Macrolides and Torsadogenic Risk: Emerging Issues from the FDA Pharmacovigilance Database

Introduction: Concern exists on the pro-arrhythmic potential of macrolides, namely Torsade de Pointes (TdP). Recent evidence has challenged the common opinion of considering azithromycin a safer therapeutic option, causing emerging regulatory and clinical interest. Materials and Methods: We analyzed cases of drug-induced TdP (2004-2011) submitted to the publicly available FDA Adverse Event Reporting System (FAERS). Four groups of mutually exclusive events were identified in decreasing order of drug-attributable risk: 1) TdP; 2) QT interval abnormalities; 3) ventricular arrhythmia (VA); 4) Sudden Cardiac Death (SCD). They were combined into case definition A (TdP/QT abnormalities) and case definition B (VA/SCD). Both case-by-case analysis (information on concomitant drugs, especially QT-prolonging agents listed by Arizona CERT, and disproportionality approach (Reporting Odds Ratio, ROR, with 95%CI) were carried out. Results: Over the 8-year period, macrolides were associated with 183 and 419 cases of interest (case definition A and B, respectively). Clarithromycin was the most frequently reported (84 and 162 cases), followed by azithromycin (63 and 140). Only 27% of cases of TdP/QT abnormalities with azithromycin occurred in patients >65 years of age (63, 47 and 44% for clari-, ery- and telithromycin, respectively). In cases of TdP/QT abnormalities, concomitant QT-prolonging drugs (Arizona CERT lists 1 or 2) were recorded with a proportion very different among macrolides (11 to 89%). The highest percentage of fatal outcome was recorded for azithromycin (17%). Disproportionality was found for azithromycin, clarithromycin and telithromycin for both events of interest, whereas erithromycin showed disproportion only for TdP/QT abnormalities. Conclusions: Despite inherent limitations of spontaneous reporting analyses, the remarkable proportion of fatal cases and the occurrence of TdP-related events in middle-aged patients strengthen the view that caution is needed before considering azithromycin as a safer therapeutic option among macrolides.

[1]  T. Nolin,et al.  Antimicrobial-associated QT interval prolongation: pointes of interest. , 2006, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[2]  D. Roden.  Taking the “Idio” out of “Idiosyncratic”: Predicting Torsades de Pointes , 1998, Pacing and clinical electrophysiology : PACE.

[3]  R. Owens.  QT Prolongation with Antimicrobial Agents , 2012, Drugs.

[4]  U. Moretti,et al.  Antimicrobials and the Risk of Torsades de Pointes , 2010, Drug safety.

[5]  Stephanie J. Reisinger,et al.  Drug-versus-Drug Adverse Event Rate Comparisons , 2009, Drug safety.

[6]  John Connett,et al.  Azithromycin for prevention of exacerbations of COPD. , 2011, The New England journal of medicine.

[7]  Adem Karahoca,et al.  Data Mining Applications in Engineering and Medicine , 2012 .

[8]  H. Goossens,et al.  Comparison of outpatient systemic antibacterial use in 2004 in the United States and 27 European countries. , 2007, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[9]  C Michael Stein,et al.  Azithromycin and the risk of cardiovascular death. , 2012, The New England journal of medicine.

[10]  D. Zeltser,et al.  Torsades de pointes induced by antibiotics. , 2006, European journal of internal medicine.

[11]  H. Goossens,et al.  Exposure to antibacterial agents with QT liability in 14 European countries: trends over an 8-year period. , 2009, British journal of clinical pharmacology.

[12]  J. Korvick,et al.  Concomitant risk factors in reports of torsades de pointes associated with macrolide use: review of the United States Food and Drug Administration Adverse Event Reporting System. , 2002, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[13]  Emanuel Raschi,et al.  Drug‐induced torsades de pointes: data mining of the public version of the FDA Adverse Event Reporting System (AERS) , 2009, Pharmacoepidemiology and drug safety.

[14]  M. Hauben,et al.  Data mining for signals in spontaneous reporting databases: proceed with caution , 2007, Pharmacoepidemiology and drug safety.

[15]  G. Marchesini,et al.  The association of pancreatitis with antidiabetic drug use: gaining insight through the FDA pharmacovigilance database , 2013, Acta Diabetologica.

[16]  A. Bate,et al.  Quantitative signal detection using spontaneous ADR reporting , 2009, Pharmacoepidemiology and drug safety.

[17]  H. Goossens,et al.  European Surveillance of Antimicrobial Consumption (ESAC): outpatient macrolide, lincosamide and streptogramin (MLS) use in Europe. , 2006, The Journal of antimicrobial chemotherapy.

[18]  E. Poluzzi,et al.  Antibacterial macrolides: a drug class with a complex pharmacological profile. , 2004, Pharmacological research.

[19]  N. Karalus,et al.  Azithromycin for prevention of exacerbations in non-cystic fibrosis bronchiectasis (EMBRACE): a randomised, double-blind, placebo-controlled trial , 2012, The Lancet.

[20]  Beatrice A. Golomb,et al.  A Survey of the FDA's AERS Database Regarding Muscle and Tendon Adverse Events Linked to the Statin Drug Class , 2012, PloS one.

[21]  H. Goossens,et al.  European Surveillance of Antimicrobial Consumption (ESAC): outpatient macrolide, lincosamide and streptogramin (MLS) use in Europe (1997-2009). , 2011, The Journal of antimicrobial chemotherapy.

[22]  U. Bergman,et al.  Non-antiarrhythmic drugs prolonging the QT interval: considerable use in seven countries. , 2002, British journal of clinical pharmacology.

[23]  R. Owens.  QT prolongation with antimicrobial agents: understanding the significance. , 2004, Drugs.

[24]  R. Kovacs,et al.  Prevalence of QT Interval Prolongation in Patients Admitted to Cardiac Care Units and Frequency of Subsequent Administration of QT Interval-Prolonging Drugs , 2012, Drug Safety.

[25]  K. Southern.  Macrolide antibiotics for cystic fibrosis. , 2012, Paediatric respiratory reviews.