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By
Malambo Muzyamba
A Dissertation Submitted to the University of Zambia in Partial Fulfillment of the Requirements for the Degree of Master of Clinical Pharmacy of the University of Zambia
University of Zambia
Lusaka
2020
APPROVAL
This dissertation of Muzyamba Malambo has been approved as fulfilling the requirements or partial fulfilment of the requirements for the award of Master's Degree in Clinical Pharmacy by the University of Zambia.
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DECLARATION
I, Muzyamba Malambo hereby declare that this dissertation is my original work submitted for the degree of Master of Clinical Pharmacy at the University of Zambia. This has never been submitted in part or whole at this or any other academic institution.
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Supervisor
Ihaving supervised and read this dissertation I am satisfied that this is the original work of the author under whose name it is being presented.
I, therefore, confirm that the work has been completed according to the University of Zambia requirements.
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COPYRIGHT
No part of this thesis will be reproduced in any form or format without any written permission from me.
Muzyamba Malambo 2019. All rights reserved.
ACKNOWLEDGEMENT
It is with great pressure that I extend my gratitude to acknowledge the people who helped and supported me during this phase of my academic pursuit. This dissertation would not have become a reality without their help and support of the following people;
Mr Jimmy Hangoma for always being there to offer support and guidance during proposal development and for editing and proofreading the dissertation.
Mr Lameck Chirwa for always being there to offer support and guidance during proposal development and for editing the dissertation.
Dr Patrick Kaonga for his assistance to analyze data, his guidance and mentorship during the research and write up of the dissertation and for his time to proofread the document.
Dr Derick Munkombwe for his supervision, for taking his time to proofread, his advice and mentorship during my research.
Staff members at microbiology laboratory for teaching me the skills in Gram stain, blood culture and susceptibility testing
Clerks in the Neonatal Intensive Care Unit ward at Women and NewBorn Hospital for locating and verification of patient data during patient admission and discharge.
DEDICATION
I dedicate this dissertation to my husband, Mr Humphrey Kayukwa, my beautiful daughters Luyando and Lushomo, my sons Daniel and Lumuno, my parents Mr and Mrs Malambo for their love, support and patience during my studies. Above all, I would like to thank the almighty God for the strength and wisdom given to me to accomplish this task.
ABSTRACT
Antibiotics are the most commonly prescribed and used drugs in the treatment of neonatal sepsis. Inappropriate use of antibiotics is associated with increased microbial resistance and neonatal mortality. Therefore, this study was set out to determine the antibiotic prescribing patterns for empirical therapy of neonatal sepsis at Women and Newborn Hospital in Lusaka, Zambia. This will help public health to combat inappropriate antibiotic prescribing and prevent antibiotic resistance and reduce mortality. This was a cross-sectional study conducted at the Women and Newborn Hospital, Neonatal intensive care unit Lusaka, Zambia, from May 2018 to August 2018. Data on 134 neonates were collected using a structured questionnaire. Data on demographic characteristics, appropriateness of dose, the frequency of administration, duration of treatment, and most prescribed antibiotics and conditions affecting the neonates were collected. Systematic sampling was used for the selection of participants. Before initiation of treatment, a single blood sample was collected from each neonate for culture and susceptibility testing. Samples were cultured on blood agar, chocolate and MacConkey. The organisms isolated from positive culture were identified using conventional biochemical techniques. Data analysis was conducted using STATA version 13. Of the 134 neonates studied, total inappropriateness was 39.1(29.2%) The dose inappropriate was 10(7%), inappropriate frequency of administration 15(11%) and inappropriate duration of treatment 15.01(11.2%). The most inappropriate prescribed drug was imipenem at least 11times out of 134. The most common condition associated with inappropriateness was sepsis with respiratory distress 14(10.4%) other conditions 12(9.0%) and sepsis with low birth weight 8(6.0%). Of all the samples that were cultured only 22(16.4%) samples had bacterial growth (12Coagulase Negative-Staphylococcus, 5Gram-negative bacilli, 2Escherichia coli and 3 Klebsiella). Coagulase Negative-Staphylococcus was susceptible to amikacin, gentamycin chloramphenicol, and vancomycin and intermediately susceptible to ciprofloxacin and resistant to co-trimoxazole and penicillin. Gram-negative bacilli were susceptible amikacin, imipenem and resistant to ceftriaxone, penicillin gentamycin and ciprofloxacin. While Escherichia coli and Klebsiella sp were resistant to ceftriaxone, gentamycin and penicillin and susceptible to amikacin, chloramphenicol and Imipenem. In the multivariate logistic analysis, only antibiotics and disease state were significantly associated with inappropriateness. In conclusion: There seems to be inappropriate prescribing of antibiotics in neonates with sepsis at Women and Newborn Hospital in Zambia. There is a need for the hospital (NICU) to enforce adherence to treatment protocols by the prescriber.
Key words: Inappropriate, Antibiotic prescribing, Neonates, Sepsis
TABLE OF CONTENTS
TOC \o "1-3" \h \z \u HYPERLINK \l "_Toc959223" CERTIFICATE OF APPROVAL ii
HYPERLINK \l "_Toc959227" DECLARATION iii
HYPERLINK \l "_Toc959228" COPYRIGHT STATEMENT iv
ACKNOWLEDGEMENT HYPERLINK \l "_Toc959229" v
HYPERLINK \l "_Toc959230" DEDICATION vi
ABSTRACT HYPERLINK \l "_Toc959231" .....vii
HYPERLINK \l "_Toc959232" TABLE OF CONTENTS viii
HYPERLINK \l "_Toc959233" LIST OF TABLES x
LIST OF FIGURES......xi
LIST OF APPENDICES.....xii
ABBREVIATIONS AND ACRONYMS..................................................................................xiii
HYPERLINK \l "_Toc959235" DEFINITION OF TERMS xv
HYPERLINK \l "_Toc959236" CHAPTER ONE: INTRODUCTION 1
HYPERLINK \l "_Toc959238" 1.1 Background 1
HYPERLINK \l "_Toc959239" 1.2 Statement of the Problem 3
HYPERLINK \l "_Toc959240" 1.3 Justification of the Study 4
HYPERLINK \l "_Toc959241" 1.4 Research Question 4
HYPERLINK \l "_Toc959242" 1.5 Main Objective 5
HYPERLINK \l "_Toc959243" 1.6 Specific Objectives 5
1.7 Conceptual Framework..6
1.8 Organisation of the Dissertation6
HYPERLINK \l "_Toc959244" CHAPTER TWO: LITERATURE REVIEW 7
2.1 Burden of neonatal sepsis..................7
2.2 Commonly encountered bacterial pathogens...10
2.3 Risk factors for neonatal sepsis10
2.4 Diagnosis of neonatal sepsis....10
2.5 Review of antibiotics prescribing patterns...11
HYPERLINK \l "_Toc959249" CHAPTER 3: METHODOLOGY 17
HYPERLINK \l "_Toc959252" 3.1 Study Design 17
HYPERLINK \l "_Toc959253" 3.2 Study Site 17
HYPERLINK \l "_Toc959254" 3.3 Study Population 17
HYPERLINK \l "_Toc959255" 3.3.1 Inclusion Criteria 17
HYPERLINK \l "_Toc959256" 3.3.2 Exclusion Criteria 17
HYPERLINK \l "_Toc959257" 3.4 Sample Size Determination and Sampling Method 17
HYPERLINK \l "_Toc959258" 3.5 Variables 18
HYPERLINK \l "_Toc959259" 3.6 Data Collection 19
HYPERLINK \l "_Toc959261" 3.7 Data Collection Tools 20
HYPERLINK \l "_Toc959262" 3.8 Data Analysis 20
HYPERLINK \l "_Toc959263" 3.9 Ethics Considerations 21
3.10 Limitation of the Study..21
HYPERLINK \l "_Toc959264" CHAPTER 4: RESULTS 22
HYPERLINK \l "_Toc959266" 4.1 Demographics and clinical characteristics of neonates 23
HYPERLINK \l "_Toc959267" 4.2 Appropriateness of antibiotics prescribing patterns 23
HYPERLINK \l "_Toc959268" 4.2.1 Documentation of dose and frequency of administration 23
4.2.2 Documentation of the Duration of Treatment.24
4.3 Antibiotics Prescribing Pattern Conforming to the Local Antibiotics Protocol....25
4.3.1 Most Prescribed Antibiotics25
4.3.2 Association between Antibiotics Prescribed, Condition and Change of Antibiotics and Inappropriateness.............26
4.4 Microbial Susceptibility to Prescribed Antibiotics..........................27
4.5 Association between Baseline and Clinical Characteristic with Inappropriateness in neonates.28
HYPERLINK \l "_Toc959269" CHAPTER 5: DISCUSSION 29
CHAPTER 6: CONCLUSION AND RECOMMENDATIONS...38
HYPERLINK \l "_Toc959271" 6.1 Conclusion 38
HYPERLINK \l "_Toc959273" 6.2 Recommendations 38
HYPERLINK \l "_Toc959281" REFERENCES 39
APPENDICES......44
LIST OF TABLES
Table 3. 1: Main study variables and scales of measurements..20
Table 4.1: Baseline characteristics of neonates admitted at Neonatal intensive care....24
Table 4.2: Association between antibiotics prescribed, conditions, change of antibiotics and inappropriateness at Neonatal intensive care..28
Table 4.3: Microbial susceptibility to Antibiotics at Neonatal intensive care...........29
Table 4.4: Multivariable logistic regression between baseline and clinical characteristic with inappropriateness in neonates at Neonatal intensive Care Unit...30
LIST OF FIGURES
Figure1.1: Conceptual framework of a factor associated with inappropriate prescribing patterns..6
Figure 4.1: Appropriateness of antibiotic prescribing at Neonatal intensive care.....25
Figure 4.2: Duration of antibiotic treatment at the Neonatal intensive care unit ......................26
Figure 4.3: Most prescribed antibiotics at the Neonatal intensive care unit..................................27
LIST OF APPENDICES
Appendix A: Gyssens et al. form.......48
Appendix B: Participant information sheet49
Appendix C: Consent form51
Appendix D: Questionnaire...52
Appendix E: Ethics Approval Letter..54 HYPERLINK \l "_Toc959285"
ABBREVIATIONS AND ACRONYMS
ASP Antimicrobial Stewardship Programs
CoNS Coagulase-negative Staphylococcus
CRP C-reactive protein
CSF Cerebrospinal fluid
E. coli E s c h e r i c h i a C o l i
E D L E s s e n t i a l D r u g L i s t
E O S E a r l y O n s e t S e p s i s
G A G e s t a t i o n a l A g e
G B S G r o u p B s t r e p t o c o c c u s
I F N - G a m m a interferon
IL (6, 8) Interleukin
LBW Low Birth Weight
LOS Late-onset Sepsis
MDR Multi-Drug Resistance
NICU Neonatal Intensive Care Unit
PCT Procalcitonin
sICAM soluble intercellular adhesion molecule
SP Species
SSA Sub-Sah a r a n A f r i c a
S T G S t a n d a r d T r e a t m e n t G u i d e l i n e
T N F - T u m o r n e c r o s i s f a c t o r - a l p h a
U N Z A - H S R E C U n i v e r s i t y o f Z a m b i a H e a l t h S c i e n c e s R e s e a r c h E t h i c s C o m m i t t e e
U T H s University Teaching Hospitals
WHO World Health Organization
WNH Women and Newborn Hospital
ZDHS Zambia Demographic and Health Survey
DEFINITION OF TERMS
Antibacterial drugs: Anything that destroys bacteria or suppresses their growth or their ability to reproduce (Medical Dictionary, 2008).
Antibiotic: A group of drugs used to treat infections caused by bacteria and to prevent bacterial infection in cases of immune system impairment (Medical Dictionary, 2008).
Antimicrobial: A drug used to treat a microbial infection. "Antimicrobial" is a general term that refers to a group of drugs that includes antibiotics, antifungals, antiprotozoal, and antivirals.
Antibiotic resistance: The ability of bacteria and other microorganisms to withstand an antibiotic to which they were once sensitive (and were once stalled or killed outright). Also called drug resistance (Medical Dictionary, 2008).
Appropriate use of medicines: Requires that patients receive medications appropriate to their clinical needs, in doses that meet their requirements, for an adequate period, and at the lowest cost to them and their community (WHO.2011).
Inappropriate use of medicines: Refers to prescribing that fails to conform to good standards of treatment. This may manifest in five different ways, namely: under-prescribing, over-prescribing, incorrect prescribing, extravagant prescribing, and multiple prescribing (WHO.2011).
Neonatal sepsis: Neonatal sepsis is a blood infection that occurs in an infant younger than 28 days old (Medical Encyclopedia).
Appropriate drug use: Appropriate use of medicines requires that "patients receive medications appropriate to their clinical needs, in doses that meet their requirements, for an adequate period, and at the lowest cost to them and their community (WHO.2011).
CHAPTER ONE: INTRODUCTION
1.1Background
Antibiotics are the most commonly prescribed drugs in the neonatal intensive care unit because of sepsis. Neonatal sepsis is referred to as a clinical syndrome that is marked by signs and symptoms of infection in the first 28 days of life, with or without isolation of a pathogen ADDIN EN.CITE Verma201551515117Verma, PradeepBerwal, Pramod KumarNagaraj, NiranjanSwami, SarikaJivaji, PrathushaNarayan, SatyaNeonatal sepsis: epidemiology, clinical spectrum, recent antimicrobial agents and their antibiotic susceptibility patternInt J Contemp PediatrInt J Contemp Pediatr176-80232015(Verma et al., 2015). It presents with nonspecific signs and symptoms and if not treated promptly can result in long term consequences such as neurodevelopmental problems and can lead to death ADDIN EN.CITE Klinger200945454517Klinger, GilLevy, ItzhakSirota, LeaBoyko, ValentinaReichman, BrianLerner-Geva, LiatIsrael Neonatal NetworkEpidemiology and risk factors for early onset sepsis among very-low-birthweight infantsAmerican journal of obstetrics and gynecologyAmerican journal of obstetrics and gynecology38. e1-38. e6201120090002-9378(Klinger et al., 2009) ADDIN EN.CITE Klinger200945454517Klinger, GilLevy, ItzhakSirota, LeaBoyko, ValentinaReichman, BrianLerner-Geva, LiatIsrael Neonatal NetworkEpidemiology and risk factors for early onset sepsis among very-low-birthweight infantsAmerican journal of obstetrics and gynecologyAmerican journal of obstetrics and gynecology38. e1-38. e6201120090002-9378. Neonatal sepsis is known as the main cause of neonatal mortality accounting to many neonatal deaths worldwide (Depani et al., 2011) ADDIN EN.CITE Depani201143434317Depani, Sarita JLadhani, ShamezHeath, Paul TLamagni, Theresa LJohnson, Alan PPebody, Richard GRamsay, Mary ESharland, MikeThe contribution of infections to neonatal deaths in England and WalesThe Pediatric infectious disease journalThe Pediatric infectious disease journal345-34730420110891-3668. A study was done in Zambia by ADDIN EN.CITE Turnbull201130303017Turnbull, EleanorLembalemba, Mwila KBr a d G u f f e y , M <