Discovery of antibiotics, the mode of action, and resistance mechanism have been researched in academia over several decades and more recently, the pharmaceutical companies have also joined in these researches (Davies &Davies, 2010, p.417). Antibiotics are natural products which offer challenges with respect to the biosynthetic pathways, chemical nature, biochemical mode of action, and evolution (Brötze & Brunner, 2008, p. 564). The complete laboratory synthesis of these natural products is complex mainly because of the complex chirality and functionality of the small molecules (Nicolaou, & Montagnon, 2008). The discovery of the first antibiotic, penicillin, was done in 1928 however, the complete structure was revealed in 1949 while its total synthesis was confirmed in 1959 (Davies et al., 2010). Currently, the understanding of how antibiotics work is still limited and it is only in a few instances that their interactions have been interpreted in reference to defined phenotypes. On the other hand, there is sufficient knowledge on antibiotic biological natural functions as well as the ecological and evolutionary aspects of their biological and chemical reactions (Allen, Donato, &Wang et al., 2010, p.251; Aminov,2009, p. 2970. ).
The development of several antibiotic-resistant microbes’ generations as well as their microbial populations distribution through the entire biosphere results from years of selection pressure that is unremitting, from antibiotic human applications through misuse, overuse, and under use. According to Barker, Linsley, &Kane (2016), when studying evidence, it is important to understand it, appraise it, and apply it to practice. This paper looks at the evolution of antibiotic resistance and has been triggered by the latest news on the development of last-line antibiotic resistance. The article in question states a number of comments made by the leading health professionals in reference to their being a decline in last line antibiotic resistance and methods to ensure that trend continues. The argument and for and against these statements will be analyzed and a final conclusion will be made in this paper.
The search terms that were used included: NHS, Klebsiella, e-coli, 21st century, PHE, causes of antibiotic resistance, NMC, antibiotic resistance mechanisms, drug-resistant bacteria, and last-line. The search was done in various engines including PubMed, CINHAL, and PsycInfo with a total of 84 results. The search dates were limited to 2013-2017. 26 results of the 84 were close enough in relevance with the key themes being the role played by pharmaceutical companies, human interference, and synthetic approaches to development of new drugs
According to the article, Professor Davies states that the healthcare industry is doing all it can to ensure reduction in mortality due to antibiotics does not increase as a result of drug resistance. This has been supported by the major reforms in the UK healthcare policy with success case examples such as decrease of MRSA in 2013/2014 which was a result of introduction of performance targets and mandatory surveillance (Public Health England, 2015) as well as introduction of 13-valent conjugate vaccines for pneumonia (Department of Health, 2011).
Further, Professor Davies states that we all have a role to play and patients should not demand for antibiotics when they are not clinically justified. Patients use diverse types of pressure, both direct and indirect, to influence the decision different types of direct and indirect pressure to influence the decision made by Physicians with regard to antibiotics prescription and this needs to be put into consideration when planning interventions for reducing antibiotic prescriptions that are unnecessary . It thus becomes necessary for Physicians to develop strategies that are effective in resisting prescription requests that are explicit or implicit (Strumilo, Chlabic, &Pytel et al., 2016, p. 63).
In the article, it is suggested that safely reducing the amount of antibiotics that are prescribed inappropriately is a critical part in reducing resistance. According to Public Health England (2015), Physicians tend to prescribe to their patients, the “last line” broad-spectrum antibiotics, piperacillin-tazobactam and carbapenems as opposed to prescribing the narrow spectrum antibiotics. The PHE recommends that these antibiotics be reserved for the treatment of resistant infections and utilized only in the instances where standard antibiotics have proved ineffective.
The government is not doing all that it can with reference to involving the major stakeholder in the fight against antibiotics resistance namely, the pharmaceutical companies and more specifically, regulation concerning new drug development. Major interest of pharmaceutical companies has been muted by existing regulatory hurdles. Adverse effects’ tolerance has been decreased among most drug classes such as the antibiotics. There has been escalation of approval requirements for new drugs entering the clinical phase from non-inferiority demonstration to superiority and sometimes there is a lack of a clear guideline on trials for antibiotics which have impeded development (Spellberg, Guidos & Gilbert et al., 2008, p. 155). Pharmaceutical companies thus find themselves faced with a paradox where calls are issued by the federal agencies and enactment of policies limits the development appeal.
On a neutral ground it may be seen that both the pharmaceutical companies and the regulatory boards play a part in antibiotic resistance development. The factors as pertaining the pharmaceutical companies, make the antibiotic development investment too risky, and with cost per drug estimated at approximately 1.7 billion Euros, there is minimal reward to be enjoyed by the pharmaceutical companies. The net present value (NPV) is a metric used by the pharmaceutical companies in determining the investment avenues at the suitable time. NPV is a projected future revenues risk-adjusted measure of an initial development drug discounting investment as well as other future projected expenses. An example of NPVcharacteristic for an antibiotic that is injectable can be approximately 100, and this is not appealing in comparison to a typical drug for cancer which is approximately 300 or for a neuroscience drug that is approximately 720(Svennebring & Wikberg, 2013, p. 140)
Since 1998, UKs Pfizer Wyeth, GlaxoSmithKline, AstraZeneca, and America’s Johnson and Johnson are the only companies that have gone to the extent of developing phase 1 of antibiotic development (Boucher,Talbot, & Benjamin, et al., 2013, p. 1685). Others have closed or downsized their R&D departments of antibiotic development and these are Wyeth, Roche, Proctor and Gamble, GlaxoSmithKline, Bristool-Myers Squibb, Eli Lilly, and Sanofi Aventis. As at the end of 2013, there were only four big pharmaceutical companies that still had their antibiotic division as functional(Boucher et al., 2013) . To date, there has been no government that has successfully discovered and even developed antibiotics and the future is not so promising on the same(Sipahi, 2008, p. 523). As a result, most of what is being done is taking place in small pharmaceutical companies, academic institutions, and small biotech entities. However, in Japan, large pharmaceuticals are still involved in development of antibiotic (Jabes, 2011, p. 564; Moellering, 2011, p. 2).
To counter the closing down of R&D departments, enactment of new policies needs to be been done with incentives being offered in an attempt to reverse the issue. Several players have been involved including the European Center for Disease Prevention and Control (ECDC), and the World Health Organization (WHO) (Europa, 2011; WHO, 2016; EMA, 2009)
In developed countries, the large amounts of antibiotics that are prescribed are indicative of the amount of effort that needs to be put in reducing the misuse of antibiotics.(Jabes, 2011). However, not all patients access antibiotics through prescription from Physicians. In several other countries, it is easy for one to get antibiotics over the counter which are also unregulated (Europa, 2011). The lack of regulation means that there is ease in access of antibiotics, which are cheap and in plenty prompting overuse. Further, the possibility of purchasing antibiotics online has made these drugs available and accessible in countries where there is no regulation (Euopa, 2011). Hence, patients do not need to demand for antibiotics as stated by the Professor, they can simply buy on-line. The focus should be on making these antibiotics unavailable without proper prescription.
In addition misuse of antibiotics in both developed and developing countries is also witnessed in livestock growth supplements (EMA, 2009). In some developed countries, approximately 80% of the antibiotics in the market are consumed by livestock in order to promote their growth and minimize incidences of infection(Shlaes 2010; Jabes, 2011). Treatment of livestock with antibiotics improves the animals’ overall health, results in higher quality and larger yields.
When humans consume food or animal products, they ingest the antibiotics. This means that resistant bacteria find themselves in the human system a discovery made over 35 years ago when there were high incidences of antibiotic resistance in farm animal and farmers intestinal flora (WHO, 2016). Recent methods of molecular detection have also shown that resistant bacteria find their way to meat products sold to consumers (WHO, 2016). How this happens is that antibiotics ingested by animals consumed as meat suppressor kill susceptible bacteria allowing for bacteria that is antibiotic resistant to thrive; the resistant bacteria enter the human food supply; when persons consume these foods the bacteria get to the body system and cause infections that result in adverse consequences in their health (EMA, 2009). Hence, even when patients do not demand for antibiotics prescription, they still get to ingest the same through consumption of meat from livestock previously treated with antibiotics
Further, the professor stated in the article that the general population has a role to play in preventing infection through good hygiene. However, the sale of antibacterial products that are meant for cleaning and hygienic purposes may add to the growing problem as they can limit immunities’ development to environmental agents in adults and children (Applebaum, 2012, p. 2062). As a consequence, versatility in the immune system is compromised thought eh possible increase in mortality and morbidity as a result of infections that are usually non-virulent (Europa, 2011). Here, the hygiene related companies are in fact responsible for misuse as a result of their heavy marketing and advertising of their products.
Considering the duration of time that it takes for bacteria to develop resistance to several natural antibiotics products together with the dissemination ease of resistant genes, development of antibiotics that are synthetic is a plausible option. However synthetic antibiotics are very rare with the only examples being diarylquinolines, oxazolidinones, quinolones, and sulpha drug. These are outnumbered 2:1 by antibiotics made from natural products as well as their semi-synthetic variations (Zakeri & Lu, 2013, p. 358), with focus on development which lies primarily in penetration of the bacterial cell. This is especially true for bacteria that are gram negative which are resistant to a variety of antibiotics naturally due to their outer membrane that bar several amphipathic drugs this is in addition to the resistant inner membranes and efflux pumps that are highly active and which detect hydrophilic molecules very fast (Delcour, 2009, p. 808). The challenges with uptake of the prokaryotic means that administration of antibiotics needs to be in concentrations that are 2-3 times higher than for other therapeutics used in treatment of diseases. Thus, this impacts the window for therapy which can in turn lead to concerns on toxicity (Lewis, 2013, p. 371).
Hence, development of synthetic antibiotics that are not prone to resistance can result in fewer occasions where patients demand for them. This is because, treatment using the first line of synthetic antibiotics will ensure that the infection is cleared and in case of recurrence, the same first line antibiotic will be used as there will be no incidence of antibiotic resistant bacteria in the patient. These rationale implies that the cost of manufacturing antibiotics will also go down as no new, stronger, and more effective versions will be needed to treat a particular infection; the first line antibiotic will be all that is needed. The challenge then to the big pharmaceutical companies’ R&D divisions will be to create synthetic antibiotics for each known bacterial infection. This then, will require the Medicines and Healthcare Products Regulatory Agency to be more flexible in its requirements for synthetic antibiotic approval in all trial phases as well as in the final approval stage.
The resistance to antibiotics including carbapenems has raised an alarm with regard to susceptibility of patients to increased poor health outcomes including mortality. While the article offers hope in stating that there is a decline in last line antibiotic resistance, the recommendations made by the experts are not 100 percent viable. A more solid and viable option would be to develop new antibiotics that are effective and can inhibit any antimicrobial resistance. According to the international medical community, most new and promising antibiotics are the ones that are species specific as the toxicity involved is low risk since they target specific bacteria without damaging normal flora of bacteria. The antibiotics that are species-specific also contain promising properties with regard to potential resistance development in that while there may be emergence of broad spectrum compounds resistance in any bacteria (as well as the commensally ones) which are transferred to the pathogen , the possibility is still much lesser in the narrow spectrum antibiotics which only act as pathogen target(Lee, Liang, Cheen, 2011, p. 38). This class of antibiotics development will need diagnostic test introduction which will be able to identify quickly, the disease causing bacteria in order for the MRSA drug indicated (Pourmand, Hassanzadeh & Mashhadi et al., 2014, p. 341) to be effective.
The Gram negative specific antibiotics will need to be developed with the knowledge that these bacteria possess a difficult -to- permeate membrane and efflux pumps that eject large drug amounts. In order to circumvent this, the new antibiotics that are developed ought to be relatively hydrophilic with masses less than 600 Da as well as have atoms that are not usually present in natural compounds, such s boron and fluoride (He, Starr, & Wimley 2015, p. 8). The future hope of introducing new antibiotics is related to platforms that are effective and which allow drug combination development. A combination based therapy of a new drug development reduces the development of pathogen resistance. Therefore, the new development possibility of drugs that are based on combinations and which are placed in the market as single pill would impact significantly, the development of antibiotic resistance by pathogens.
Conclusion and recommendation
The decline in resistance to last line antibiotics is an issue for debate. According to the article, the number of antibiotic resistance of cabarpenems has declined and while it is a first in the UK history, the recommendations made by the experts on maintaining this trend are not sue footed. The experts have asserted that safely reducing the amount of antibiotics that are prescribed inappropriately is a critical part in reducing resistance. Further, the general population has a role to play in preventing infection through good hygiene and that we all have a role to play and patients should not demand for antibiotics when they are not clinically justified. Finally, that the healthcare industry is doing all it can to ensure reduction in mortality due to antibiotics does not increase as a result of drug resistance.
However, as has been discussed in the essay, patient misuse of antibiotics cannot be stopped by merely not demanding for the same from Physicians. The availability of antibiotics over the internet and in poorly regulated countries enables persons to access these without the need for prescriptions. In addition, the use of antibiotics as growth enhancers in livestock results in consumption of the same by human beings in meat which result in development of resistance. With regard to good hygiene, it is necessary for one’s body to develop natural immunities against pathogens and that can only be achieved through specific limited exposure to pathogens hence over- practicing good hygiene can prove to be counter-productive. Finally, while the healthcare industry is willing to do all that it can to ensure reduced mortality due to antibiotic resistance, this, as shown from past history, is impossible without proper regulation that allows for fast and effective development of antibiotics and more specifically synthetic antibiotics that are deter bacterial resistance.
Healthcare that is scientifically based has the highest probability of resulting in patient outcomes that are optimal (Brown, 2013). The unsuitable and excessive utilization of antibiotics by humans and livestock alike in treatment of disease to which they are ineffective, necessitates the need to develop new drugs which will then be used consistently on animals and humans (Goel, Watal, & Oberoi, 2011, p. 1625).
It is necessary that the cost of development of drugs and related risks are reduced for companies that conduct the research as currently it takes over a decade to introduce a new drug in the market. The costs are more than 1 billion Euros which is more than 50% of the costs in clinical trials phase III (Lachmann, 2012, p. 1179) .In order for efficacy and safety of drug testing to be done in a shorter time and at lower costs, part of the phase III should be replaced with larger clinical trial phase II. This has been successful in fighting AIDS through the fast approval of ARVs (Tilloston, 2010, p. 752).
New antibiotics development is a global concern and hence must be intensified and since evolution of pathogens is continuous and natural selection will result in drug resistance. The way forward is the implementation of antimicrobial stewardship systems , hence, guidelines on antibiotic theories that are based on increased infectivologist involvement as well as strict control measures infection and prevention application (Isaacs & Andressen, 2013, p. 90). This will guarantee a better future for coming generations.
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