Group Report: Tetracyclines
Tetracyclines are a large family of broad-spectrum antibiotics. They are produced by the Streptomyces genus of Actinobacteria. (Todar K.T 2009). Aureomycin was the first tetracycline antibiotic to be discovered in 1945 by Benjamin Duggar.
Subsequent modifications and discoveries have led to the enlargement of the family of tetracycline drugs. The general structure of Tetracyclines is:
The term ‘tetracycline' comes about from the four fused rings.
The presence of different functional groups on the basic skeleton results in different antibiotics of the same family. The structures of doxycycline and aureomycin are given below:
[Structure 3 & 4: Comparison between doxycycline (left) and aureomycin (right)]
The success with this class of antibiotics stimulated the development of many chemically altered antibiotics, and in doing so has proved to be one of the most important and beneficial discoveries made in the field of antibiotics.
Tetracyclines are used to treat many gram-positive and gram-negative bacteria. They are also effective on some protozoa. In other words they are used against a large variety of infections. (Todar K.T 2009). However due to the issue of bacterial resistance, these antibiotics have significantly decreased in value. (Speer et al.1992).
Tetracyclines are mainly used as a treatment for acne, eye infections, pneumonia, gonorrhea, Rocky Mountain spotted fever, urinary tract infections and Lyme disease. (Ogbru and Marks 2008). Other bacterial infections which usually result in the prescription of tetracyclines include Chlamydia, rickettsia, brucella and the spirochaeta. As well as the previously mentioned, there are many other infections in which tetracyclines are administered since it is such a broad spectrum antibiotic.
Tetracyclines, for example Tetracycline hydrochloride, Demeclocycline hydrochloride, Doxycycline, Lymecycline, Oxytetracycline, Tigecycline are essentially able to treat the same infections. Minocycline, another member of the tetracycline family, has a broader spectrum; it is active against Neisseria Meningitidis as well as the infections treated by the other tetracyclines.
Tetracyclines have similar side effects but each individual drug does come with some added ones. These include nausea, vomiting, diarrhoea, dysphagia (difficulty in swallowing), and oesophageal irritation. Other rare side effects have been noted such as acute renal failure and skin discolouration. (Joint Formulary Committee 2007, British Medical Association and Royal Pharmaceutical Society of Great Britain2008).
The dosages of tetracyclines i.e. when taken orally are usually 250mg, every 6 hours. This should be increased in severe infections to 500mg every 6-8hours. However this dosage does not apply to the different types of tetracyclines; each specific tetracycline has a specific dosage according to its strength. (Joint Formulary Committee 2007, British Medical Association and Royal Pharmaceutical Society of Great Britain 2008).
Mechanism of Action of tetracyclines
In order to understand the mechanism of action of tetracyclines, and therefore their role as antibiotics, it is important to have a basic understanding of bacterial protein synthesis in bacteria. An outline of this process at the ribosomal level is given in the diagrams below:
Tetracyclines also bind to DNA, proteins and synthetic polynucleotides but it is only the binding to ribosomes that is inhibitory and, therefore, has a therapeutic effect (Gale et al., 1981).
The structure of the tetracycline drug molecules can affect their antibacterial activity. “Features important for antibacterial activity among the tetracyclines are maintenance of the linear fused tetracycle, naturally occurring (a) stereochemical configurations at the 4a, 12a (A-B ring junction), and 4 (dimethylamino group) positions, and conservation of the keto-enol system (positions 11, 12, and 12a) in proximity to the phenolic D ring” (Chopra and Roberts, 2001). Research carried out by McCormick et al. (1957 cited Gale et al., 1981) also draws attention to the fact that the configuration of the 4-dimethylamino group must not be reversed (which would give 4-epitetracycline) as this would cause antibacterial activity to be lost.
However, since the precise mechanism by which tetracylines work is not fully understood, further knowledge of how the structure of the drug molecules affects their function as antibiotics is not known.
Social impact of tetracyclines
The basic health of a population is essential for society. The US Food and Drug Administration, as well as the British National Formulary list a range of indications for administering tetracyclines. A target area concerning the use of tetracyclines is the current epidemic of sexually transmitted infections (STIs). One bacterium susceptible to tetracyclines includes Chlamydia trachomatis which is responsible for Chlamydia. If untreated, Chlamydia can lead to serious health complications including infertility and as the condition exhibits asymptomatic effects, rapid intervention is necessary.
National statistics state that Chlamydia is the most common STI in the UK and has been on the rise since the early 1990's. Chlamydia can potentially affect any sexually active individual; however figures dictate that 15 to 24 year olds are at higher risk and the majority of cases are found in women. Chlamydia infections can possibly spread in pregnant women, passing the disease onto their children who may be born premature and with serious conditions such as blindness and pneumonia. The issue for society arises as tetracyclines, normally the primary choice for Chlamydia patients, have been shown to possess toxic effects on bones and therefore must not be distributed to children under the age of eight and pregnant women if impaired development of the foetus's bone structure is possible.
An additional common use for tetracycline is in patients with acne. Tetracycline is often prescribed for patients with moderate to severe acne. The drug targets inflammatory lesions caused by Propionbacterium acnes affecting the pilosebaceous unit of the skin. The University of Newcastle-Upon-Tyne reported in the ‘Journal of Dermatological Treatment' that there was a shift in the peak age incidence of acne between 14-26 year olds. Therefore acne is making an impact on the working population.
Although tetracyclines target bacterial diseases, a preventative approach to control the spread of disease would be ideal. However demographic changes, including a steep increase in populations and consequently urbanisation leads to overcrowding. The resulting situation can potentially lead to poor sanitisation and the spread of diseases including respiratory infections. In more economically developed countries this issue can be tackled as tetracyclines are dispensed for diseases including respiratory mycoplasma infections and exacerbations of chronic bronchitis caused by Hemophilus influenza. However on a global scale, lesser economically developed countries without funding or national health services, as in the UK, see an increased level of occurrence of diseases in lower and middle social classes.
Our final point concentrates on one of the drawbacks of tetracyclines. As tetracyclines are common broad spectrum antibiotics, their use has encouraged evolutionary transformation and subsequently the prevalence of bacterial resistant strains. Resistance of tetracyclines has been identified and so to a certain degree, limits their use. Future implications include the degree of effectiveness they directly impose on infections. There are many relative contributors when discussing the cause of resistance strains. For example many doctors have been criticised for prescribing antibiotics too freely to the extent that the European centre of Disease Prevention and Control sent out letters to every general practioner to reiterate to them the complications of routinely prescribing these drugs.
Many civic groups have been created to increase public awareness of the dangers of resistance strains of antibiotics including tetracyclines. The underlying fear is that antibiotics will eventually cease to be the effective tool in fighting infections, limiting choices for both physicians and patients. In November 2008, 27 European member nations celebrated ‘Antibiotic Awareness Day'. Their objectives included raising awareness on how to use antibiotics in a responsible way, hoping for them to remain effective for the future.
Economic impact of tetracyclines
Tetracyclines are antibiotics which are produced by the pharmaceutical industry. Ultimately, any profit made by the industry results in indirect revenue for the country. So it follows that the greater the sale, the greater the tax revenue. Furthermore, in producing drugs that would keep a population healthy, the number of man hours lost to illness is reduced. In producing new and established drugs, the pharmaceutical industry creates opportunities for a great number of highly skilled workers. In the process of producing these drugs, the pharmaceutical industry must consider the most cost efficient means available.
There are many economic factors that pharmaceutical industries must address when formulating a new drug. Antibiotics such as tetracyclines can be used to treat a wide range of infections, meaning there is high demand for them and a lot money invested in their development and production. The production of antibiotics is worth millions of pounds and continues to expand each year. Over 10,000 antibiotic substances have been discovered and this number is increasing as new antibiotics are being created and developed synthetically.
The discovery of new antibiotics is a very complex process which takes years and furthermore is very costly. Microorganisms are cultured and then tested for their therapeutic index by allowing them to diffuse onto a range of different products such as bacterial cultures. This is to observe the effectiveness of their antibacterial properties. However, most of these antibiotics produced in this way have already been discovered. Therefore these new compounds may be modified to fulfil different roles and target different bacteria. Pfizer were the original producers of the first tetracyclines and are the main choice when the proprietary band is prescribed. However, the non-proprietary is most commonly prescribed - most likely due to cost for the NHS.
The production of antibiotics is said to be a batch process, as contamination would be more likely within a continuous process. Although a continuous process is quicker, the wastage caused by contamination means it isn't a cost effective process. Fermentation is used to allow the selected microorganisms to multiply and produce the antibiotic on a large scale. The selected organism which produces the antibiotic is isolated and a starter culture is made to increase the numbers of available organisms. Next, the medium is transferred to fermentation tanks where the microorganisms are allowed to grow and multiply, so large amounts of the antibiotic are produced. After a number of days a maximum level of antibiotic will have been produced by the microorganisms and separation of the products can begin. Various different purification methods can be used e.g. organic chemicals, leaving a purified powder. This whole process takes a few days meaning huge quantities can be manufactured each year worth millions of pounds to the producers.
Different formulations are then produced such as tables, capsules, intravenousdrips. The type of formulation will affect how much the drug will cost the customer. For example tablets are the cheapest as they are the easiest to produce and they are combined with cheap materials/ chemicals in formulation. Conversely, an intravenous preparation will be more expensive as a solvent is used to dissolve the drug. Packaging and transport costs also affect the economic factors related to the drug. Tablet formulations are cheap as they are packed tightly in boxes and are not easily damaged. This contrasts to the high cost required to transport other formulations in suitable conditions. Environmental factors can affect the drug such as temperature and suitable transportation methods are needed to deliver the product safely without damage.
It is important to consider Quality Assurance throughout the production process. As mentioned earlier it is very easy for contamination to occur during the manufacture. So Quality Assurance is completed by checking the product on a regular basis. This is very time consuming and requires staff, however, if contamination were to occur there would be a greater loss of money through wastage and time. It is also very important to ensure the highest quality of product is produced as patients' health is dependent on the drug and if errors were to occur, the company in fault could be fined and acquire a bad reputation.
In the manufacture process the major costs of the materials is in the production of the fermentation culture. It contains essential ingredients that the microorganisms need for growth and reproduction. Most importantly there will be a carbon source (molasses/ sugars). Nitrogen is also essential mostly in metabolic pathways which take place in the organism. Other elements are also necessary: phosphorus, iron, and copper. These are added as salts. Also, to prevent foaming during fermentation, anti-foaming agents such as octadecanol are used.
The majority of the materials used in production would be sourced locally however more specific materials may need to be imported from other countries. Importing the materials will introduce greater costs in the production due to transportation and workers' wages. However, it would benefit the overall economy as more jobs would be produced in the country of origin and the money would ultimately be returned, with a profit to the producers, through the sale of the product.
Another area that requires a certain amount of economic consideration is the energy requirements in the production and distribution stages. Certain temperatures need to be produced to enable the fastest rate of reaction, and many pieces of equipment will be used which require electricity to power them. A lot of energy will also be required for transportation like petrol for lorries.
When a customer is prescribed tetracyclines, they are required to pay the standard NHS prescription cost of 7.20 pounds due to it being a Prescription only medicine. However the tablets themselves are relatively cheap; according to the BNF 1 tablet costs approx 20p therefore the real cost of a pack for a complete course may be cheaper than the standard NHS charge. But the fact that the cost is relatively high may prevent overuse/misuse. Another problem the NHS may consider is whether its use outweighs its higher cost of production/purchase. However, since tetracyclines are so cheap to manufacture, there is no issue with distributing this drug on the NHS with the usual levy charge.
The maximum shelf life for tetracyclines is 1 year after which it can deteriorate into a toxic compound. This time is relatively long and so is an advantage to the manufacturer. To save further costs it may be kept in a powder form to prevent hydrolysis in solution, which could decrease the shelf life further still. Once taken, their half life is 6-11 hours (Paracetamol 1-4 hrs) meaning they will be fully functional for a long time. Therefore a lower dosage is required hence lowering the cost of production even further. The type of formulation will also affect the antibiotic's strength/effectiveness; if they are injected they will be even more effective as they will reach the target area more quickly, through the blood stream. However the cost of production would be much higher and therefore this formulation may only be chosen in preference of the cheaper tablets in certain circumstances.
There are other similar competitive drugs on the market for example penicillins. However tetracyclines are normally chosen by preference. This may be due to the fact that fewer people are allergic to them, they have fewer side effects or because they are very broad spectrum antibiotics. Other pharmaceutical companies create competition for each other as they may produce the same drugs as each other or may produce cheaper alternatives that are just as effective. This creates lowering prices and can affect the economy of the companies. This can be prevented by patenting laws. When new drugs are discovered the pharmaceutical company will obtain a patent for this drug allowing them sole production rights. However, after a certain length of time these run out.
Development of new drugs is a very costly process but due to bacterial resistance, new antibiotics are always required. This may mean discovering new antibiotics or modifying existing ones to allow them to remain in use for longer. Antibiotics are an essential part of medicine and therefore play a major part in the economy.