resistance occurs when microbes have the ability to grow in the presence of the agent which in normal situations would result in the death or limit the growth of that microbe. (5)
There are many risk factors involved in the development of antimicrobial resistance. The main reason behind the development of drug resistance comes down to the evolution of microbes. In particular these can be classed into the biological causes of drug resistance. Microbe growth can be inhibited by antimicrobials in some circumstances due to variation some microbes carry resistant genes which allow them to survive in the presence of antimicrobials, as a result these variations lead to the survival and thus the profiliferation of the resistant microbes, leading to complete drug resistance if these strains were to be acquired, this is illustrating in figure 1. (6)
Another form of natural resistance can be due to mutations. Since microbes develop every few hours, they have the advantage to evolve rapidly unlike other organisms; as a result of this mutations are more likely to occur. Microbes can also adapt rapidly to new environmental conditions. In the presence of antimicrobials there is pressure involving the ability to survive this can lead to the mutations, these mutations essentially lead to the development of different antimicrobial strains that are not affected by a particular anti microbial agents. (6)
Microbes also have the ability to transfer genes across to one another whilst dividing; this means genes which lead to the development of resistance can also be exchanged thus leading to antimicrobial resistance. (6)
The way in which antimicrobials are used can aid the development of resistance, some examples of patterns involving inappropriate usage include, the prescribing of inappropriate antimicrobial, if a particular antimicrobial is not the most effective drug for use the chances of drug resistance development is higher. The inappropriate prescribing is also down to the inadequate diagnosis which results from the diagnosis made from insufficient information. The wide use in hospital care also contributes to antimicrobial resistance, there is also some evidence showing that the use of antimicrobials in agriculture is also influencing resistance. (6)
One category of antimicrobials is antibiotics; antibacterial resistance is common and problematic, intrinsic resistance is where the bacterial species lacks the receptor for the antibiotics action or is impermeable to the drug. The main problem involves acquired drug resistance. This occurs when a species that was previously treatable by a certain antibiotic but now no longer is affected by it. ( 7 last years lecture notes)
The examples of ways in which acquired drug resistance can occur in bacterial cells are shown in figure 2.
Metabolic bypass is where the elements required by a bacterial cell are replaced, and other cascade pathways are undergone in order to gain what the cell required, this is essentially a form of adaptation. One example is in resistance of the drug trimethoprim which blocks a certain metabolic pathway involving folic acid, however certain plasmids within the cell can provide for alternative enzymes which are important for this metabolic process thus resisting the effects of the drug and bypassing the initial reaction. Bacterial cells can increase the production of the target site, as a result the antibiotic is used up faster, an example of this is in the overproduction of penicillin - binding protein 4 can increase beta-lactam resistance in staphylococcus aureus cells by mopping up the antibiotic. They can also adapt leading to the reduced uptake causing less damage to the bacterial cell, for example mutations involving changes in the outer membranes of gram - negative species can prevent the uptake of beta-lactams, aminoglyocises and tetracycline's. Efflux is the removal of a cellular component out of the cell; in terms of resistance this would mean pumping out the antibiotic that enters the cytoplasm as much as possible. For example s aureus has many efflux pumps for macrolides and fluoroquinolones. An alteration in structure of the target is another mechanism of adaptation in the development of drug resistance, lastly bacteria also have the ability to destroy the antibiotic by enzymes, and for example resistance to beta-lactams is facilitated by the secretion of beta-lactamases enzymes, which cleave the beta - lactam ring. This is common in many bacterial species. (7 last years lecture notes)
One common example of bacteria which has become resistant to antibacterial exposure is the MRSA also known as Methicillin - resistance staphylococcus aureus. Originally staphylococcus aureus bacterium was discovered in the 1880's, it is one of the most dangerous kinds of bacteria due to its ability to cause various degree of damage to the human body and due to the difficulty of treating infections cause by this bacteria it poses a major risk to those acquiring the bacteria. S. aureus typical lives on the skin and can be passed on easily usually by skin to skin contact. Symptoms to a S. aureus infection include superficial lesions, infections of the hairfolicle, acne and sties amongst other more serious effects. (8- S.Aureus book) with the discovery of penicillin, the treatment of these infections became successful. Due to the misuse and overuse of anbiotics there was the development of the natural evolution of new strains. In the 1950's staphylococcus aureus developed a resistant strain towards Pencillin, as a results a new form of penicillin was introduced to treat infections caused by this particular strain and counteract the increasing problem of penicillin resistant staphylococcus aureus. In 1961 however it was found that a new staphylococcus aureus strain could resist Methicillin, now known as MRSA. MRSA is resistant to the whole class of antibiotics known as beta-lactams. (9 national institute) (9)
Another type of drug resistance strain is the vancomycin resistant enterococci also known as VRE and are strains of the bacterium enterococci. Enterococci are gram positive facultative anaerobic cocci and are commonly found in the human digestive tract of the human body, the female genital tract and skin. Urinary tract infections are the most common infections caused by the entr=ococci bacteria with the most severe of infections being endocarditic. (10 - entorciiclo book) This particular resistant strain of drug was discovered in the 1985. It is known that the mechanism of resistance is due to the alteration of the structure of the cell membrane of the bacterium. (11 national institute)
To highlight drug resistance from parasite, one important health challenge faced today is the resistance of malaria towards antimalarials. Today this is a worldwide problem. According to the world health organisation (WHO) 36 % of the global population live in areas where there is a risk of malaria transmission. Malaria is a very diverse condition and varies widely across different parts of the world and this is partly the challenge of treating the various strains of the parasite. Antimalarial drug resistance has been defined as being of a malarial strain to survive and multiply despite the administration and absorption of a drug in doses equal to or higher than those usually recommended but within the tolerance of the subject (48-13). The reason for malaria resistance is due to mutations which occur in the parasite, these mutations lead to the development of new strains that become less responsive to a specific antimarial or a specific group of antimalarials. In order for resistance to a drug to occur some drugs require single point mutations however some drugs require multiple mutations. (51-14). the three classes of drug where resistance has already occurred are chloroquine, the antifolate combination drug and atovaquone. The way in which chloroquinine resistance occurred was due to the development of the increased capacity of the parasite to efflux the chloroquinine, as a result therapeutic levels required for the inhibition of haemoglobin polymerisation couldn't be reached and treatment would fail (52-15). The antifolate combinations of drugs have also developed resistance due to the specific gene mutations encoding for resistance to the enzymes: dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) (48-16). The drug atovaquone acts through the inhibition of the electron transport at the cytochrome bc1 complex (56-17), since it was initially used alone there was a greater chance of resistance to develop, and this occurred; however is it still used in combination with a drug called proquanilin in malrone. (35-18). (19 references within pdf)
In cancers drug resistance is a phenomenon whereby malignant tumours loose their responses to therapeutic agents; it is recognised as being the major obstacle to be overcome during the systemic therapy of cancers. (20 Random book). A cancer can be defined as a diseases caused by changes in a cells expression of genes whereby the process of proliferation exceeds that which is required for normal cell functioning. One particular branch of resistance in cancer is chemotherapy resistance. Chemotherapy resistance occurs when cancers which initially were responding to therapy and suddenly begin to grow, and the effects of a chemotherapy agent wear away, in situation like this the regimen usually would need changing. The common ways that cancer cells are able to become resistance include; increased efflux of drugs, a common problem is when there is the aquration of multiple drug resistance. The anticancer agent can also be deactivated by particular enzyme within the cell. Through evolution there would be the reduced drug permeability of the drug to enter the cell or by the change in binding sites, (21wikipedia). Due to the development of drug resistance, drug therapy is usually given in combination.
Multiple drug resistance arises out of structural and function changes of cancerous cells, particularly in the cell membranes, metabolic processes within the cytoplasm or the cell organelles or nucleus. Multiple drug resistance is a general term given to a group of modification, over expression or amplicfations of molecules that affect the cellular pathways, some of these modifications include: p-glycoprotein over expression. P - Glycoprotein also known as permeability glycoprotein is involved in the transport of various substrates across the membrane. It is part of a group of proteins called the ATP - binding cassette transporters (ABC). ABC transporters are also over expressed. Protein Kinase C is a family of enzymes involved in the controlling of the function of other proteins and in tumour cells it is known to be activated more by tumour promoter phobol ester and can phosphorylate potent activators of transcription leading to and increased expression of oncogenes promoting cancer progression. In MDR it is know that Protein Kinase C is over expressed (22 pkc wiki). Tubulin mutation occurs, tubulin are targets for anticancer drugs like taxol, tesetaxel, vinblastine and vincristine. Episomes are particles of the genes of a certain cell which are present in the cell cytoplasm, in MDR it is known that episomes are amplified. The formation of double minute chromosomes. Altered cellular calcium levels. Topoisomerase II mutation and altered reduction - oxidation, and the over expression of cytoplasmic 22-K DA sorcin. (23 book)
Cisplatin is a common chemotherapeutic drug and is known to be highly effective in the treatment of various types of carcinomas; it however has unfortunately encountered drug resistance. The common ways in which cisplatin is known to acquire resistance from cancer cells are, the decrease in intracellular concentration of cisplatin due to the decrease in uptake, in order for cisplatin to work it chloride atoms are substituted by water molecules on uptake into the cell due to the differences in the concentrations of these ions, this from is the active form of the drug and can be taken up into the nucleus, the uptake of the drug into the cell is known to be either by passive diffusion and active transport, in resistance the active uptake of the drug is reduced. The other mechanism by which resistance occurs is that within a cancer cell cisplatin can interact with a variety of other molecules including the two examples of sulphur containing molecules: metallothionein and glutathione, subsequently as a result of this interaction it can be removed from the cell. Metallothionein is able to detoxify heavy metal ions in the cell; in this case the metal ion would be platinum. Glutationine is also involved I nthe detoxifation. G can bind to platinum forming complexes which can then be eliminated fro the cell. A final contributor to cisplatin resistance is an increase in the ability of the cell to be able to remove cisplatin - DNA adducts. (24, 25, 26 chem. Cases - 2 refs and journal - 1 ref)
Overall drug resistance has been described as the single most common reason for discontinuation of a drug therapy. (Chemcases 27)2. Resistance costs money, livelihoods and lives and threatens to undermine the effectiveness of health delivery programmes (WHO 28). According to antimicrobial treatment, many diseases caused by microbes are becoming difficult to treat because of antimicrobial resistance. The mechanisms of resistance towards antimicrobial agents have been highlighted upon in this essay. The commonest examples of antimicrobial resistant organisms and infections include: HIV virus, staphylococcal infection, tuberculosis, influenza, gonorrhoea, Candida infection and malaria. According to the world health organisation antimicrobial resistance is a global health concern, speicallfaclly because resistance kills, it hampers the control of infectious diseases, it increases the cost of healthcare, it threatens health security and damages trade and economics amongst many others (WHO from above 1). Some of the solutions towards combating antimicrobial resistance are to: surveillance of antimicrobial use, avoid using antibody unnecessarily, reduce the doses and counsel patients to complete dose courses. To use specific antibodies to treat the infections (narrow spectrum). To improve infection control in hospital (prevention). Discovery and development of new antimicrobials and vaccines. (WHO 29)
In cancer treatment involving primary chemotherapy where the use of a chemotherapeutic agent is the main treatment for a cancer, the chances of drug resistance occurring is the highest. Today this is combacted by using a combination of chemotherapy whereby two or more drugs are used providing the don't carry any dangerous interactions so the chances of cancer destruction is higher and resistance development is low.