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Effects of the Fluoroquinolones Moxifloxacin and Levofloxacin on the QT Subintervals: Sex Differences in Ventricular Repolarization.

ABSTRACT: Women are associated with longer electrocardiographic QT intervals and increased proarrhythmic risks of QT-prolonging drugs. The purpose of this study was to characterize the differences in cardiac electrophysiology between moxifloxacin and levofloxacin in men and women and to assess the balance of inward and outward currents through the analysis of QT subintervals. Data from 2 TQT studies were used to investigate the impact of moxifloxacin (400 mg) and levofloxacin (1000 and 1500 mg) on QT subintervals using algorithms for measurement of J-T_peak and T_peak -T_end intervals. Concentration-effect analyses were performed to establish potential relationships between the ECG effects and the concentrations of the 2 fluoroquinolones. Moxifloxacin was shown to be a more potent prolonger of QT interval corrected by Fredericia (QTcF) and had a pronounced effect on J-T_peak c. Levofloxacin had little effect on J-T_peak c. For moxifloxacin, the concentration-effect modeling showed a greater effect for women on QTcF and J-T_peak c, whereas for levofloxacin the inverse was true: women had smaller QTcF and J-T_peak c effects. The different patterns in repolarization after administration of both drugs suggested a sex difference, which may be related to the combined I_Ks and I_Kr inhibitory properties of moxifloxacin versus I_Kr suppression only of levofloxacin. The equipotent inhibition of I_Ks and I_Kr appears to affect women more than men. Sex hormones are known to influence cardiac ion channel expression and differences in QT duration. Differences in I_Kr and I_Ks balances, influenced by sex hormones, may explain the results. These results support the impact of sex differences on the cardiac safety assessment of drugs.

SUBMITTER: Taubel J

PROVIDER: S-EPMC7027842 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveTo evaluate whether oral ciprofloxacin, levofloxacin, ofloxacin and moxifloxacin increase the risk of ventricular arrhythmia in Korea's general population.DesignPopulation-based cohort study using administrative claims data on a national scale in Korea.SettingAll primary, secondary and tertiary care settings from 1 January 2015 to 31 December 2015.ParticipantsPatients who were prescribed the relevant study medications at outpatient visits.Primary outcome measuresEach patient group that was prescribed ciprofloxacin, levofloxacin, ofloxacin or moxifloxacin was compared with the group that was prescribed cefixime to assess the risk of serious ventricular arrhythmia (ventricular tachycardia, fibrillation, flutter and cardiac arrest). Using logistic regression analysis with inverse probability of treatment weighting using the propensity score, OR and 95% CI for serious ventricular arrhythmia were calculated for days 1-7 and 8-14 after the patients commenced antibiotic use.ResultsDuring the study period, 4 888 890 patients were prescribed the study medications. They included 1 466 133 ciprofloxacin users, 1 141 961 levofloxacin users, 1 830 786 ofloxacin users, 47?080 moxifloxacin users and 402?930 cefixime users. Between 1 and 7 days after index date, there was no evidence of increased serious ventricular arrhythmia related to the prescription of ciprofloxacin (OR 0.72; 95% CI 0.49 to 1.06) and levofloxacin (OR 0.92; 95% CI 0.66 to 1.29). Ofloxacin had a 59% reduced risk of serious ventricular arrhythmia compared with cefixime during 1-7 days after prescription. Whereas the OR of serious ventricular arrhythmia after the prescription of moxifloxacin was 1.87 (95% CI 1.15 to 3.11) compared with cefixime during 1-7 days after prescription.ConclusionsDuring 1-7 days after prescription, ciprofloxacin and levofloxacin were not associated with increased risk and ofloxacin showed reduced risk of serious ventricular arrhythmia. Moxifloxacin increased the risk of serious ventricular arrhythmia.

Project description:Background Diagnosis of congenital long-QT syndrome (LQTS) is complicated by phenotypic ambiguity, with a frequent normal-to-borderline resting QT interval. A 3-step algorithm based on exercise response of the corrected QT interval (QTc) was previously developed to diagnose patients with LQTS and predict subtype. This study evaluated the 3-step algorithm in a population that is more representative of the general population with LQTS with milder phenotypes and establishes sex-specific cutoffs beyond the resting QTc. Methods and Results We identified 208 LQTS likely pathogenic or pathogenic KCNQ1 or KCNH2 variant carriers in the Canadian NLQTS (National Long-QT Syndrome) Registry and 215 unaffected controls from the HiRO (Hearts in Rhythm Organization) Registry. Exercise treadmill tests were analyzed across the 5 stages of the Bruce protocol. The predictive value of exercise ECG characteristics was analyzed using receiver operating characteristic curve analysis to identify optimal cutoff values. A total of 78% of male carriers and 74% of female carriers had a resting QTc value in the normal-to-borderline range. The 4-minute recovery QTc demonstrated the best predictive value for carrier status in both sexes, with better LQTS ascertainment in female patients (area under the curve, 0.90 versus 0.82), with greater sensitivity and specificity. The optimal cutoff value for the 4-minute recovery period was 440 milliseconds for male patients and 450 milliseconds for female patients. The 1-minute recovery QTc had the best predictive value in female patients for differentiating LQTS1 versus LQTS2 (area under the curve, 0.82), and the peak exercise QTc had a marginally better predictive value in male patients for subtype with (area under the curve, 0.71). The optimal cutoff value for the 1-minute recovery period was 435 milliseconds for male patients and 455 milliseconds for femal patients. Conclusions The 3-step QT exercise algorithm is a valid tool for the diagnosis of LQTS in a general population with more frequent ambiguity in phenotype. The algorithm is a simple and reliable method for the identification and prediction of the 2 major genotypes of LQTS.

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Effects of the Fluoroquinolones Moxifloxacin and Levofloxacin on the QT Subintervals: Sex Differences in Ventricular Repolarization.

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