UZWRSS153 Evidence and Research : Types Bacteria

Introduction

Every antibiotic type binds to specific proteins within the cell wall of bacteria with the aim of disrupting key cellular processes (Kohanski,, Dwyer,& Collins, 2010, p. 423). Since antibiotics are broadly diverse in activities, they display equally broad types of toxicity against different bacteria types. Antibacterial molecule production by bacteria has been going on for many years prior to human existence for example, in soil, antibiotics are produced by bacteria to help in killing other bacteria or fungi that are in competition for limited resources (Aminov, 2010, p. 134). Genes that are resistant evolve through mutation accumulation which allows survival of bacteria in the presence of molecules that are toxic. Division and subsequent multiplication of bacteria can result in mutations occurring in the DNA and which in most instances, affect organism survival in a negative way. However, there are instances when the occurrence of the mutation results in a positive impact on the survival of the bacteria. When an antibiotic is present, a mutation that helps the bacteria to be resistant to the toxic environment is an advantage for the bacteria as it will grow rapidly and divide even faster and soon dominate the surrounding population (Aminov, 2010).  It therefore comes as no surprise that most human antibiotics sourced from nature such as soil bacteria, already have existing genes that confer resistance to drugs for example, penicillin resistant gene was discovered even before the drug was approved (Wright, 2010, p. 123)

While resistance to antibiotics has always been in existence, it is the rampant human use that has exacerbated this epidemic that is currently in progress. The resistance to the last line antibiotic has been as a result of a series of confounding factors which will be discussed in this essay.

Search terms

The search terms used in deriving appropriate literature were: drug resistant bacteria, 21st century, overuse, causes of antibiotic resistance, pharmaceutical companies, future, last line antibiotic resistant mechanisms, challenges, latest developments, NHS, PHE, NMC- in search engines including CINHAL, PsychInfo, and PubMed. There were 47 results of which 21 were the most relevant. Articles search range date was from 2007-2017. The key themes in the chosen articles was: causes of Antimicrobial Resistance (AMR) public behaviour and perception, commercial pressures, clinical usage, regulation, synthetic drugs as the solution

Public behaviour and perception

In the article, the Chief Medical Officer(CMO) stated that reducing the number of inappropriate antibiotic prescribing is a key way of fighting drug resistance. This has also been supported by  Lee, Cho, & Jeong et al., (2013, p. 4274) who suggest that in cases such as nosocomial pneumonia and  intra-abdominal infections, adherence to guidelines for prescription that is appropriate, for effectiveness of antibiotics (such as, carbapenems), can reduce new resistance selection. While this may be true, it may not be effective. The lay public perception on antibiotics as an effective and quick antidote to most illnesses has resulted in behaviours that supersede the prescribing Physician’s control (Khalid, Mahsood, & Ali, 2016, p. 801). One such behaviour is hoarding where a patient will not complete his/her prescribed dosage of antibiotics. This may not impact the immediate health outcome of the person; however, when the hoarding is done against a perceived need in the future, there is an increase in potential misuse on a non-susceptible microorganism. Another way is through non-prescription purchase. Antimicrobial access control is not universal and in some countries the sale and production of the same is completely or relatively regulated. This results in variability in the quality of the therapeutic materials that are availed to the public, and  in large amounts and at low costs.  The internet has enabled the easy and global access of antibiotics including those that are restricted such as ciprofloxacin and rifampicin (Khalid et al., 2016)

Commercial pressures

The CMO in the article in question stated that each person has a role to play in preventing infection through good hygiene. The NHS also recommends that for one to maintain good health and prevent skin complaints and infections, one needs to maintain daily hygiene (NHS, 2017).Consequently, there has been an increase in commercial pressure on the public through campaigns that hint that one has to be completely free of any microorganisms. The commercials advertise that for one to be permanently and continuously healthy, then one needs a routine cleansing of the guts, mouths, and skin from microbial agents. Further, one must routinely disinfect the surfaces that one comes onto regular contact with for example, floors and tables.

While this is applicable to some extent for example, the cooking surface needs to be clean at all times, there is potential for abuse of the same. The complete and general elimination of microorganisms from an individual and his/her environment is neither possible nor necessary for good health (Aliello, Larson, &Levy, 2007, p.137) .

Recent studies indicate that a comprehensively equipped immune system development needs for one to be exposed to environmental microorganisms (Maslowski & MacKay, 2011, p. 5). By being exposed, one develops a specific antibody cohort that generate cells which live in one’s body throughout one’ s life and also forms the basis of effective vaccination. In normal circumstances, such cell cohorts including their immunities triggered by the same, are generated in one’s body at early years of growth and exposure to other novel antigens in later years in life, supplements the initial immunities. When commercials emphasize on over cleanliness, this ultimately inhibits exposure to environmental antigens and subsequently hinders development of immunities in adults as well as children. As a result, when such a person or child is infected by microorganisms that are less virulent, he/she is able to succumb to morbidity or even mortality (Round, O’Connell, & Mazmanian, 2010, p.220).

Clinical usage

In the article, Dr Susan stated that there has been a decrease in the number of overall antibiotic prescription given by physicians. The Public Health England Report (2016) also stated that for the first time, the prescription of antibiotics by clinicians and GPs had reduced across the entire healthcare system (PHE, 20016). However, the first overuse source within clinical practice is the physicians empirical antimicrobial usage. The random application of antibiotics by physicians is mainly due to shortcomings in practice in accurate and rapid diagnosis of infectious disease, the pathogen that causes the disease, and of more importance, how susceptible the pathogen is to the antibiotic therapy. For accurate diagnosis, it is necessary that multiple lab tests are done for a particular diagnosis to be made and these may take days or weeks to compete. It is understandable that a patient with life threatening condition may require immediate diagnosis and prescription. Such a situation often takes action in the form of different antibiotics being administered simultaneously, with the aim that one will successfully control the pathogen. This antibiotic over-application often takes place within a hospital setting and on patients that are admitted hence, controlling the drugs through developing and implementing of diagnosis that is rapid and accurate can minimize the impact of the illness (Kuehn, 2013 p. 2135). However, serial antibiotic application by physician is more widespread than the need for empirical treatment (Kuehn & IDSA, 2013,p. 2385).

The Nursing and Midwifery Council (NMC) Professional Conduct  states that nurses are expected to identify and minimize any risks to their patients and one such way of fulfilling this is through participation in antimicrobial stewardship. This means ensuring proper utilization and promotion of the most suitable antibiotic therapy including dosage, administration route, and duration. However, in most cases, the serial antimicrobial application is caused by the patient who demands for an immediate relief from his/her illness (Cliodna, McNulty, & Boyle et al., 2007, p. 810). In one extreme, the patient can belligerently demand for antibiotics while the other is when a doctor over-prescribes an antibiotic with the aim of pleasing the patient and getting repeat business. In addition application of prescription antimicrobials is often done in a fixed regimen that dictates the period, rate, and dose. In most cases, the period is between 5-7 days with some doctors extending to 14 days or longer.  The base assumption underpinning such time periods is that high doses administered over a long time will eliminate the infectious pathogen. However, studies done recently demonstrate that relapse rates are significantly less in persons where treatment stops as the symptoms manifestation decreases in comparison to those who take the entire course of the treatment regimen (Ferry, Holm, & Stenlund et al. 2007, p. 49; Jansåker, Frimodt-Møller, & Bjerrum,2016, p. 727) By limiting treatment course, to the minimum required dosage and period necessary for achievement of a clinical result,  the non-combatant organism’s selective pressure in a patient  and the environment as well, is limited  and so too is the overall adaptive response of the microbial agent.  

Regulatory

In the article Professor Sally asserts that the healthcare industry does not want to see the progress made in reducing drug resistance reversed. Further, she also  asserts that the industry must do all it can to fight drug resistant infections. The PHE in its 2015 annual report gives guidance to GPs and clinicians on effective methods of avoiding unnecessary prescription of antibiotics as well as information on AMR (PHE, 2015) However, doing all it can, is not possible. For over ten years, there has been change in the regulation which has resulted in increased infeasibility of trial design requirements that enable approval of new antibiotics  for use by humans (Spellberg & Baser et al., 2011; Shlaes et al., 2013; Spellberg, 2010). The reasons behind this is complex which has resulted partly due to statistical and scientific concerns and which are propelled by dangerous and irrational extremes by highly embarrassing and public failures in post-marketing due to antibiotic toxicity as was seen with telithromycin(Spellbberg, 2010; Echols, 2012). In the long run, the statistical concerns have dominated the considerations with regard to trial standards which have sacrificed the clinical feasibility and reality.

Several years elapsed before clear guidance for trials were released with regard to new antibiotics. Once the guidance’s were released, they created infeasible trial standard which were also nonsensical (Echols, 2012; Spellberg, 2012). Some experts went so far as to express their doubt in the effectiveness of antibiotics and mentioned that placebos could be more effective for infections that were lethal such as (Community Acquied Pneumonia (CAP) (Spellberg & Lewis et al. 2011; Spellbeerg & Talbot et al., 2008). This resulted in forwarding of proposals that demanded that placebos be used as part of future studies of antibiotics with regard to treatment of CAP(Pakhale, Mulpuru, &Verheji et aal., 2014). These and similar proposals were given credence and serious discussion and were only dismissed after expensive and extensive effort and dialogue that went on for over a year(Spellberg et al., 2011).

Other examples of damaging and unreasonable new trial standards elements included banning administration to patients of new pre-study antibiotics for those who were to be enrolled in clinical trials of the same. This inhibited enrolment of patients with critical illness. At the same time, the requirement for studies was administration of intravenous therapy on multiple days, within hospital settings, for diseases such as Urinary Tract Infection (UTI), pneumonia and intra-abdominal infections. This too eliminated any possibility for enrolment of non-critically ill patients. Hence, the end result is that there were very few patients that were eligible for enrolment at any given time.

New requirements were also outlined where patients were to be considered evaluable for drug efficacy only in the event there was identification of etiologic bacteria that resulted in a pneumonia study size that was double or triple the original size. This led to shrinking of non-inferiority margins because of mathematical arbitrary manipulations that were utilized in discounting the antibiotic treatment effect best-guess for various disease sizes which further divided the sizes of the samples (Spellberg, Lewis et al., 2011)

The resultant 10 year loss in time on discussing, debating, and deliberating had a substantial exacerbation on the time, cost, and risk for the development of new antibiotics and was also the same time that other economic realities and scientific challenges were having similar effects. The net result was that there was a marked decrease in companies and scientific experts that were willing to remain engaged in new antibiotic development. The resultant effect is that the resistance to currently present antibiotics in the market has continued to grow even as no new stronger and more effective options are being produced (Spellberg, Lewis et al., 2011).

Discussion

The fight against antibiotic resistance can only be effective when there are new drugs that are being manufactured and which can counter bacteria mutations. While there are many other factors that have contributed to antibiotic resistance as discussed in the essay, the real issue lies in the fact that there are no new antibiotics being manufactured and those that are currently in the market have developed resistance including carbapenems. It is therefore the proposal of this essay that foe resistance to be reduced and halted altogether, new systems of manufacture need to be seriously considered.

There are two major ways in which the pool of antibiotics can be changed with regard to discovery and development (Spellberg, Blaser, &Guidos et al., 2011, p. 397). The first of these is altering the screen substrate by finding new sources for natural chemical substrates which will increase the probability of discovering chemical scaffolds that are novel. This can then become iterative modification and substitution focus in optimizing effects. There has only been a small successful microbial life culture and hence new metabolomics, proteomic, or biochemical studies of the said microbes can yield scaffolds that are entirely new for development in the future (Spellberg. Lewis, et al., 2011). In addition, writings by experts have suggested enriching chemical scaffold libraries that are appropriate chemically, to penetrate into and avoid efflux from bacteria (Silver, 2011, p. 71).

The second of these approaches is instead of screened substrate modification, the physiological modification can be done on the screening conditions (Fahnoe, Flanagan, & Gibson et al., 2012). Traditionally, rich media has been used on screens for the support of microbial growth that is robust. However, the environment of the host is often times very hostile  in innate (such as pH, complement, and phagocytes changes) and adaptive (such as immunity that is cell and antibody mediated) defence elements of the host as well as restriction of nutrient  that the host factors actively mediate (such as carbon and trace elements source sequestration). It is highly possible that screening done in media that has more trace nutrient or physiological pH level with altered sources of carbon (Spellberg, Talbot, &Brass et al., 2008, p. 249) or with constituents of host defence such as serum in place, would lead to the different scaffold identification as therapies that are promising even from the exact chemical libraries.

Conclusion

The article states that  resistance to last line antibiotics is a war that has seen some recent progress in a positive direction. This assertions have been backed by various sources as discussed in the essay. Further, recommendations  made include  personal good hygiene, reducing the number of inappropriate antibiotic prescribing, and by inference, continued reduction in the number of overall antibiotic prescription given by physicians. The article also states that the healthcare industry is doing all it can to ensure that the progress made in reducing drug resistance is not reversed.

While the aforementioned suggestions are noble and seemingly sound solutions, their applicability is debatable. There are several factors that dispute the applicability of the said solutions. The first is that drug regulatory boards make it nearly impossible for new antibiotics to be clinically tried and approved. The last ten years has seen change in the regulation which has resulted in increased infeasibility of trial design requirements that enable approval of new antibiotics  for use by humans (Spellberg & Baser et al., 2011; Shlaes et al., 2013; Spellberg, 2010). Secondly, with regard to clinical usage, the random application of antibiotics by physicians is mainly due to shortcomings in practice in accurate and rapid diagnosis of infectious disease, the pathogen that causes the disease, and of more importance, how susceptible the pathogen is to the antibiotic therapy. Thirdly misleading advertisements which infer that one needs to maintain good health while in essence the complete and general elimination of microorganisms form an individual and his/her environment is neither possible nor necessary for good health. Lastly, the lay public perception on antibiotics as an effective and quick antidote to most illnesses has resulted in behaviours that supersede the prescribing Physician’s control

When all is said and done, the war against antibiotic resistance begins with the regulation of antibiotic development. There are three elements that are necessary for reform in regulations of new antibiotic development standards. The first of these is the need for the relevance and feasibility of the non-inferiority traditional designs. Recent guidelines have been released by the European Medicines Agency which meet these objectives and which set achievable, reasonable, and logical standard for such researches (EMA, 2012; EMA, 2011). The release of updated guidelines for trials that focus more on feasibility and clinical and scientific rigor is expected such that non-inferiority meaningful therapies become viable for utilization by patients (Shlaes, Sahn, & Opiela et al., 2013, p. 4605).

Second, focus should be shifted to facilitation of new antibiotic development that meets unmet, high impact needs(Rex, Eisenstein, Alder, et al., 2013, p. 269). The European Medicines Agency (EMA)  has stated that they support such approaches to novel developments and have proceeded to release draft guidance’s that are reflective of these support sentiments (EMA, 2012)

Trials that choose to focus on bacterial pathogens that are highly resistant for which there exists minimal available evidence, will mean a lesser time and cost for conducting and can be utilized in supporting premium pricing. This is a favourable option for patients as it focuses on the real unmet needs as well as in helping to prevent overuse and misuse, post marketing. The feasibility of conducting researches such as these will increase as time progresses with increased availability of molecular diagnostic rapid tests (IDSA, 2011)

Thirdly, harmonisation is necessary between the European and US regulators as well as other regulators across the globe. The existence of the EMA is very different with regard to its legal and political climate in comparison to other eregualtory bodies such as the Federal Drug Administration (FDA) (Spellberg, 2010, p. 299; Echols, 2012, p. 1311).  An approach that is harmonised across the globe will ultimately be necessitated in facilitating availability of new antibiotics in the era of the global village economy.

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