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Dissertation Chengwen Teng Copyright by Chengwen Teng 2019 The Dissertation Committee for Chengwen Teng Certifies that this is the approved version of the following dissertation: ADVERSE DRUG REACTIONS ASSOCIATED WITH ANTIBIOTICS: AN ANALYSIS OF THE FDA ADVERSE EVENT REPORTING SYSTEM Committee: Christopher R. Frei, Supervisor Kelly R. Reveles James P. Wilson Elizabeth A. Walter Carlos A. Alvarez ADVERSE DRUG REACTIONS ASSOCIATED WITH ANTIBIOTICS: AN ANALYSIS OF THE FDA ADVERSE EVENT REPORTING SYSTEM by Chengwen Teng Dissertation Presented to the Faculty of the Graduate School of The University of Texas at Austin in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy The University of Texas at Austin December 2019 Dedication I dedicated this dissertation to my family, who have supported and loved me unconditionally. Acknowledgements I would like to thank my supervisor, Dr. Christopher Frei, for his mentoring and support. Dr. Frei has guided me in every aspect of research, including literature review, generating research ideas, research proposal writing, data analysis, interpretation of data, and manuscript writing. He is a great mentor. In addition, I express my appreciation to my dissertation committee members, Dr. Kelly Reveles, Dr. James Wilson, Dr. Elizabeth Walter, and Dr. Carlos Alvarez. Thank you for your guidance and support throughout this dissertation project. Moreover, I express my gratitude to Dr. Kirk Evoy for his guidance on manuscript writing. I would also like to thank Dr. Frei’s research group members Dr. Obiageri Obodozie-Ofoegbu, Xavier Jones, Dr. Daryl Gaspar, Kaitlin Kennedy, Taylor Patek, Courtney Baus, Dr. Lindsey Groff, Dr. Victor Encarnacion, and Dr. Huda Razzack. I really appreciate your kind help. Furthermore, I would like to thank The University of Texas at Austin Pharmacotherapy Division graduate students Dr. James Shurko and Shiraz Halloush for organizing social events and fun. Lastly, I would like to thank my former classmates at Yangzhou High School, Dr. Guanbo Chen, Dr. Yuanzhen Li, Le Tao, Chunming Li, and Dr. Tian Liu; my former classmates at Wuhan University, Dr. Li Li, Dr. Jiatian Lu, Dr. Qianfan Zhang, Dr. Hao Yang, Dr. Yijing Liu, and Liangbo Jiang; my former roommates at the University of Southern Mississippi, Yongliang Shi and Chen Xia; my former colleague at the University of Alabama at Birmingham, Dr. Yifeng Gao; my former classmates at the University of Oklahoma College of Pharmacy, Dr. Ankush Rehan, Dr. Jeremy Benson, Dr. Tianyun Gao, and Dr. Joshua Johnston; for friendship and advice. v Abstract ADVERSE DRUG REACTIONS ASSOCIATED WITH ANTIBIOTICS: AN ANALYSIS OF THE FDA ADVERSE EVENT REPORTING SYSTEM Chengwen Teng, Ph.D. The University of Texas at Austin, 2019 Supervisor: Christopher R. Frei Antibiotics are associated with adverse drug reactions (ADR), such as Clostridium difficile infection (CDI), Torsade de pointes/QT prolongation (TdP/QTP), acute kidney injury (AKI), hypoglycemia, and rhabdomyolysis. ADRs lead to significant morbidity and mortality, as well as high health care costs. However, data on the ADR profiles of antibiotics are limited. The FDA Adverse Event Reporting System (FAERS) provides real-world data on ADRs of antibiotics. Using FAERS, this study 1) discovered new ADR associations for FDA-approved antibiotics, 2) identified an antibiotic-ADR association that was worse for patients on two drugs than on either drug alone, 3) determined if a recent FDA warning for hypoglycemia should apply to the entire fluoroquinolone class or just selected members of that class, and 4) detected an antibiotic class-ADR association that was worse in a special population, such as elderly patients. The Medical Dictionary for Regulatory Activities (MedDRA) was used to identify ADR cases. Reporting Odds Ratios (RORs) and corresponding 95% confidence intervals vi (95%CI) for the association between antibiotics and ADRs were calculated. An association was considered statistically significant when the lower limit of the 95%CI was greater than 1.0. This study evaluated the association between antibiotics and certain ADRs, which were CDI, TdP-QTP, AKI, hypoglycemia, and rhabdomyolysis. Several new antibiotic-ADR associations were found, which were associations between amikacin and TdP-QTP, between ertapenem and hypoglycemia, and between meropenem and rhabdomyolysis. Patients on vancomycin and piperacillin-tazobactam had higher association with AKI than those on vancomycin alone and those on piperacillin- tazobactam alone. Moxifloxacin and levofloxacin were associated with hypoglycemia, when patients were also taking sulfonylureas or meglitinides. Ciprofloxacin was not associated with hypoglycemia. The association between penicillin combinations and CDI in patients 65 years or older was higher than that in patients less than 65 years old. The findings of this study will aid clinicians to select antibiotics for patients with bacterial infections. vii Table of Contents List of Tables .................................................................................................................... xii List of Figures .................................................................................................................. xiii Chapter One: Overview of the FDA Adverse Event Reporting System ...........................1 Structure of the FDA Adverse Event Reporting System ............................................1 Disproportionality Analysis in the FDA Adverse Event Reporting System ..............2 Limitations of the FDA Adverse Event Reporting System ........................................4 Chapter Two: Specific Aims .............................................................................................5 Chapter Three: Clostridium difficile Infection Associations with Important Antibiotic Classes ..........................................................................................................7 Introduction .................................................................................................................7 Methods ......................................................................................................................8 Data Source .....................................................................................................8 Study Design ...................................................................................................8 Drug Exposure Definition ...............................................................................9 Adverse Drug Reaction Definition .................................................................9 Statistical Analysis ........................................................................................10 Results .......................................................................................................................11 Discussion .................................................................................................................15 Limitations ................................................................................................................18 Conclusions ...............................................................................................................18 viii Chapter Four: Torsades de pointes and QT Prolongation Associations with Antibiotics ....................................................................................................................19 Introduction ...............................................................................................................19 Methods ....................................................................................................................20 Data Source ...................................................................................................20 Study Design .................................................................................................21 Drug Exposure Definition .............................................................................21 Adverse Drug Reaction Definition ...............................................................21 Statistical Analysis ........................................................................................21 Results .......................................................................................................................22 Discussion .................................................................................................................24 Limitations ................................................................................................................26 Conclusions ...............................................................................................................26 Chapter Five: Acute Kidney Injury Associations with Antibiotics ................................27 Introduction ...............................................................................................................27 Methods ....................................................................................................................29 Data Source ...................................................................................................29 Study Design .................................................................................................29 Drug Exposure Definition .............................................................................29 Adverse Drug Reaction Definition ...............................................................30 Statistical Analysis ........................................................................................30
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