Introduction:
Vancomycin is an antibiotic. It can either be injected or taken orally. When taken orally it is used to treat “colitis (inflammation of the intestine caused by certain bacteria)” along with other bacterial infections. It works by inhibiting the growth of the bacterium. However, the Vancomycin injection is more widely used to treat infections such as; urinary tract infections, bone and joint infections, skin infections, and pneumonia. What makes vancomycin so important is the fact it can treat infections that are resistant to other antibiotics as well as infections in people who are allergic to penicillin. As with all antibiotics it will not be used to treat a cold/flu or any other viral infections. Vancomycin is known as ‘The drug of last resort’ as it is being use less frequently in hope to prolong or eradicate that chance of certain bacteria developing resistance to it.
1) Basic biology
Vancomycin is a glycopeptide antibiotic produced by strains belonging to the Micropolyspora orientalis species1. It was first discovered in 1952 from soil samples originating from Borneo where it was found that the sample contained Amycolatopsis orientalis. This organism, present within the soil sample secreted a compound (now known as vancomycin) which reacted positively against most gram positive microbes2
A lot is still unknown about Amycolatopsis orientalis, however it has many different strains some of which are used in the production of antibiotics besides vancomycin. The strain most commonly used in vancomycin production is characterized by a sparse white aerial mycelium with long chains of smooth spores as depicted in figure 1.5
Figure1
2) Nature of product.
Vancomycin, which has molecular formula C66H75CL2N9O244 , works to inhibit peptidoglycan synthesis in the cell walls of prokaryotic cells. Vancomycin molecules binds to prokaryotic cells via a complementary binding site to the D-ala-D-ala sequence of the bacterial cell. The D-ala-D-ala sequence is then held within a deep cleft of the antibiotic which results in the inhibition of a number of processes involved in one of the earliest production steps of cell wall synthesis2. The partially completed cell wall allows water to move freely into the cell via osmosis and consequently the cell will burst by lysis.
Figure23
3) Industrial bioprocess of production of Vancomycin
Amycolatopsis Orientalis Growth
1. A very small, cooled sample of the Amycolatopsis Orientalis organism is transferred to an agar containing plate where it is given an ideal environment to multiply in numbers for 24 hours.
2. This sample of the organism is then transferred from the agar containing plate to a shake flask. This provides a larger volume so more of the bacteria can multiply. A suspension of Amycolatopsis Orientalis is created and then transferred finally to a Seed Tank.
3. A seed tank is essentially a shake flask in a larger volume. It provides an ideal environment to maximise bacterial growth. After 24-48 hours in the seed tank and a sufficient amount of Amycolatopsis Orientalis has been produced. The preparation of Vancomycin can begin.
Preparation of Vancomycin
1. Aerobic Fermentation – Fermentation is a metabolic process in which this case shows Amycolatopsis Orientalis converting a carbohydrate such as starch into Vancomycin. The aerobic part of this just means in the presence of oxygen. The ideal temperature for this process is 29-30C which is positive economically as only a small amount of energy is needed to heat the fermentation tank which correlates to a lower cost. This is the stage where Vancomycin is actually produced.
2. Ion Exchange Chromatography – This stage involves the separation of ionisable molecules based on their overall charge. This technique enables the separation of similar types of molecules that would be difficult to separate by other methods because the charge carried by the molecule of interest (Vancomycin in this case) can be readily manipulated by changing buffer pH.
3. Separation by Reverse Osmosis and Ultrafiltration – This stage involves a solvent passing through a porous membrane in the opposite direction to that of osmosis (against the concentration gradient) when subjected to a hydrostatic pressure greater than the osmotic pressure. Ultrafiltration is the part of the process where particles bigger than 1 nanometres are retained while the solvent and smaller solutes are forced across the membrane by hydrostatic forces. These to processes happen simultaneously leaving behind the Vancomycin product.
4) Safety issues associated with organism, process or product
There are few safety issues associated with the production of Vancomycin this is a because it is produced a relatively low temperature (30 degrees Celsius) and at a reasonable pressure.
Two potential safety issues that could arise, if not handled correctly are;
• Disposing of the bacterial waste products. This is specifically important with the production of vancomycin because the yield is so low meaning there is a large amount of bacteria waste. “Contaminated biohazard waste must be collected by a licensed biohazardous waste hauler.” If this was not disposed of correctly it could contaminate our water cycle which would have negative impacts on human and animal life.
• Mutant resistant strains of bacteria which may become resistant to Vancomycin if the antibiotic course is not finished and therefore did not completely get rid of your bacterial infection. This remaining bacterium could then potentially become a resistant strain of bacteria through further mutations. In America, each year $21 billion is spent to treat antibiotic resistant infections which isn’t always successful. On average this claims about 23000 lives a year. To avoid this, it is vital that the course of antibiotics is finished. Resistant strains produce a D-Ala-D-Ala sequence which is not complementary to the biding site of the vancomycin molecule; the vancomycin molecule becomes obsolete as a result of this which then leads to cell wall synthesis proceeding without inhibition. Developing resistance is a global challenge with most antibiotics with Vancomycin there is no exception. Many steps are now being taken so that this happens less often.
5) Environmental
During some of the processes of involved in the synthesis of this antibiotic there will be cooling and heating of the substances. This requires large amounts of energy that is provided via the combustion of fossil fuels to form of electricity. Not only does burning fossil fuels release harmful greenhouse gasses into the atmosphere but the mining processes involved in the extraction of the fossil fuels are likely to disrupt the delicate balance with the eco-system.
The synthesis of this antibiotic is a difficult process and consequently there is a low yield of vancomycin produced; As a result there are significant amounts of unreacted raw material which need to be disposed of in a safe manner this is solely to prevent residues of the fermented bacteria or vancomycin within the raw material from entering the natural environment where the fermented bacteria culture can grow to pose risks to wildlife, endemic plant species or even humans if it ends up in the water supplies. As for the vancomycin residue, it is possible that exposure in the natural environment could cause certain bacterial strains to develop resistance to the drug which further poses health risks to humans (as mentioned in the safety section).
6) Commercial and economic issues
The cost of vancomycin is dependent on the type of the drug purchased. It is sold as Vancocin (oral version of vancomycin) which can be taken as a 14-day course at a cost of between $1000-$15006 or as an intravenous form that is significantly cheaper at $6 a dose and $84 for an entire 14-day course. The length of treatment using the oral form and the dosage vary among patients which likely means the standard price of $1000 can rise exponentially leading to a host of complications when the drug is unaffordable.
Vancomycin is used widely to treat numerous bacterial infections; this versatility has led to many resistant strains of the bacterium2 and there is growing fear that continual usage will lead to the drug becoming obsolete. Considering this, it is reasonable to assume that these prices are merely used by pharmaceutical companies to deter the unnecessary use of the drug. Conversely As depicted in figure2 vancomycin molecules have numerous cyclic rings, unnatural sugars and amino acids as well as being a zwitterion. The structural complexity of vancomycin means that it is very difficult to carry out synthesis of the molecule clinically from scratch and as a result sufficient amounts of vancomycin are unable to be produced via industrial scale production2. The supply and demand of this antibiotic is skewed and in economic terms a high demand but low supply results in the aforementioned prices.
Drug Penicillin (ampicillin 500 mg) Azithromycin (500 mg) Erythromycin (1g) Vancomycin (1g)
Costs ($) 2.90 7.20 2.50 7.50
Table 17
7) Competing technologies to the same product
Currently there are no competing technologies of Vancomycin that proves to be as effective against the wide range of infections that Vancomycin has already been proved to treat. Vancomycin is known as the ‘drug of last resort’ as it is being used less frequently in hope to prolong or eradicate the chance of certain bacteria developing resistance to it.
8) What the future might hold for the product or process
As the production of vancomycin has a very low percentage yield and therefore a lot of waste, the future will most likely include a more efficient production of such an important antibiotic which eliminates waste products. However, the future is an unknown medium and because of this we do not know what the future will hold. Vancomycin may well become redundant as a new and improved antibiotic takes its place which has less side effects and can be produced at cheaper costs, in turn making Vancomycin less attractive for use. Although, being said using alumina for the resin in ion exchange chromatography is currently being tested as it is less expensive than the alternative. However, as with most tests this does come at a cost, this being said, it does have negative implications on purity of the product.
At the moment, there are no technologies which can produce Vancomycin more efficiently so there is no direct competition to the product. Personally, I would say Vancomycin’s biggest competitor would be bacteria because clearly if all bacteria. It’s a global challenge to ensure Vancomycin is used carefully because if bacteria become resistant to Vancomycin, there would be no use for this, or maybe more generally any antibiotic.
Conclusion
It was very interesting to research such an important medicine to find out that it’s production, in the schemes of things, is relatively simple. However, there doesn’t seem to be a large amount of information available for Vancomycin which suggests that there is a degree of uncertainty about whether this production could perhaps be done under different conditions to make it cheaper and therefore more readily available to everyone due to its importance.