PATHOLOGY AND TREATMENT OF BACTERIAL INFECTIONS

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CHAPTER 2 LITERATURE REVIEW

INTRODUCTION

This chapter provides an analysis of published literature that pertains to the effectiveness of antimicrobial stewardship on promoting the appropriate use of antimicrobials. It examines the causes and effects of antimicrobial resistance and the impact of ASP which aims to limit the spread of antimicrobial resistance. The main purpose of the literature review is to review previous studies on the implementation and impact of ASP as well as its effect on limiting adverse drug effects on hospital admitted patients. The theoretical basis of the main focus of the study is introduced and a detailed context of the literature review is provided.

 SEARCH STRATEGY

The literature review was based on South African and international resources, with a focus on the scourge of antimicrobial resistance and the effects of antimicrobial stewardship. Various data search engines such as Google Scholar, Cochran database of systematic review and Pubmed, were utilised to obtain the materials for the literature review. The topic and the aims of the study were used as the basis for the subheadings of the literature review.
Search terms used for the literature included, antimicrobial management, antimicrobial stewardship, antimicrobial resistance, appropriate antimicrobial use, judicial antimicrobial use, acquisition of antimicrobial resistance, factors promoting antimicrobial resistance, hospital-acquired infections, nosocomial infections. Manual search of local conferences, theses, and dissertations to identify relevant articles was also performed. Additional sources including South African National Department of Health (NDoH), South African Antimicrobial Stewardship Program (SAASP), Centre for Disease Prevention and Control (CDC) and World Health Organization (WHO) as well as reference list of relevant articles, book chapters and reviews were also searched.
The literature search was restricted to English language publications. The review included studies that considered the implementation and the effectiveness of antimicrobial stewardship interventions in hospitals.

 PATHOLOGY AND TREATMENT OF INFECTIONS

Infectious diseases currently cause about one-third of all human deaths in the world (Alberta, Johnson, Lewis, Raff, Roberts & Walter, 2002: 1485). In order to understand how the bacteria spread and become a burden to human health, the knowledge of colonization and invasion of the host by bacteria will be discussed in subsequent sections.

 Bacterial mechanisms for invading the host

Microbes are ubiquitous in nature and humans are constantly exposed to them, some are harmless but may cause infectious diseases leading to acute or chronic illness (Albiger, Dahlberg, Henriques-Normark & Normak 2007:511). Only a marginal bacterial species have the ability to cause disease in humans (Alberta et al 2002:1490). Some bacteria have evolving mechanisms that aids them to successfully colonize and survive within the human body (Stones & Krachler, 2015: 2626). But their localization in the human body is normally restricted to certain areas of the body including: the skin, respiratory and gastrointestinal tracts (Alberta et al. 2002: 1501; Ribert & Cossart 2015: 173).
Opportunistic pathogens take advantage of injuries or breaches to penetrate the host barriers (Ribet & Cossart 2015: 173). Whereas, some bacteria produce proteases and directly target host mucins, which plays a role in limiting the microbial invasion of the microflora to reach the epithelial layer (Ribet & Cossart 2015: 174). Since microbiota play an important role in aiding host barriers against invading pathogens by competing for nutrients and niches with pathogens, and enhancement of host defence mechanism (Kamada, Chen, Inohara & Nunez 2014: 686- 687), the pathogens may involve triggering mucosal inflammation to alter the composition of the microbiota, to escape the host barriers. Subsequently increasing mucosal antimicrobial peptides to which pathogens may be resistant to, compared to the resident bacteria (Ribet & Cossart 2015: 175).
A variety of bacterial pathogens have acquired the ability to survive and replicate within macrophages after they have been taken up into a cell by phagocytes or receptor-mediated endocytosis (Alberta 2002: 1507; Chiang, Uzoma, Moore, Gilbert, Duplantier & Panchal 2018: 2). This mechanism protects the pathogen from the complement or adaptive immune system and helps the pathogen avoid competing with other resident microbes (Chiang et al 2018: 2).
According to Stones and Krachler (2015:2626) different bacterial species display a wide array of specialized cell surface organelles or macromolecules (pili or fimbriae) which aid in mediating attachment to target host structures for the colonization and penetration of the host. They adhere to the host by either using adhesions or through a non-specific adherence mechanism such as electrostatic forces and lipophilic/ hydrophobic interaction (Adlerberth, Cerquetti, Poillane, Wold & Collignon 2000: 225). These macromolecules help to overcome peristalsis in the gut and the flushing action of mucus, saliva, and urine, which remove non-adherent bacteria (Alberta et al. 1502- 1503). The pathogen that manages to survive the immune onslaught and penetrates host cells and the mucosal layer can exert their pathogenic effect and therefore replicate further.

Antimicrobial treatment of bacterial infections

According to Varley, Sule, and Absolom (2009: 184) throughout history, infectious diseases have been treated with a variety of herbal remedies; and the first true antimicrobial agent in the world was salvarsan, used for the treatment of syphilis and was discovered in 1909 by Paul Ehrlich (Varley et al. 2009:184; Saga & Yamaguchi 2009:104). Saga and Yamguchi (2009: 104) state that the originally discovered drugs were synthetic compounds and had limitations in terms of safety and efficacy, and in 1928, Fleming discovered a safe and efficient antibiotic, the penicillin.
Subsequently, new classes of antimicrobial agents were developed leading to a surge of the discovery of antimicrobial therapy (Saga & Yamguchi 2009: 104). Since then, the development of antimicrobials has greatly reduced mortality and morbidity from infectious diseases (Song 2003: 1). Because of antimicrobials development, millions of lives have been saved and important medical procedures including surgery and cancer chemotherapy enabled (WHO 2017:12).

 THE DEVELOPMENT OF ANTIMICROBIAL RESISTANCE

Since their conception antimicrobial agents have been used to treat infectious disease and have been successful in reducing illness and death from infectious microbial species (Baker, Thomson, Weill & Holt 2017: 733; Brinkac, Veerhies, Gomez & Nelson 2017: 1002;Premanandh, Samara & Mazen 2016: 1). Lately, the effectiveness of the agents has declined, whereas, the frequency of antimicrobial resistant pathogens have increased (Michael, Dominey-Howes, Labbate 2014:1; Palmer & Kishony 2013: 243). In addition, the development of novel antimicrobial agents has dramatically declined (Spellberg, Powers, Brass, Miller & Edwards, Jr. 2004: 1279-1280). The situation is exacerbated by the rapid development of antimicrobial resistance, which renders the existing microbial agents obsolete (Perron, Inglis, Pennings & Cobey 2015: 211). Such occurrence puts a strain in the effective treatment of common nosocomial infection leading to a significant deterioration of clinical outcome (Dik, Poelman, Friedrich, Ronday, Lo-Ten-Foe, van Assen, van Gemert-Pijnen, Niesters, Hendrix & Sinha 2015: 93).
Hospitals are an important breeding ground for the development and spread of antimicrobial resistant bacteria (Struelens 1998: 652). Infections acquired in the hospital (HAIs) are a cause of significant morbidity and mortality, worsened by the development of antimicrobial resistant infections in patients receiving health care (Brink, Feldmann, Duse, Gopolan, Grolman, Mer, Naicker, Paget, Perovic & Richards 2006: 153; Struelens 1998: 652). The Centres for Disease Control and Prevention (CDC) define HAI as a localized or systemic condition resulting from an adverse reaction to the presence of an infectious agent(s) or its toxin(s) that develop during hospitalization, with no evidence that the infection was present or incubating at the time of admission to the acute care setting (Horan & Gaynes 2008: 309). WHO (2002: 1) emphasizes that a patient must be admitted for a reason other than the developed infection.
Weinstein (1998: 417) points out that HAI typically affects patients, who are immunocompromised because of age, underlying diseases, or medical or surgical treatment. As a consequence to the patients’ frail conditions, exposure to heavy antimicrobial use, overcrowded and poor ventilated wards, surgical procedures, and daily invasive procedures, patients admitted to ICUs are the most susceptible to nosocomial infections (Baker et al 2017: 735; Valles, Leon & Alvarez-Lerna 1997:387). Furthermore, patients who are treated with inadequate antibiotic therapy are at risk of a poor outcome and are a high risk of spreading the resistant pathogen further (Acar, 1997: 17). Moreover, inadequate antibiotics therapy originate from inappropriate interpretation or use of microbiological test results; lack of microbiologically confirmed diagnosis; laboratory test errors; failure to submit appropriate specimen for culture; misuse of microbiology resources (Moreney-Patvin, Schwartz & Weinstein 2017: 382).
The agents of utmost importance in HAI include Streptococcus spp., Acinetobacter spp., enterococci, Pseudomonas aeruginosa (P. aeruginosa), coagulase-negative staphylococci, Staphylococcus aureus (S. aureus), Enterobacteriaceae, K. pneumonia (Klebsiella pneumonia), Escherichia coli (E. coli) (Babamahmoodi, Ahangarkani & Davoudi 2015: 153; WHO 2002: 2). A retrospective descriptive study from Kimberly hospital Burn Unit, showed Staphylococcus aureus, coagulase-negative Staphylococcus (CNS) and methicillin-resistant S. aureus (MRSA) as the most common pathogens isolated (40.17%) on wound swabs, whereas in blood cultures S. aureus (32.08%), K. Pneumonia (20.75%) and P. aeruginosa (16.98%) were the most frequent pathogens found (Giaquinto-Cilliers, Hoosen, Govender & van der Merwe 2014: 30).
Owing to the increased incidence of HAI with antibiotic-resistant bacteria, antibiotic resistance has become a critical challenge for infective disease management. More than 70% of the bacteria that causes HAIs are resistant to at least one antibiotic (Krzowska-Firych, Kozlowska, Sukhadia & Al-Mosawi 2014: 784). Lately antimicrobial resistance (AMR) is recognized globally as one of the greatest threats to human health (Llor & Bjerrum 2014: 229), and further, microbes have developed resistance to the majority of available antimicrobials (Laxminarayan, Duse, Wattal, Zaidi, Wertheim, Sumpradit, Vlieghe, Hara, Gould, Goossens, Greko, So, Bigdeli, Tomson, Woodhouse, Ombaka, Peralta, Qamar, Mir, Kariuki, Bhutta, Coates, Bergstrom, Wright, Brown & Cars 2013:1057), consequently complicating the management of infectious diseases.

CHAPTER 1  ORIENTATION TO THE RESEARCH STUDY
1.1 INTRODUCTION
1.2 BACKGROUND TO THE RESEARCH PROGRAM
1.3 RESEARCH PROBLEM
1.4 RESEARCH QUESTION AND HYPOTHESIS
1.5 AIMS OF THE STUDY
1.6 SIGNIFICANT OF THE STUDY
1.7 DEFINITIONS OF TERMS
1.8 RESEARCH DESIGN
1.9 METHODLOGY
1.10 SCOPE OF THE STUDY
1.11 LIMITATIONS OF THE STUDY
1.12 STRUCTURE OF THE THESIS
CONCLUSSION
CHAPTER 2  LITERATURE REVIEW
2.1 INTRODUCTION
2.2 SEARCH STRATEGY
2.3 PATHOLOGY AND TREATMENT OF BACTERIAL INFECTIONS
2.3 THE DEVELOPMENT OF ANTIMICROBIAL RESISTANCE
2.4 MECHANISMS OF ANTIMICROBIAL RESISTANCE
2.5 BARRIERS TO APPROPRIATE ANTIMICROBIAL PRESCRIBING
2.6 THE BURDEN OF ANTIMICROBIAL RESISTANCE
2.7 ANTMICROBIAL STRATEGIES IN GENERAL
2.8 ASP IN SOUTH AFRICA
2.9 ASP IN THE ICU
2.10 BARRIERS TO IMPLEMENTATION OF ASP
2.11 SUCCESSEST OF ASP
2.13 THEORETICAL FRAMEWORK
2.12 THE RE-AIM FRAMEWORK FOR IMPACT EVALUATION
2.13 CONCLUSION
CHAPTER 3  RESEARCH DESIGN AND METHODS
3.1 INTRODUCTION
3.2 RESEARCH DESIGN
3.3 RESEACH METHOD
3.4 MEASURES TO ENSURE VALIDITY AND RELIABILITY
3.5 ETHICAL CONSIDERATION
3.6 CONCLUSION
CHAPTER 4
4.1 INTRODUCTION
4.2 DEMOGRAPHIC AND CLINICAL CHARACTERISTICS
4.3 STATISTICAL DESCRIPTION OF THE DATA
4.4 QUESTIONNAIRE EVALUATION
4.5 THE CAPACITY TO PRESCRIBE ANTIMICROBIALS
4.7 INCIDENCE OF DIFFERENT BACTERIA IN THE ICU
4.8 IMPACT OF ASP
4.10 CONCLUSION
CHAPTER 5  SUMMARY AND DISCUSION
5.1 INTRODUCTION
5.2 SUMMARY OF THE STUDY
5.3 STUDY DESIGN AND SETTING
5.4 SUMMARY OF THE RESULTS
5.5 CONCLUSION
CHAPTER 6  STRATEGIES TO IMPROVE THE ASP PERFORMANCE
6.1 INTRODUCTION
6.2 ANTIMICROBIALPRESCRIBING CAPACITY
6.3 CONCLUSION
CHAPTER 7  RECOMMENDATIONS, LIMITATIONS AND CONCLUSION
7.1 INTRODUCTION
7.2 CONTRIBUTION OF THE STUDY
7.3 LIMITATIONS OF THE STUDY
7.4 RECOMENDATIONS FOR FUTURE RESEARCH
7.5 CONCLUDING REMARKS
REFERENCES AND BIBLIOGRAPHY
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