Anti-infective drug therapy may lead to dysrhythmia risk

April 2007

Drug-induced prolongation of the QT interval and resultant ventricular dysrhythmia, including torsades de pointes, is not a new phenomenon.

This adverse event was initially tied to antiarrhythmic medications but is well described with anti-infective agents, as well. In fact, during recent years, there have been numerous antibacterials either withdrawn from the U.S. market or abandoned in various phases of clinical development due to their potential to cause this life-threatening toxicity.

In addition, among the 20 top drugs associated with torsades de pointes (TdP) over a 16-year period in the United States, three of these were anti-infective agents. It is therefore important for clinicians to have an understanding of this risk associated with these drugs.

Anti-infective agents warrant particular attention, as these are frequently added to complicated drug regimens when complete information regarding a drug regimen may be lacking.

Drug risk factors

Certain anti-infective drug classes, such as the macrolides, azole antifungals and anti-malarial drugs, have all been implicated. In fact, the ability to prolong the QT interval often varies among members of these drug classes. For example, while clarithromycin and telithromycin are clearly associated with prolonged QT and resultant TdP, other agents, such as azithromycin (Zithromax, Pfizer) , are less strongly associated.

Much attention has been directed toward the risks for QT prolongation stemming from the quinolone anti-infective agents. Several members of this class have been withdrawn or abandoned due to this toxic effect.

Of the agents currently available, moxifloxacin has recently gained additional attention as the agent selected by the FDA to be the positive control for phase-1 studies assessing QT prolongation potential for new agents. This decision was based on the ability of moxifloxacin to reliably prolong the QT interval by 5 Msec. However, this was considered a level that was safe and not associated with significant risk of TdP in patients without other risk factors.

In addition to antimicrobial agents themselves being associated with a risk for prolonged QT interval, many of these agents are also involved in pharmacokinetic drug-drug interactions that may result in prolonged QT, as well.

Whenever a drug associated with prolonged QT is administered with an agent that decreased metabolism of that drug, the risks for prolonged QT are increased. The best example of this is for agents metabolized via the cytochrome P450 enzyme system. Several anti-infective agents are inhibitors of CYP450 and, therefore, may potentiate the toxic effects of other agents when given concomitantly.

These interactions can occur within the anti-infective drug class. One example is the addition of erythromycin to a HIV-positive patient receiving ritonavir (Norvir, Abbott) as part of a highly-active antiretroviral therapy regimen. The azole antifungals are all inhibitors of cytochrome P450 system to some degree, and therefore each of them can potentiate the QT prolonging effects of other agents, such as the Classs III antiarrhythmics. These examples all relate to pharmacokinetic interactions that can occur. Pharmacodymic reactions are namely synergistic QT prolongation that can be observed when two QT prolonging agents are used together.

Patient risk factors

Avoiding the use of any agent with a possible risk for drug-associated dysrythmia is not feasible. Furthermore, not all patients with prolonged QT interval ultimately developed TdP. Therefore, knowing which patients might be at increased risk for TdP in the setting of a prolonged QT interval may aid in drug selection. The table lists risk factors that have been associated with developing TdP.

Resources for clinicians

The Center for Education, Research and Therapeutics at the University of Arizona maintains a Web site devoted to medications associated with TdP (www.torsades.org).

On this Web site, medications can be checked for their associated risk for prolonged QT and TdP. The medications are grouped into four different categories:

• Category 1: medications with a known, documented risk of causing TdP.
• Category 2: medications with possible risk for TdP based on published reports of QTc prolongation or TdP.
• Category 3: medications to be avoided in patients with congenital long QT patients.
• Category 4: medications unlikely to cause TdP, but have been weakly associated with these events.

This Web site is an excellent resource when trying to learn more about medications at risk, as well as for checking the risks of a specific patient medication profile. It is regularly maintained and updated by a scientific advisory panel.

Published recommendations for appropriate use of agents known to prolong the QT interval routinely suggest a careful analysis of the risk-benefit ratio before starting therapies known to prolong the QT interval to reduce the risk of TdP. This is often a difficult decision for clinicians.

Although routine baseline monitoring is not recommended for the majority of agents, it is wise to review available electrocardiogram data when possible if starting an agent associated with QT prolongation. As always, careful screening for drug-drug interactions is essential to help determine risks associated with the addition of an anti-infective agent. Additional monitoring may be warranted to prevent the occurrence of untoward events.

For more information:

• Owens RC Jr. QT Prolongation with Antimicrobial Agents. Drugs. 2004;64:1091-1124.
• Roden DM. Drug-induced Prolongation of the QT Interval. N Engl J Med. 2004;350:1013-1022.
• Yap YG, Camm AJ. Drug Induced QT Prolongation and Torsades de Pointes. Heart. 2003;89:1363-1372.
• Additional information from the Center for Education, Research and Therapeutics at the University of Arizona is available online at www.torsades.org.