FACTORS INFLUENCING ANTIBIOTIC USE IN THE PAEDIATRIC INTENSIVE CARE UNIT AT UNIVERSITAS HOSPITAL FROM 1998 TO 2007 by RIANA VAN WYK B. Pharm. A dissertation submitted in fulfilment of the requirements for the Magister in Medical Sciences degree M.Med.Sc. (Pharmacology) in the Faculty of Health Sciences at the University of the Free State Bloemfontein February 2013 Supervisor: Prof. A. Walubo TABLE OF CONTENTS STATEMENTS viii ACKNOWLEDGEMENTS x LIST OF FIGURES xi LIST OF ACRONYMS/ABBREVIATIONS xxi ABSTRACT xxii PUBLICATIONS AND CONGRESS/CONFERENCE PRESENTATIONS xxiv CHAPTER 1 GENERAL INTRODUCTION 1 CHAPTER 2 FACTORS THAT INFLUENCE ANTIBIOTIC USE PART I: ANTIBIOTIC FACTORS 2.0 Introduction 3 2.1 Pharmacology of some antibiotics 3 2.1.1 Introduction 3 2.1.2 Mechanism of action 4 2.1.2.1 Inhibitors of bacterial cell wall synthesis 4 2.1.2.2 Inhibitors of bacterial protein synthesis 5 2.1.2.3 Inhibitors of bacterial nucleic acid synthesis 5 2.1.2.4 Anti-metabolites 5 2.1.3 Spectrum of antibiotic activity and common indications 5 2.1.3.1 Penicillins 6 2.1.3.2 Cephalosporins 6 2.1.3.3 Carbapenems 7 2.1.3.4 Aminoglycosides 7 2.1.3.5 Glycopeptides 7 2.1.3.6 Sulphonamides 8 i 2.1.3.7 Fluoroquinolones 8 2.1.3.8 Macrolides 8 2.1.3.9 Metronidazole 9 2.1.4 Pharmacokinetics 9 2.1.4.1 Absorption 9 2.1.4.2 Distribution 9 2.1.4.3 Metabolism and excretion 10 2.1.5 Adverse effects 11 2.1.6 Drug interaction 12 2.2 Some clinical aspects of antibiotic use 13 2.2.1 Antibiotic combinations 13 2.2.2 Pharmacodynamics 14 2.2.3 Dosage and duration of therapy 15 2.2.4 Antibiotic availability and cost 16 2.2.5 New antibiotics 16 2.2.6 Personal preferences 16 CHAPTER 3 FACTORS THAT INFLUENCE ANTIBIOTIC USE PART II: BACTERIAL FACTORS 3.0 Introduction 17 3.1 Antibiotic resistance 17 3.1.1 Introduction 17 3.1.2 Mechanisms of antibiotic resistance 18 3.1.2.1 Enzymatic inactivation 19 3.1.2.2 Modification of the site of action 20 3.1.2.3 Development of alternative metabolic pathways 20 3.1.2.4 Reduced antibiotic accumulation 20 3.1.3 Testing for antibiotic resistance 21 3.1.4 Driving factors for increased antibiotic resistance 22 ii 3.1.5 Impact of antibiotic resistance 24 3.2 The epidemiology and pathogenesis of selected bacteria 25 3.2.1 Empirical and prophylactic antibiotic use 25 3.2.2 Disease pattern 25 3.2.3 Pathogenesis of the bacteria 25 3.2.3.1 Gram-positive bacteria 26 3.2.3.2 Gram-negative bacteria 27 3.3 Antibiotic resistance in South Africa 29 3.3.1 Gram-positive bacteria 29 3.3.2 Gram-negative bacteria 30 CHAPTER 4 FACTORS THAT INFLUENCE ANTIBIOTIC USE PART III: PATIENT FACTORS 4.0. Introduction 32 4.1 Age 32 4.2 Weight 33 4.3 Genetic factors 33 4.4 Hepatic- and/or renal function 33 4.5 Underlying diseases and the immune status 34 4.6 The critically ill patient 34 4.7 Invasive devices 35 4.8 Local factors at the site of infection 37 4.9 Patient compliance 37 CHAPTER 5 FACTORS THAT INFLUENCE ANTIBIOTIC USE PART IV: ENVIRONMENTAL FACTORS 5.0 Introduction 39 iii 5.1 The Queuing Theory 39 5.2 Procedure for the Queuing Theory 40 5.3 Types of queues 41 5.3.1 Single-Server, Single-Line Model 41 5.3.2 Multiple-Server, Single-Line Model 43 CHAPTER 6 STUDY PROTOCOL 6.1 Aim and Objectives 44 6.1.1 Summary of observations from the review 44 6.1.2 Aim of the study 45 6.1.3 Specific objectives of the study 45 6.1.4 Expected outcome 46 6.2 Methods 46 6.2.1 General 46 6.2.2 Procedures 46 6.2.3 Data analysis 48 6.2.4 Evaluation of the Paediatric Intensive Care Unit performance 48 CHAPTER 7 RESULTS PART I: ADMISSION CHARACTERISITICS 7.1 Admissions 49 7.2 Patient demography 51 7.2.1 Age 51 7.2.2 Gender 51 7.2.3 Weight 52 7.3 Problems/diagnoses on admission and during stay in the Paediatric Intensive Care Unit 54 iv 7.3.1 Problems/diagnoses on admission 54 7.3.1.1 Referring source 56 7.3.1.2 Post-operative care 57 7.3.2 Problems/diagnoses during stay in the Paediatric Intensive Care Unit 58 7.3.2.1 Medical complications 58 7.3.2.2 Surgical procedures 58 7.3.2.3 Invasive devices 59 7.3.2.4 Antibiotic allergies 59 7.4 Outcome and length of stay in the Paediatric Intensive Care Unit 60 7.4.1 Outcome 60 7.4.2 Length of stay in the Paediatric Intensive Care Unit 60 7.5 Evaluation of the Paediatric Intensive Care Unit performance 61 7.5.1 Application of the Queuing Theory 64 7.6 Summary 65 CHAPTER 8 RESULTS PART II: ANTIBIOTIC USE IN THE PAEDIATRIC INTENSIVE CARE UNIT PATIENTS 8.1 An overview of the antibiotics prescribed 67 8.2 Antibiotics initiated before admission and continued in the Paediatric Intensive Care Unit 72 8.3 Antibiotics initiated/modified within the first three days in the Paediatric Intensive Care Unit 75 8.4 Antibiotics initiated/modified after three days in the Paediatric Intensive Care Unit 78 8.5 Antibiotic combinations prescribed 81 8.5.1 Two-combination antibiotic regimen 82 8.5.2 Three-combination antibiotic regimen 83 8.6 Antibiotic use by clinical diagnosis/problem 84 8.6.1 Pneumonia 84 v 8.6.2 Septicaemia 88 8.6.3 Urinary tract infection 88 8.6.4 Post-operative care 90 8.7 Antibiotics prescribed for different ages 91 8.8 Route of administration 95 8.9 Antibiotic cost 95 8.10 Summary 97 CHAPTER 9 RESULTS PART III: THE PREVALENCE AND PATTERN OF ANTIBIOTIC RESISTANCE IN THE PAEDIATRIC INTENSIVE CARE UNIT 9.1 Culture and Sensitivity 100 9.2 Bacteria 102 9.2.1 Gram-positive bacteria 102 9.2.2 Gram-negative bacteria 105 9.2.3 Specimens 106 9.2.3.1 Specimens and bacterial growth 107 9.3 The prevalence and pattern of antibiotic resistance 109 9.3.1 Gram-positive bacteria 116 9.3.2 Gram-negative bacteria 119 9.4 Summary 130 CHAPTER 10 EVALUATION FOR FACTORS INFLUENCING ANTIBIOTIC USE IN THE PAEDIATRIC INTENSIVE CARE UNIT 10.1 Accomplished factors 132 10.2 Persistently challenging factors 133 10.2.1 Bacterial factors 133 vi 10.2.1.1 Clinical diagnosis 133 10.2.1.2 Innate resistance 137 10.2.1.3 Interaction of bacterial and host factors 137 10.2.1.4 Disease pattern 138 10.2.2 Antibiotic factors 139 10.2.2.1 New antibiotics 139 10.2.2.2 Overuse of antibiotics 139 10.2.2.3 Personal preferences 140 10.2.3 Environmental factors 141 10.2.3.1 Length of stay 141 10.2.3.2 Treatment guidelines 141 CHAPTER 11 DISCUSSION 143 CHAPTER 12 CONCLUSION AND RECOMMENDATIONS 146 BIBLIOGRAPHY 148 APPENDICES 154 Appendix A 154 Appendix B 158 Appendix C 166 Appendix D 188 SUMMARY 201 OPSOMMING 203 vii SUPERVISOR STATEMENT I, Professor A. Walubo, the supervisor of this dissertation entitled: Factors influencing antibiotic use in the Paediatric Intensive Care Unit at Universitas Hospital from 1998 to 2007, hereby certify that the work in this project was done by Riana van Wyk at the Department of Pharmacology, University of the Free State. I hereby approve submission of this dissertation and also affirm that it has not been submitted previously to this or any other institution or the assessors, either as a whole or partially, for admission to a degree or any other qualification. Signature Date viii STUDENT STATEMENT I, Riana van Wyk, certify that this dissertation hereby submitted by me for the M.Med.Sc. Pharmacology degree at the University of the Free State is my independent effort and had not previously been submitted for a degree at another university or faculty. I furthermore waive copyright of the dissertation in favour of the University of the Free State. Signature Date ix