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PSYC3003 Literature Review

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Course Code: PSYC3003
University: University Of Southampton

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What do junior doctors perceive as the barriers to complying with the principles of antimicrobial stewardship?

Antibiotics are among the most common antimicrobial prescribed medicines. However, there is an alarming increase of bacterial resistance amidst the plethoric availability of antimicrobial agents. The arising antimicrobial resistance (AMR) has gained global attention for common bacterial infections such as Staphylococcus aureus that was once treatable are now incurable (Papoutsi et al., 2018, p.1).
An AMR research commissioned by the UK government depicts an estimate of 10 million deaths in one year by the year 2050 due to drug resistance (de Kraker, Stewardson, and Harbarth, 2016, p.1002184). In addition to this mortality and morbidity burden, antimicrobial resistance has affected other therapeutic procedures such as the surgical procedures where the antibiotics are used prophylactically with the intention of curbing infections. Even chemotherapeutical cancer treatment is affected by the AMR burden (Laxminarayan et al., 2013, pp.1057-1098).
Also, there is a significant financial burden as a result of the increased high second line and third line medicines, extended hospitalization and certain complications resulting from failed therapies. The world economy is likely to suffer losses of about US$ 100T due to reduced production as a result of AMR by the 2050 (de Kraker, Stewardson, and Harbarth, 2016, p.1002184). There is an urgent need to reinforce the already available set of strategies aimed at preventing the occurrence and spread of AMR. There is a positive relationship between antimicrobial usage and AMR (Sun, Klein and Laxminarayan, 2012, pp.687-694). Studies have shown that there is an everyday inappropriate use of the antibiotics in acute care facilities (Stuurman, van Keulen and Kluytmans, 2013, pp.3729-3731). The new resistance of various bacterial strains majorly results from the prolonged and inappropriate use of the antibiotics. Multiple factors contribute to the inappropriate prescription of these antimicrobials among healthcare professionals. For example, the lack of accessing the local antibiograms and poor choice of the antibiotics during therapy. These challenges have led to the establishment of the antimicrobial stewardship programs (AMS) in healthcare settings throughout the world to limit the emergence and spread of AMR as well as improve patient outcomes upon treatment (Carlet et al., 2012, p.11).
Mostly, prescription of the antibiotics is done by recognized expertise, however, in real situations, the decisions regarding the medicine are often made by the junior staff such as junior doctors. These junior staff may or may not receive guidance from their seniors which leaves themselves entirely to depend on for decision making (Charan et al., 2013, pp.188-196). This paper seeks to evaluate the barriers to effective implementation of the AMS strategies among the junior doctors. However, it is necessary to first understand the classes of antimicrobial and resistant to the antimicrobials.
Antimicrobial classification
An antimicrobial agent is any natural, semisynthetic or synthetic substance which kills or inhibits the growth of microorganism without killing the host. Primarily, antimicrobials are derived from fungi, bacteria or can be manufactured synthetically or semi-synthetically. Fungal derivatives are majorly obtained from Penicillium spp and the Streptomyces spp. Bacillus spp is the source of many bacterial derived antimicrobials. Semisynthetic are as a result of chemical alterations of the naturally existing antimicrobials while the synthetic ones such as sulfonamides are purely derived from chemicals. Antimicrobials have been in place and commonly used for about 2000 years. In the ancient times, the Greeks and Egyptians treated certain infections utilizing some plant extracts as well as specific molds (Alharbi et al., 2015, pp.600-603). Remarkably in the 19th-century scientists, Louis Pasteur and Jules Francois realized antagonism between bacteria and discussed its applicability in medicine to control bacterial infections (Punitha et al., 2013, pp.2746-2750). Later in 1928, a natural antimicrobial antifungal was discovered by Alexander Fleming who was referred to as Penicillium rubens and then called penicillin. This antimicrobial successfully treated Streptococcus infection when it was widely used in 1942 (Derderian, 2007, pp.1-5). Another antimicrobial that naturally occurs in Streptomyces fungi called Streptomycin, an aminoglycoside, was discovered in 1944 by Waksman. This was a timely discovery for the antibiotic was effective against most gram-negative bacteria that had penicillin resistance. Other significant developments are those of broad-spectrum Chloramphenicol and chlortetracycline that were discovered in 1947 and 1948 respectively (Zaffiri, Gardner and Toledo-Pereyra, 2012, pp.67-77).
The antimicrobials are categorized regarding the microorganisms they affect. For example, antibiotics act against bacteria, antifungals are effective against fungi, antiviral act against viral infections and antiparasitic act against parasites. Antibiotics are the most widely studied antimicrobial agents in most cases the term is interchangeably used to refer to antimicrobials. Also, the antimicrobial agent can be classified by their function. For example, the antimicrobials that destroy the microorganism are termed as microbicides such as bactericidal antibiotics which include cephalosporins, aminoglycosides, fluoroquinolones, vancomycin, daptomycin, and metronidazole. Those that limit microbial growth are referred to as biostatic such as bacteriostatic drugs for instance macrolides, tetracyclines, trimethoprim and sulfonamides (Bahar and Ren, 2013, pp.1543-1575). Mainly, there are three types of classification schemes commonly used based on the molecular structure, mode of action and spectrum of activity (Etebu and Arikekpar, 2016, pp.90-101).
Chemical or molecular structure
The standard molecular structure classifications include ‘beta-lactams, macrolides, tetracycline, quinolones, oxazolidinones, glycopeptides, and sulphonamides’ according to Adzitey (2015, p.36).
The beta-lactam antibiotics contain a very reactive chemical ring composed of 3-carbons and 1-nitrogen ring. The responsive ring affects the essential process of bacterial cell wall therefore killing or inhibiting its proliferation. These drugs bind to the bacteria’s enzyme called penicillin-binding protein (PBP) which is responsible for the synthesis of peptidoglycan for the cell wall. Various types of beta-lactams include the cephalosporins, penicillins, carbapenems, and monobactams (Etebu and Arikekpar, 2016, pp.90-101).
The penicillin class contains a nucleus of the 6-animopenicillanic acid ring together with other ringside chains. Some penicillin members include penicillin G, penicillin V, methicillin, nafcillin, ampicillin, amoxicillin, carbenicillin, piperacillin, mezlocillin, oxacillin and ticarcillin.
Cephalosporin have a 7-aminocephalosporanic acid nucleus with a side chain of 3, 6-dihydro-2 h-1,3-thiazine rings. These antibiotics are used against penicillinase-producing and methicillin-susceptible species of Streptococcus and Staphylococcus. They are also effective against infection caused by Proteus mirabilis, Klebsiella pneumonia, Haemophilus influenza, Enterobacter aerogenes, some Neisseria and Escherichia coli. Their side chains attach themselves to the PBP causing blood-brain barrier resisting the degeneration by the penicillinase facilitating its entry to the Gram-negative bacteria (Etebu and Arikekpar, 2016, pp.90-101).
Monobactams differ from other beta-lactams in that their ring is not fused with any other ring and letting it stand alone. In this class, Aztreonam is the only available drug which is used to treat Gram-negative aerobes such as Pseudomonas and Neisseria (Etebu and Arikekpar, 2016, pp.90-101)
Carbapenems are a broad-spectrum antibiotic that contains clavulanic acid which is capable of resisting the hydrolytic action of the beta-lactamase produced by bacteria as a resisting mechanism against beta-lactams. An excellent example of the carbapenem is Thienamycin such as imipenem (Papp-Wallace, 2011, p.296).
The macrolides characteristically have macrocyclic rings with deoxy sugars of L-cladinose and D-desosamine attached to them. These antibiotics bind to the bacterial ribosome inhibiting the addition of amino acids to the polypeptide chains in the process of protein synthesis. This leads to the destruction of the bacteria with a broad spectrum activity (Etebu and Arikekpar, 2016, pp.90-101).
The tetracycline beta-lactams have four carbon rings. They inhibit protein synthesis by hindering the addition of amino acids to the polypeptide chain in the process of protein synthesis. Tetracycline produced through biosynthesis are referred to as the first generation while those derived from semi-synthetic methods are called the second generation. The other ones obtained from total synthesis are regarded as the third generation (Fuoco, 2012, p.1).
Quinolones are compounds of nalidixic acid that interfere with DNA in the process of transcription and transcription of the bacteria. Generally, they contain two rings in their beta-lactam structure although the recent quinolones have an added ring which increases their efficiency.
The other class of beta-lactam is the aminoglycosides with a structure having 3-amino sugar attached to glycosidic bonds. They usually connect to the ribosomal units of the bacteria inhibiting protein synthesis. They are effective against both Gram-positive and Gram-negative bacteria hence broad-spectrum activity.
The structure of a sulphonamide contains a sulfonyl group attached to an amine group. They inhibit the synthesis of tetrahydrofolic acid which is a coenzyme responsible for the combination of amino acids such as thymidine. Such an activity ultimately protein synthesis killing the bacteria.
The glycopeptides have cyclic peptide consisting of seven amino acids unto which two sugars are bound (Bang et al., 2013, p.11). These drugs also interfere with protein synthesis.
Oxazolidinones are synthetic antibiotics that are believed to inhibit protein synthesis. They bind to the P site of the 50S ribosomal killing Gram-positive bacteria.
Mode of action
Under this classification the antibiotics function by inhibiting cell wall formation, destruction of the cell membrane structure and its functions, inhibiting the structure and function of nucleic acid, protein synthesis inhibition and blocking crucial metabolic pathways.
Inhibition of the cell wall formation
Most bacteria cells have a peptidoglycan layer protecting its cell contents from osmotic pressure and other prevailing harsh environmental conditions. This layer is vital for the survival of the microorganism, and it is synthesized with the help of PBPs and which contains the transpeptidase and transglycosylase enzymes. These enzymes are responsible for adding disaccharide pentapeptides to lengthen the already available peptidoglycan molecule. Antibiotics such as penicillin prevent the crosslinking of the peptidoglycan molecules by inhibiting the peptide formation by the PBPs. Other drugs such as vancomycin impede the growth of the bacteria by blocking the activity of the transpeptidase and transglycosylase enzymes by binding to the peptidoglycan molecule. 
Destruction of the cell membrane
Some antibiotics for example daptomycin inhibit the formation of the new cell membrane by depolarizing it. The depolarization of the calcium-dependent cell membrane affects its structure and physiology. Other drugs such as polymyxins cause the disintegration of the cell membrane by attaching itself to the lipopolysaccharide layer (Laverty, Gorman and Gilmore, 2011, pp.6566-6596).
Inhibition of nucleic acid formation
Nucleic acids are vital in the transcription and replication of DNA for the survival and posterity of the bacteria. The whole process relies on the activity of enzymes such as the helicase enzyme that unwinds the double helix DNA. Drugs such as quinolones disrupt the functioning of the helicases stopping DNA replication. Others affect the effective operation of the topoisomerase II and topoisomerase IV which ultimately causes the cessation of RNA formation by changing RNA polymerase. This makes these drugs to be sufficient to Gram-positive bacteria and some Gram-negatives.
Protein synthesis inhibition
Proteins are very vital in the structural composure, metabolic and physiological functions of the microorganism. The DNA and the other ribomolecules are responsible for the type of proteins formed. Antimicrobial agents such as erythromycin block the protein synthesis at either the initiation, translation or elongation phase of the process as it binds to the 50S ribosome.
Blockage of vital metabolic pathways
For example, sulphonamides mimic the bacterial substrate for cellular metabolism. Therefore, the enzymes for this process attach to the drug rather than the actual substrate. Therefore, inhibiting both RNA and DNA production by mimicking of the folic acid.
Antimicrobial Resistance
The diminishing effectiveness of anti-infection agents in treating primary diseases has enlivened as of late, and with the emergence of untreatable strains of carbapenem-resistant Enterobacteriaceae, we are at the beginning of a post-antibiotic period (Laxminarayan et al., 2013, pp.1057-1098). The resistance is as a result of mutations in the microbes and the selection challenges from the antimicrobial agents that becomes advantageous to the mutated strains.
Also, suboptimal antibiotic dosage facilitates the gradual selection of resistance. The ability to resist an antibiotic is contained in the bacterial chromosomes as well as in the transmissible extrachromosomal components. The antibiotic-resistant strains such as the Methicillin-resistant Staphylococcus aureus (MRSA) then spread rapidly through interspecies gene transmission in the favorable conditions such as poor hygiene. Now antibiotics resistant has set in every part of the world in the various settings, and its effects are overwhelming. Increased deaths, increased hospitalization, and medication costs and the inability to treat the once treatable diseases have accompanied the widespread antibiotic resistance. This has led to the establishment of programs called antimicrobial stewardship to curb the problem.
Antimicrobial stewardship.
As the creation of new antimicrobials is lengthy and costly, execution of strict AMS programs is fundamental to hold the therapeutic viability of the present antimicrobials. The term ‘antimicrobial stewardship’ is characterized as an authoritative or social insurance framework to deal with advancing and checking prudent utilization of antimicrobials to save their future viability (Morris et al., 2012, pp.500-506). Antimicrobial Stewardship is a central rule recognized in the Five Year Antimicrobial Resistance Strategy and Chief Medical Officer’s report (Hutter et al., 2013, p.31).
The underpinning principle in the antimicrobial stewardship program is creating awareness and educating the prescribers to adhere to the evidence-based prescription of the antibiotics. The AMS recognizes that the adherence to the diagnostic tests is vital in safeguarding the already available medicines as the search for new more effective antibiotics continues (Piddock, 2012, pp.249-253). It is believed that better access and usage of the diagnostic tests will facilitate proper use and prescription of antimicrobials through informed decisions. Further, the AMS aims to ensure that the prescribers of antimicrobials only do so when necessary with the most appropriate drug at the right time, dosage and for the correct duration (Ashiru-Oredope et al., 2012, pp.51-63). The AMS intervention has been classified into three categories regarding the intervention strategy undertaken. They include the persuasive approach through education and promotional programs, the restrictive intervention which leads to changes in the prescription processes and the structural intervention which entails the computerized system for laboratory tests and prescription. In the UK a wide range of the AMS programs has been established through hospital pharmacy initiatives and in the medical institution council’s safe prescription working group. These initiatives carry out the distribution of educational material, auditing, and feedback of performance, a manual and automatic reminder as well as lectures and seminars (Pulcini and Gyssens, 2013, pp.192-202).
There is less comprehension of how antimicrobial endorsing mediations ought to be custom fitted to address the particular needs of specialists in training such as the junior doctors, as most studies consider that the specialists are a regular group of healthcare experts with comparable necessities (Brennman and Mattick, 2013, pp.359-372). The junior doctors require to understand AMS and implement it with ease as they are involved in antibiotic prescriptions and most cases without the guidance of the senior doctors. Therefore, it is essential to look into the hindrances that they face or likely to encounter in the process of adhering to AMS interventions while at work.
Adzitey, F., 2015. Antibiotic classes and antibiotic susceptibility of bacterial isolates from selected poultry; a mini review. World s Veterinary Journal, vol. 6, no. 1, 2015, p. 36.
Alharbi, N.S., Alharbi, S.A., Salmen, S.H., Chinnathambi, A., Al-Johny, B.O. and Wainwright, M., 2015. 2 Mycelium of Fungi Isolated from Mouldy Foods Inhibits Staphylococcus aureus including MRSA-A Rationale for the Re-introduction of Mycotherapy?. Saudi Journal of Biological Sciences, vol. 22, no. 5, 2015, pp. 600-603.
Ashiru-Oredope, D., Sharland, M., Charani, E., McNulty, C. and Cooke, J., 2012. Improving the quality of antibiotic prescribing in the NHS by developing a new Antimicrobial Stewardship Programme: Start Smart—Then Focus. Journal of antimicrobial chemotherapy, vol. 67 (suppl_1), pp.i51-i63.
Bahar, A. and Ren, D., 2013. Antimicrobial peptides. Pharmaceuticals, vol. 6, no. 12, pp.1543-1575.
Bang, J.K., Lee, J.H., Murugan, R.N., Lee, S.G., Do, H., Koh, H.Y., Shim, H.E., Kim, H.C. and Kim, H.J., 2013. Antifreeze peptides and glycopeptides, and their derivatives: potential uses in biotechnology. Marine drugs, vol. 11, no. 6, pp. 2013-2041.
Brennan, N. and Mattick, K., 2013. A systematic review of educational interventions to change behaviour of prescribers in hospital settings, with a particular emphasis on new prescribers. British journal of clinical pharmacology, vol. 75, no. 2, pp. 359-372.
Carlet, J., Jarlier, V., Harbarth, S., Voss, A., Goossens, H. and Pittet, D., 2012. Ready for a world without antibiotics? The pensières antibiotic resistance call to action, Antimicrobial Resistance and Infection Control, vol. 1, no. 1, p. 11
Charani, E., Castro-Sanchez, E., Sevdalis, N., Kyratsis, Y., Drumright, L., Shah, N. and Holmes, A., 2013. Understanding the determinants of antimicrobial prescribing within hospitals: the role of “prescribing etiquette”. Clinical Infectious Diseases, vol. 57, no. 2, pp. 188-196.
De Kraker, M.E., Stewardson, A.J. and Harbarth, S., 2016. Will 10 million people die a year due to antimicrobial resistance by 2050?. PLoS medicine, vol. 13, no. 11, p. e1002184.
Derderian, S.L., 2007. Alexander Fleming’s miraculous discovery of Penicillin. Rivier Academic Journal, 3(2), pp.1-5.
Etebu, E. and Arikekpar, I., 2016. Antibiotics: classification and mechanisms of action with emphasis on molecular perspectives. Int J Appl Microbiol Biotechnol Res, vol. 4, pp.90-101.
Fuoco, D., 2012. Classification framework and chemical biology of tetracycline-structure-based drugs. Antibiotics, vol. 1, no. 1, pp. 1-13.
Huttner, A., Harbarth, S., Carlet, J., Cosgrove, S., Goossens, H., Holmes, A., Jarlier, V., Voss, A. and Pittet, D., 2013. Antimicrobial resistance: a global view from the 2013 World Healthcare-Associated Infections Forum. Antimicrobial resistance and infection control, vol. 2, no. 1, p. 31.
Laverty, G., Gorman, S.P. and Gilmore, B.F., 2011. The potential of antimicrobial peptides as biocides. International journal of molecular sciences, vol. 12, no. 10, pp. 6566-6596.
Laxminarayan, R., Duse, A., Wattal, C., Zaidi, A.K., Wertheim, H.F., Sumpradit, N., Vlieghe, E., Hara, G.L., Gould, I.M., Goossens, H. and Greko, C., 2013. Antibiotic resistance—the need for global solutions. The Lancet infectious diseases, vol. 13, no. 12, pp. 1057-1098.
Morris, A.M., Brener, S., Dresser, L., Daneman, N., Dellit, T.H., Avdic, E. and Bell, C.M., 2012. Use of a structured panel process to define quality metrics for antimicrobial stewardship programs. Infection Control & Hospital Epidemiology, vol. 33, no. 05, pp. 500-506.
Papoutsi, C., Mattick, K., Pearson, M., Brennan, N., Briscoe, S. and Wong, G., 2018. Interventions to improve antimicrobial prescribing of doctors in training (IMPACT): a realist review. BMJ Open, vol. 5, no. 10, p. e009059.
Papp-Wallace, K.M., Endimiani, A., Taracila, M.A. and Bonomo, R.A., 2011. Carbapenems: past, present, and future. Antimicrobial agents and chemotherapy, vol. 55, no. 11, pp. 4943-4960.
Piddock, L.J., 2012. The crisis of no new antibiotics—what is the way forward?. The Lancet infectious diseases, vol. 12, no. 3, pp. 249-253.
Pulcini, C. and Gyssens, I.C., 2013. How to educate prescribers in antimicrobial stewardship practices. Virulence, vol. 4, no. 2, pp. 192-202.
Punitha, J.T., Ananthalakshmi, S., Gowri, M. and Anu, M., 2013. INTERNATIONAL JOURNAL OF PHARMACY & LIFE SCIENCES. Int. J. of Pharm. & Life Sci.(IJPLS), vol.4, no.6, pp.2746-2750.
Stuurman, A., van Keulen, P. and Kluytmans, J., 2013. Antibiotic Misuse A Global Crisis. hospital [in Chinese], vol.23,no.15, pp.3729-3731.
Sun, L., Klein, E.Y. and Laxminarayan, R., 2012. Seasonality and temporal correlation between community antibiotic use and resistance in the United States. Clinical infectious diseases, vol.55, no.5, pp.687-694.
Zaffiri, L., Gardner, J. and Toledo-Pereyra, L.H., 2012. History of antibiotics. From salvarsan to cephalosporins. Journal of Investigative Surgery, vol.25, no.2, pp.67-77.

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