Effect of Combined Fluoroquinolone and Azole Use on QT Prolongation in Hematology Patients

Abstract

bQTc prolongation is a risk factor for development of torsades de pointes (TdP). Combination therapy with fluoroquinolones and azoles is used in patients with hematologic malignancies for prophylaxis and treatment of infection. Both drug classes are implicated as risk factors for QTc prolongation. The cumulative effect on and incidence of QTc prolongation for this combination have not been previously described. A retrospective chart review was performed with hospitalized inpatients from 1 September 2008 to 31 January 2010 comparing QTc interval data from electrocardiogram (ECG) assessment at baseline and after the initiation of combination therapy. Ninety-four patients were eligible for inclusion. The majority, 88 patients (93.6%), received quinolone therapy with levofloxacin. Fifty-three patients (56.4%) received voriconazole; 40 (42.6%) received fluconazole. The overall mean QTc change from baseline was 6.1 (95% confidence interval [CI], 0.2 to 11.9) ms. Twenty-one (22.3%) of the studied patients had clinically significant changes in the QTc while receiving combination fluoroquinolone-azole therapy. Statistically significant risk factors for clinically significant changes in QTc were hypokalemia (P ‫؍‬ 0.03) and a left-ventricular ejection fraction of <55% (P ‫؍‬ 0.02). Low magnesium (P ‫؍‬ 0.11), exposure to 2 or more drugs with the potential to prolong the QTc interval (P ‫؍‬ 0.17), and female sex (P ‫؍‬ 0.21) trended toward significance. Combination therapy with fluoroquinolone and azole antifungals is associated with increased QTc from baseline in hospitalized patients with hematologic malignancies. One in five patients had a clinically significant change in the QTc, warranting close monitoring and risk factor modification to prevent the possibility of further QTc prolongation and risk of TdP. C ombination fluoroquinolone-azole prophylaxis and therapy is common in the hematology patient population. Prophylaxis with these agents has been shown to decrease both bacterial and fungal infections (1-5), and recommendations for use are incorporated as part of the Infectious Diseases Society of America's clinical practice guidelines on the use of antimicrobial agents in neutropenic patients with cancer (6) and the National Comprehensive Cancer Network's guidelines on prevention and treatment of cancer-related infections (7). However, both classes of agents have the potential to prolong the QTc interval and increase the risk for torsades de pointes (TdP) (8-10), with episodes of TdP reported with both azoles and fluoroquinolones (11)(12)(13)(14)(15)(16)(17)(18)(19).The risk of QTc prolongation and TdP in hematology patients on a combination of fluoroquinolone and azole therapy has not been well defined. While it is known that both classes of agents have been associated with QTc prolongation and torsades de pointes, it is not well understood to what degree the combination can increase the QTc interval within this population or whether the combination poses an increased risk of TdP.The measured QT interval from an el...

QTc prolongation during ciprofloxacin and fluconazole combination therapy: prevalence and associated risk factors

“…Zeuli et al . recommended that these haematology patients are monitored extensively . In line with this study, ciprofloxacin has recently been added to the list of QTc‐prolonging drugs with a known risk of TdP according to the CredibleMeds® QT drug list by the AZCERT .…”

“…Zeuli et al . studied the effect of fluoroquinolone and azole therapy on QTc prolongation in 94 haematology patients. In this retrospective study, 21 (22%) patients had clinically significant changes from baseline in the QTc interval, and several associated risk factors were found, such as hypokalaemia ( P = 0.03) and a left ventricular ejection fraction of <55% ( P = 0.02).…”

Drug interaction at hERG channel: In vitro assessment of the electrophysiological consequences of drug combinations and comparison against theoretical models

“…Consequently, it can result in modification of the cardiac clinical symptoms related to one or both of them. Both, epidemiological studies and adverse reaction reporting systems data confirm that DDIs are one of the common additional risk factors for reported QT prolongation or TdP (Boyce, Baisley, & Warrington, ; Heist & Ruskin, ; Katoh et al, ; van der Sijs et al, ; Zeuli, Wilson, & Estes, ). An example of the drug‐triggered QT prolongation resulting from the interaction between drugs is combination of terfenadine and ketoconazole (KETO).…”

Drug-induced proarrhythmia: risk factors and electrophysiological mechanisms

“…[64][65][66] These incidents were confirmed in larger cohort studies. [67][68][69] An experimental study suggested substantial inhibition of hERG potassium channels by fluconazole, which might induce acquired LQTS and thereby explain the potential proarrhythmic effect. 70 However, this study was conducted in human isolated kidney cells and not myocardial tissue.…”