Antibiotic usage in South Africa: A longitudinal analysis of medicine claims data WE Agyakwa 25036718 Dissertation submitted in fulfilment of the requirements for the degree Magister Pharmaciae in Pharmacy Practice at the Potchefstroom Campus of the North-West University Supervisor: Prof MS Lubbe Co-Supervisor: Dr JR Burger Assistant Supervisor: Dr N Katende Kyenda November 2014 Acknowledgements All thanks and praise to the Almighty God. His unfailing love and faithfulness has been my anchor and strength. My sincerest gratitude goes to my supervisor, Prof. MS Lubbe for her extraordinary expertise, leadership, patience and wonderful words of encouragement. I am grateful for the valuable time spent to ensure perfection at all times. To my co-supervisors, Dr. JR Burger and Dr. NL Katende-Kyenda, thank you for inspiring and encouraging me to pursue excellence. I am grateful for the sacrifices made and the patience to impact knowledge. My gratitude goes to Ms. Marike Cockeran for the time and patience taken to ensure the accuracy of the statitiscal analyses of the study. Thank you, Ms. Anne-Marie Bekker, for your immense assistance during the data analyses. Your kind words were always refreshing. To Mrs. Helena Hoffman, I am very grateful for all the updates you provided with regard to my study. I am thankful for the time taken to go through my dissertation and the compilation of the reference list. To the INTRA-ACP Mobility Scheme, I am grateful for funding my study in this institution. Lastly, to my husband, Mr. Victor Owusu, thank you for supporting me throughout my study in this institution. Your constant love and prayers have been central in completing this study. Finally brothers, whaterver is true, whatever is honourable, whatever is just, whatever is lovely, whatever is commendable, if there is any excellence, if there is anything worthy of praise, think about these things. Phlippians 4:8. i Table of contents Acknowledgements ........................................................................................................... i List of tables .................................................................................................................... vii List of figures ..................................................................................................................... x List of acronyms and abbreviations ................................................................................... xi Abstract and keywords ................................................................................................... xiv Uittreksel en trefwoorde ................................................................................................... xvi Preface ........................................................................................................................ xviii Authors’ contributions (Study and manuscript 1).............................................................. xix Authors’ contributions (Study and manuscript 2)............................................................... xx Authors’ contributions (Study and manuscript 3).............................................................. xxi Chapter 1: Introduction ................................................................................................... 1 1.2 Background ..................................................................................................... 1 1.3 Problem statement ......................................................................................... 4 1.4 Aim of study .................................................................................................... 5 1.4.1 General research goal ..................................................................................... 6 1.4.2 Specific research objectives ............................................................................ 6 1.5 Method of research ......................................................................................... 6 1.5.1 Literature review .............................................................................................. 7 1.5.2 Empirical investigation ..................................................................................... 7 1.5.2.1 Study design ................................................................................................... 7 1.5.2.2 Data source ..................................................................................................... 8 1.5.2.2.1 Validity and reliability of data ........................................................................... 8 1.5.2.3 Study population ........................................................................................... 10 1.5.2.4 Study variables.............................................................................................. 12 1.5.2.4.1 Independent variables ................................................................................... 12 1.5.2.4.2 Dependent variables ..................................................................................... 14 1.5.2.5 Statistical analyses ........................................................................................ 16 ii Table of contents (continued) 1.5.2.5.1 Descriptive statistics ...................................................................................... 16 1.5.2.5.2 Inferential statistics ........................................................................................ 19 1.5.3 Measures to ensure validity of study results .................................................. 22 1.6 Ethical aspect of research ............................................................................. 28 1.7 Chapter division ............................................................................................ 28 1.8 Chapter summary .......................................................................................... 28 Chapter 2: Introduction to literature review ................................................................ 29 2.2 Antimicrobial agents ...................................................................................... 29 2.2.1 Classification of antimicrobial agents ............................................................. 29 2.2.2 Pharmacological sub-groups of antibiotics .................................................... 30 2.2.2.1 Penicillins ...................................................................................................... 30 2.2.2.2 Cephalosporins ............................................................................................. 34 2.2.2.3 Carbapenems and monobactams.................................................................. 35 2.2.2.4 Glycopeptides ............................................................................................... 36 2.2.2.5 Lipopeptides .................................................................................................. 37 2.2.2.6 Aminoglycosides ........................................................................................... 39 2.2.2.7 Macrolides ..................................................................................................... 40 2.2.2.8 Lincosamide .................................................................................................. 41 2.2.2.9 Tetracycline and related drugs ...................................................................... 42 2.2.2.10 Chloramphenicol ........................................................................................... 43 2.2.2.11 Sulphonamides and trimethoprim .................................................................. 44 2.2.2.12 Fluoroquinolones ........................................................................................... 45 2.2.2.12.1 Structural-activity relationship of fluoroquinolones ......................................... 46 2.2.2.12.2 Mechanism of action of fluoroquinolones....................................................... 46 2.2.2.12.3 Classification of fluoroquinolones .................................................................. 46 2.2.2.12.4 General pharmacokinetic properties of fluoroquinolones ............................... 49 iii Table of contents (continued) 2.2.2.12.5 Clinical uses of fluoroquinolones ................................................................... 50 2.2.2.12.6 Drug-drug interactions involved with fluoroquinolones ................................... 51 2.2.2.12.7 Adverse drug reactions associated with fluoroquinolones ............................. 52 2.2.2.12.8 Use of fluoroquinolones in children less than eighteen years ........................ 53 2.3 Antimicrobial resistance ................................................................................ 58 2.3.1 Definition of antimicrobial resistance ............................................................. 58 2.3.2 Risk factors for emergence of antimicrobial resistance .................................. 58 2.3.3 Mechanisms of antimicrobial resistance ........................................................ 59 2.3.3.1 Efflux-mediated antimicrobial resistance ....................................................... 60 2.3.3.2 Alterations in cell wall structure ..................................................................... 60 2.3.3.3 Target site mutation ...................................................................................... 61 2.3.3.4 Protection of target site by proteins ............................................................... 61 2.3.3.5