Antibiotic-induced QT interval Prolongation: Drugs implicated and safety measures for risk minimization

Abstract

Introduction: QT interval Prolongation (QTP) and arrhythmias (Torsades de Pointes, TdP), a serious adverse drug reaction, have been associated with many commonly used antibiotics in recent times. The comparative risk of different drugs has not been explored, as well as the strategies for their early risk detection and comparative evaluation.Objectives: The objective of this study was to explore and evaluate the association between TdP/QTP and many available antibiotics using the FDA Adverse Event Report System (FAERS).Methods: FAERS reports from January 1, 2004 to June 30, 2019 were analyzed. The Medical Dictionary for Regulatory Activities (MedDRA) was used to identify TdP/QTP cases. We calculated the Reporting Odds Ratios (RORs), Proportional ADR Reporting Ratio (PPR), and Yule?s Q, Chi Square with Yate?s correction for the association between each antibiotic and 4 different categories (Group 1: Standarized Medical Querry in MedDRA for QT Prolongation, Group 2: Preferred MedDRA terms for QT interval prolongation, GROUP 3: Unspecific symptoms related with arrhythmia, Group 4: MedDRA Terms linked to ventricular arrhythmia . An association was considered to be statistically significant when the lower limit of the 95%CI was greater than 1.0 (ROR or PPR), greater than 0 (Yule?s Q) or the P value was less than 0,05 (Chi Square).Results: A total of 371.002.880 reports (including 7.889.404 TdP/QTP reports) were considered, after inclusion criteria were applied. The most frequently used antibiotics in the hospital setting were linked to prolongation of the QT interval. They were in decreasing order of risk: Ticarcillin + clavulanic acid, Piperacillin + Tazobactam, Ceftriaxone, Ciprofloxacin, Ampicillin + Sulbactam, Moxifloxacin, ampicillin, amoxicillin + Clavulanic acid, Metronidazole, amoxicillin, levofloxacin. The aforementioned antibiotics presented increased risk in the four categories (standardized search strategy, risk of arrhythmias, risk of nonspecific symptoms, and asymptomatic alterations of the QT interval).Conclusion: The prolongation of the QT interval should be taken into account as a frequent and potentially risky adverse reaction in all antibiotics for hospital use. They are associated with a multiplicity of warning symptoms prior to the presence of fatal arrhythmias. The need for evolutionary clinical control for the detection of nonspecific symptoms and electrocardiographic evaluation for early prolongations of the QT interval are clear. This study confirms prior evidence for TdP/QTP associations with antibiotics and proposes safety controls for early detection and risk minimization.