Fluoroquinolones and QT prolongation research continues

August 2005

Many different pharmaceutical agents have been shown to adversely affect the time between the beginning of the part of electrocardiographic wave representing ventricular depolarization complex and the end of the T-wave (QT) interval. Although anti-infectives account for a large portion of the causative agents, the fluoroquinolone class has been the focus of late. Prolongation of the QT interval is significant due to its association with potentially life-threatening ventricular tachyarrhythmias, such as torsades de pointes. A clinician’s role in understanding which drugs may be linked with QT prolongation is vital due to patients often complicated medical histories and respective list of medications.

Torsades de pointes (TdP) and other ventricular arrhythmias result from either inherited or acquired causes. The most common acquired form is drug induced. Drugs associated with QT prolongation include Class Ia and III antiarrhythmics, azole antifungals, tricyclic antidepressants, trimethoprim-sulfamethoxazole, cisapride (Propulsid, Janssen), terfenadine, macrolide agents and fluoroquinolone agents. While medications are often a causative factor for torsades de points, there are other risk factors to consider, such as patients’ underlying comorbidities, organ impairment, electrolyte abnormalities, bradycardia and genetic polymorphisms. Pharmacists can play a significant role by identifying not only the drugs responsible for QT prolongation but also by preventing any potential drug-drug interactions, which could potentiate the QT interval.

QT prolongation most commonly results from blockage of the delayed rectifier current, IK. Drugs that exert the most potent effect on this channel, such as dofetilide (Tikosyn, Pfizer) and cisapride, tend to have the greatest ability to prolong the QT interval. Recently, the FDA recommended that newer fluoroquinolone agents — gatifloxacin and moxifloxacin (Avelox, Bayer) — undergo specific in vitro testing to determine their effects on the I_Kr channel as this is the believed mechanism by which they extend the QT interval. Different assays have been developed to aid pharmaceutical companies in determining a drug’s effect on the I_Kr potassium channel. It is important to note, however, that none of these assays have been validated in a prospective manner to determine whether a drug will have a clinical effect on the QT interval.

All fluoroquinolones have the ability to inhibit the I_Kr potassium channel. Inhibition of this channel is often reported as 50% inhibitory concentration or IC₅₀. The IC₅₀ levels reported for the fluoroquinolone agents are far greater than concentrations normally achieved in humans. Although the risk of an arrhythmic event is low, clinicians should use fluoroquinolones cautiously in specific individuals due to the potential for an arrhythmia at low inhibitory concentrations. The route of administration, IV vs. oral, has not been shown to affect QT interval prolongation.

Normal cardiac tissue has a QT interval of < 400 millisecond (ms). A QT interval > 500 ms or an increase in the interval > 60 ms from baseline has been shown to increase patients’ risk for a tachyarrhythmia or TdP. This increase warrants concern on the part of the practitioner and should result in an immediate assessment of risk factors for QT prolongation and a thorough medication history review. Atrial fibrillation, congestive heart failure, electrolyte disturbances such as hypokalemia or hypomagnesemia, renal or hepatic impairment, CYP3A4 inhibition and particularly the use of Class Ia or III anti-arrhythmics are characteristics of an individual susceptible to QT prolongation. As mentioned previously, drug-drug interactions share the role in interval prolongation with the agent responsible for the cardiac event. It is estimated that 10% of individuals who fill a prescription for a QT prolonging agent also receive another drug capable of QT prolongation.

Increasing fluoroquinolone use

Fluoroquinolone use has continued to increase as technology allows for the production of new agents within this class. Although grepafloxacin (Raxar, GlaxoSmithKline) and sparfloxacin (Zagam, Rhone Poulenc Rorer) were eventually removed from the market due to cardiac adverse events, QT prolongation is not considered to be a class effect. Following conclusion of phase-3 trials in Europe, a safety board concluded that adverse events associated with sparfloxacin were similar to comparative agents; however, sparfloxacin was voluntarily removed from the market in 2001 following reports of adverse events over an eight-month period. Of these cases, three were reversible ventricular tachycardia and two were fatalities attributed to sudden death. Upon further examination of these events, multiple risk factors for torsades de pointes were present in these patients, such as concomitant use of amiodarone. Grepafloxacin was removed in 1999 due to reports of seven cardiac-related fatalities and three cases of torsades de points. Manufacturers of grepafloxacin included the following within the contraindication section of the package insert: “because prolongation of the QT interval has been observed in healthy volunteers … Raxar (grepafloxacin) tablets are contraindicated in patients with known QT prolongation.” This medication was also contraindicated with other medications known to prolong the QT interval unless appropriate cardiac monitoring was available. Grepafloxacin and ciprofloxacin inhibit the CYP enzyme system through 1A2; however, the other fluoroquinolone agents do not inhibit CYP3A4, 2C9 or 2C19 unlike the macrolides, ketolides and azole antifungals. Although the risk for a drug-drug interaction is minimal with the fluoroquinolone agents, they do require dose adjustment in the presence of renal insufficiency to avoid supratherapeutic concentrations.

Of the fluoroquinolone agents used, ciprofloxacin remains the safest cardiac quinolone having the least effect on the I_Kr channel. Levofloxacin was introduced prior to FDA scrutiny regarding QT prolongation and therefore managed to escape intense postmarketing safety evaluations. Seventeen cases of levofloxacin-associated torsades de pointes have been reported in the literature, but most cases occurred in patients with the aforementioned risk factors. Recent experience with the newer fluoroquinolone agents, gatifloxacin and moxifloxacin, has produced few reports of TdP, but prescribing information for both products states that these agents should not be given concurrently with Class Ia or III antiarrhythmic agents. Levofloxacin, gatifloxacin and moxifloxacin are considered interchangeable from a cardiac safety standpoint when used in a nonsusceptible patient population. Gemifloxacin, the newest fluoroquinolone, carries the same precaution as both gatifloxacin and moxifloxacin regarding use with Class Ia and III anti-arrhythmics. It is considered to be similar to the newer agents but should be used cautiously as there is less postmarketing data available at this time.

Although the overall risk of QT prolongation appears to be minimal with the available fluoroquinolone agents, there are case reports of torsades de points with each agent. All fluoroquinolones have been shown to inhibit the I_Kr channel to varying degrees; therefore, they should be used with caution in susceptible individuals. Concurrent medications should be evaluated at the patient’s renal and hepatic function as well. With the widespread use of amiodarone in the cardiac population, the addition of a fluoroquinolone, such as gatifloxacin or moxifloxacin should be evaluated on a case-by-case basis.

Currently, electrocardiogram monitoring prior to the initiation of fluoroquinolone therapy in this population is not recommended. Perhaps determination of a baseline QT in susceptible patients could prevent inappropriate fluoroquinolone use and unwanted toxicity. Duration of therapy with antibiotics is usually short term but special attention should be given to those requiring prolonged antimicrobial therapy. Physician and pharmacist consideration of the risk factors that place patients at increased risk for QT prolongation may decrease the chance of potentially fatal cardiac events.

For more information:

• Owens RC Jr, Ambrose PG. Antimicrobial safety: focus on fluoroquinolones. Clin Infect Dis. 2005;(41 Suppl 2):S144-57.
• Owens R. QT Prolongation with antimicrobial agents. Drugs. 2004;64(10):1091-1124.
• Owens R. Risk Assessment for antimicrobial agent-induced QTc interval prolongation and torsades de pointes. Pharmacotherapy. 2001;21(3):301-319.