Moxifloxacin-Induced QT Prolongation and Torsades: An Uncommon Effect of a Common Drug

Badshah, Aaref; Janjua, Muhammad Mansoor; Younas, Fahad; Halabi, Abdul R.; Cotant, John F.

doi:10.1097/maj.0b013e3181a3c2c9

Cited by 21 publications

(11 citation statements)

References 12 publications

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“…The similarity between moxifloxacin and dofetilide ECG “signatures” (Fig 1) suggests that the low torsade risk of moxifloxacin may be because moxifloxacin therapeutic doses cause limited hERG potassium channel block [11]. However, rare cases of moxifloxacin-induced torsade have been reported in patients at higher risk for torsade [23–26]. Therefore, in patients exposed to higher moxifloxacin concentrations with reduced “repolarization reserve” [27] or other comorbidities that increase risk of torsade [28], moxifloxacin may exhibit an ECG signature similar to dofetilide with larger QTc prolongation, larger T-wave morphology changes and higher risk for torsade.…”

Section: Discussionmentioning

confidence: 99%

Electrocardiographic Biomarkers for Detection of Drug-Induced Late Sodium Current Block

et al. 2016

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BackgroundDrugs that prolong the heart rate corrected QT interval (QTc) on the electrocardiogram (ECG) by blocking the hERG potassium channel and also block inward currents (late sodium or L-type calcium) are not associated with torsade de pointes (e.g. ranolazine and verapamil). Thus, identifying ECG signs of late sodium current block could aid in the determination of proarrhythmic risk for new drugs. A new cardiac safety paradigm for drug development (the “CiPA” initiative) will involve the preclinical assessment of multiple human cardiac ion channels and ECG biomarkers are needed to determine if there are unexpected ion channel effects in humans.Methods and ResultsIn this study we assess the ability of eight ECG morphology biomarkers to detect late sodium current block in the presence of QTc prolongation by analyzing a clinical trial where a selective hERG potassium channel blocker (dofetilide) was administered alone and then in combination with two late sodium current blockers (lidocaine and mexiletine). We demonstrate that late sodium current block has the greatest effect on the heart-rate corrected J-Tpeak interval (J-Tpeakc), followed by QTc and then T-wave flatness. Furthermore, J-Tpeakc is the only biomarker that improves detection of the presence of late sodium current block compared to using QTc alone (AUC: 0.83 vs. 0.72 respectively, p<0.001).ConclusionsAnalysis of the J-Tpeakc interval can differentiate drug-induced multichannel block involving the late sodium current from selective hERG potassium channel block. Future methodologies assessing drug effects on cardiac ion channel currents on the ECG should use J-Tpeakc to detect the presence of late sodium current block.Trial RegistrationNCT02308748 and NCT01873950

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Section: Discussionmentioning

confidence: 99%

Electrocardiographic Biomarkers for Detection of Drug-Induced Late Sodium Current Block

et al. 2016

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“…Most reports indicating that moxifloxacin may be related to cardiac AEs such as TdP are single case reports and very often the individual had multiple risk factors for cardiac arrhythmias [57, 58]. This type of case-by-case reporting serves to highlight potential cardiac risks, but cannot be used to assess the true risk of uncommon or rare cardiac events within a large patient population.…”

Section: Discussionmentioning

confidence: 99%

Update on the Cardiac Safety of Moxifloxacin

Haverkamp

Kruesmann²,

Fritsch³

et al. 2012

CDS

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Cardiac safety was compared in patients receiving moxifloxacin and other antimicrobials in a large patient population from Phase II–IV randomized active-controlled clinical trials. Moxifloxacin 400 mg once-daily monotherapy was administered orally (PO) or sequentially (intravenous/oral, IV/PO). Across 64 trials, 21,298 patients received PO therapy (10,613 moxifloxacin, 10,685 comparators) while 6846 received sequential IV/PO therapy (3431 moxifloxacin, 3415 comparators). Treatment-emergent cardiac adverse event (AE) rates were similar for moxifloxacin and comparators in PO (6.6% vs 5.8%) and IV/PO (11.0% vs 12.0%) trials. Treatment-emergent cardiac adverse drug reactions were rare in PO (moxifloxacin 3.2% vs comparators 2.4%) and IV/PO (moxifloxacin 1.4% vs comparators 1.5%) patients. There were five (<0.02%) treatment-emergent drug-related deaths due to cardiac events out of 28,144 patients; one PO patient died treated with comparators, one patient died treated with IV/PO moxifloxacin, and three patients died after treatment with IV/PO comparators. Only one case of treatment-related non-fatal torsade de pointes occurred in the comparator arm. Incidence rates of cardiac AEs remained low in populations at elevated risk of cardiac events predisposed to QTc prolongation (i.e. community-acquired pneumonia patients admitted to the intensive care unit and/or mechanical ventilation, patients with documented prolongation of baseline QTc interval, women, and patients ≥ 65 years old). There was no evidence of unexpected cardiac events. After moxifloxacin treatment, an expected small prolongation in QTcB and QTcF was found. This analysis of numerous clinical trials shows the favorable cardiac safety profile of moxifloxacin, when used appropriately and according to its label, versus other antibiotics.

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“…Interestingly, previously reported cases of TdP have been induced by intravenous rather than oral moxifloxacin. However, objective data are lacking [36,37,38]. In other case reports, the administration of levofloxacin concomitant with other medications that may prolong the QT interval, such as fluoxetine or fluconazole, caused QTc prolongation and TdP in patients with multiple risk factors [39,40,41].…”

Section: Clinical Studies Examining the Effect Of Fluoroquinolones Onmentioning

confidence: 99%

QT Prolongation and Torsade de Pointes Induced by Fluoroquinolones: Infrequent Side Effects from Commonly Used Medications

Briasoulis¹,

Agarwal²,

Pierce

2011

Cardiology

124

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Although very useful agents, fluoroquinolones are associated with a number of adverse events, some with considerable clinical significance. Prolongation of the QT interval, for example, is an adverse effect associated with the use of fluoroquinolones. Fluoroquinolones prolong the QT interval by blocking voltage-gated potassium channels, especially the rapid component of the delayed rectifier potassium current I_Kr, expressed by HERG (the human ether-a-go-go-related gene). According to the available case reports and clinical studies, moxifloxacin carries the greatest risk of QT prolongation from all available quinolones in clinical practice and it should be used with caution in patients with predisposing factors for Torsades de pointes (TdP). Although gemifloxacin, levofloxacin, and ofloxacin are associated with a lower risk of QT prolongation compared with moxifloxacin, they should also be used with caution in patients at risk for QT prolongation. Ciprofloxacin appears to be associated with the lowest risk for QT prolongation and the lowest TdP rate. The overall risk of TdP is small with the use of fluoroquinolones. Clinicians can minimize that risk by avoiding prescriptions of multiple medications associated with QT-interval prolongation, especially in high-risk patients.

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Moxifloxacin-Induced QT Prolongation and Torsades: An Uncommon Effect of a Common Drug

Cited by 21 publications

References 12 publications

Electrocardiographic Biomarkers for Detection of Drug-Induced Late Sodium Current Block

Electrocardiographic Biomarkers for Detection of Drug-Induced Late Sodium Current Block

Update on the Cardiac Safety of Moxifloxacin

QT Prolongation and Torsade de Pointes Induced by Fluoroquinolones: Infrequent Side Effects from Commonly Used Medications

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