Date of Award


Degree Type


Degree Name

Doctor of Philosophy in Pharmaceutical Sciences


Biomedical and Pharmaceutical Sciences

First Advisor

Aisling R. Caffrey



Drug-induced QT interval prolongation is associated with rare but life-threatening ventricular arrhythmia and sudden death. To study ventricular arrhythmia and sudden cardiac death associated with QT prolongation in large databases, an accurate operational definition of this outcome is needed. Frequently prescribed macrolide and fluoroquinolone antibiotics are associated with torsades de pointes arrhythmia and sudden death. Due to the dose-dependent nature of the risk, concomitant use of multiple QT-prolonging drugs may pose a greater threat than singular use. Several observational epidemiologic studies suggest that azithromycin may have an increased risk of ventricular arrhythmia and sudden cardiac death. Meanwhile, other observational studies observed a relatively similar cardiac toxicity profile with azithromycin, as compared with no antibiotic use or other antibiotics.


The purpose of the first manuscript in this dissertation is to identify operational definitions of arrhythmias and sudden death associated with QT prolongation used in retrospective database studies and to compare validation results between algorithms. The second manuscript focuses on quantifying the risk of cardiac adverse events related to concurrent concomitant use of QT-prolonging antibiotics and other drugs with similar pro-arrhythmic potential, and the risk factors associated with such events in a national, privately insured population in the United States. The third manuscript seeks to assess the risk of ventricular arrhythmia and sudden death for macrolide and fluoroquinolone antibiotics in a national, commercially insured population in the United States and to compare these results with previously published observational studies.


In the first manuscript, we conducted a systematic literature review using PubMed to identify retrospective studies published between January 1, 2000 and August 31, 2016. We identified and reviewed studies of ventricular arrhythmia or sudden death associated with QT prolongation in large administrative databases. Validation methods and results were also extracted where validation was conducted.

In the second manuscript, we performed a retrospective case-control study using an administrative health claims database from a large national insurer from 2011 to 2013. Cases of ventricular arrhythmia or sudden death due to QT prolongation were selected using a validated algorithm identified from the first manuscript. Four controls were matched to each case on age, sex, and region. Concomitant drug use was defined as overlapping durations of prescriptions of a QT-prolonging antibiotic and one other QT drug of interest. Odds ratios of risk factors and concomitant QT-prolonging medication use were calculated using conditional logistic regression.

In the third manuscript, a retrospective cohort study was conducted in the same administrative health claims database from a large national insurer from 2011 to 2013. The study cohort consisted of patients who filled an outpatient prescription for macrolide and fluoroquinolone antibiotics, or amoxicillin. Amoxicillin episodes were 1-to-1 matched to macrolide and fluoroquinolone episodes on propensity scores. Inpatient admissions or emergency department visits with a primary diagnosis of ventricular arrhythmia were assessed within 10 days and 30 days of the prescription dispensing. Cox proportional hazard models were used to estimate the hazard ratio.


In the first manuscript, several algorithms for identifying QT prolongation in large databases have been developed and validated. We found a common algorithm for QT prolongation that was validated in Medicaid, Medicare, and the Italian National Health Service data. We also found a validated operational definition for sudden death in Medicaid data.

In the second manuscript, we found that concomitant and proximal use of QTprolonging antibiotics with other QT medications predicted ventricular arrhythmia or sudden death.

In the third manuscript, azithromycin use and fluoroquinolone use was not associated with an increased cardiac risk compared with amoxicillin. Macrolide antibiotics, as a class, increased the risk of ventricular arrhythmia and sudden death in the 10 days following the prescription dispensing.



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