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An Update on the QT-Prolonging Potential of Anti-Infective Agents
By Jessica C. Song, MA, PharmD, is Pharmacy Residency Coordinator, Santa Clara Valley Medical Center.
Jessica C. Song reports no financial relationships relevant to this field of study.
In the past decade, prolongation of the QT interval associated with polymorphic ventricular tachycardia, or torsades de pointes (TdP), has accounted for the majority of withdrawals or restriction of the use of prescription drugs from the U.S. market.1 Of note, following the removal of grepafloxacin (quinolone) from the market due to electrocardiographic-corrected QT interval (QTc) interval prolongation and associated arrhythmias (7 deaths), the FDA requested that manufacturers of recently developed quinolones document the effects of their products on QTc interval duration.2
QTc interval prolongation is a surrogate marker of cardiotoxicity, as the risk of developing TdP is proportional to the magnitude of QTc prolongation.3 An estimated 1% to 5% of drug-induced QTc interval prolongation progresses to TdP.4 The International Conference on Harmonization (ICH) stated that prolongation of QTc interval by more than 30 milliseconds and in excess of 60 milliseconds should be classified as a potential adverse effect and a definite adverse effect, respectively.5 Consequently, although a mean effect on the QTc interval of 5 milliseconds has been identified as a regulatory concern, clinicians have become more interested in determining the proportion of patients experiencing QTc values in excess of 500 milliseconds during treatment or the proportion of patients with > 30-60 millisecond QTc increases from baseline.
Numerous antimicrobial agents can prolong the QT interval and hence may increase the risk of developing TdP. However, of even greater concern to clinicians is the heightened risk of excessive QTc interval prolongation with pharmacodynamic and pharmacokinetic drug interactions. One retrospective study showed that of 5 million subjects filling prescriptions, 23% were filling prescriptions for QT-prolonging drugs.6 Of the 23% who were taking QT-prolonging drugs, nearly 1 in 10 filled overlapping prescriptions for 2 or more QT-prolonging drugs. With the aging of the U.S. population, clinicians are increasingly faced with the prospect of providing care to patients who may be taking multiple drugs with the potential to prolong the QTc interval. This article will: (1) review the propensity of currently marketed antimicrobials to induce QT-prolongation and (2) highlight clinically significant pharmacokinetic drug interactions with antimicrobials that may predispose patients to excessive QTc interval prolongation.
QT-Prolonging Anti-Infective Agents
Numerous antimicrobial agents have been shown to prolong the QTc interval, including some of the macrolides, quinolones, azole antifungals, and the ketolide, telithromycin.5-14 Macrolide-, azole antifungal- and quinolone-induced QTc prolongation appears to arise from inhibition of the human ether-a-go-go gene (HERG) potassium channel.5,15-17 Blockade of HERG-encoded rapidly activating delayed-rectifier potassium channel (Ikr) is a significant contributor to QTc prolongation, as repolarization delay results from potassium accumulation within the myocyte.3 The likelihood of inducing TdP increases with the generation of repetitive early after depolarizations, a phenomenon that can result from delayed repolarization.
At present, the utility of published cardiac risk data on anti-infective agents is limited, due to underreporting, failure to completely eliminate contributory confounding variables (cardiac disease, electrolyte abnormalities, use of other QT-prolonging drugs), and the retrospective nature of some post-marketing studies.5 However, some excellent reviews of antimicrobial- and drug-associated QT interval prolongation have been conducted by Owens et al5 and by Crouch and colleagues.7 Table 1 highlights some of the data presented in the reviews by Owens and Crouch, along with cardiac risk profiles of newer antimicrobial agents, such as voriconazole, posaconazole, and telithromycin.
The propensity of newer antimicrobial agents (posaconazole, voriconazole, telithromycin) to induce QT prolongation has not been fully established, but the product monographs and published case reports of TdP associated with these agents allows for a tentative cardiac risk assessment. Posaconazole is distinguishable from other azole antifungals, despite documented reports of TdP.10 Unlike the other azole antifungals, posaconazole weakly inhibits CYP3A4, and it neither inhibits nor undergoes metabolism by other cytochrome p450 isoenzymes, such as CYP2C9 and CYP2C19. Sansone et al evaluated the effects of posaconazole (400 mg twice daily) administered with high-fat meals to 173 healthy volunteers.18 A mean decrease in QTc interval (Fridericia correction) of approximately 5 milliseconds occurred following ingestion of posaconazole. In addition, none of the subjects displayed QTc prolongation in excess of 60 milliseconds from baseline or QTc values greater than 500 milliseconds. Of note, the manufacturer cautioned against extrapolating the results of this healthy volunteer study to acutely ill patients, who may be more predisposed to experiencing QT prolongation.10
In comparison to older antifungal agents, such as fluconazole, itraconazole, and ketoconazole, voriconazole appears to confer a similar degree of risk for QT prolongation.12-14 A literature review revealed that voriconazole has been implicated in 3 cases of QTc prolongation, which parallels the number of published cases of fluconazole-associated QTc prolongation.4 Single-dose studies of voriconazole (800 mg, 1200 mg, 1600 mg) in healthy volunteers did not reveal excessive QTc prolongation, as none of the subjects exhibited increases in QTc intervals in excess of 60 milliseconds or QTc values greater than 500 milliseconds.12
The available evidence from current literature suggests that telithromycin is associated with a comparable risk of QT prolongation to clarithromycin.5 Similar to clarithromycin, concurrent administration of telithromycin with other QT-prolonging drugs, such as ketoconazole, results in a QTc interval increase in excess of 10 milliseconds.5 In contrast, telithromycin and clarithromycin administered alone results in a mean increase in the QTc interval of 3.3 milliseconds and 6 milliseconds, respectively.5
Drug Interactions / QT Interval Prolongation
The risk of QT interval prolongation associated with most of the currently marketed quinolones (except for ciprofloxacin) is increased primarily from pharmacodynamic interactions.5 A review of the Adverse Events Reporting System (AERS) showed that nearly 25% of cases of quinolone-associated TdP occurred as a result of concomitant administration with another QT-prolonging drug. In contrast, telithromycin, clarithromycin, erythromycin, and azole antifungals, are inhibitors and/or substrates of at least one cytochrome p450 isoenzyme.5,7 Consequently, QT prolongation may be further enhanced by concomitant use of cytochrome p450 substrates and inhibitors. Table 2 highlights the major cytochrome p450 interactions associated with QT-prolonging agents.
Although the use of certain antimicrobials can predispose susceptible patients to TdP, these agents remain indispensable in the treatment of various infections. In order to minimize the risk of incurring TdP in patients receiving quinolones, azole antifungals, telithromycin, or macrolides, clinicians should be aware of factors that predispose to QT prolongation. Risk factors for QT prolongation/TdP include electrolyte disturbances (hypokalemia, hypocalcemia, hypomagnesemia), cardiac disease (myocardial ischemia, cardiomyopathy), hypertension, diabetes mellitus, hypothyroidism, obesity, alcohol/cocaine abuse, increased age, female gender, and congenital long QT interval syndrome.3,5 In addition to the information summarized in Tables 1 and 2, a comprehensive list of QTc-prolonging drugs can be found at http://www.qtdrugs.org.