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Chapter 26 : QT Prolongation with Quinolone Antimicrobial Agents

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Abstract:

The QT interval is defined as the duration between the beginning of the RS complex and the end of the T wave on the electrocardiogram (ECG). Drug-induced proarrhythmia may be a highly prevalent issue, and it is prudent that all prescribing physicians and their patients should be aware of this risk and take the precautions to minimize proarrhythmia. Although the use of QT dispersion in the assessment of drugs that prolong the QT interval needs further confirmation, it may provide information about the clinical significance of QT prolongation. The risk of QT prolongation and potentially fatal ventricular arrhythmias associated with quinolones was highlighted following the withdrawal of grepafloxacin due to several cases of sudden death and TdP, which were not anticipated during initial drug development. The cardiotoxicity of quinolones as a class remains unclear, in part because of a lack of data, especially on the newer quinolones that are yet to be marketed. What is probably clear now is that fluoroquinolones prolong the QT interval or action potential duration to different degrees, at least in animal models, although some controversy remains whether QT prolongation with quinolones is a class effect. Oral clarithromycin has also been reported to cause QT prolongation, TdP, or ventricular tachycardia in several cases. The risk of QT prolongation and TdP with other less commonly used macrolide antibiotics such as troleandomycin, josamycin, flurythromycin, and ponsinomycin is less clear. Quinolone antibiotics are widely prescribed throughout the world.

Citation: Yap Y, Camm A. 2003. QT Prolongation with Quinolone Antimicrobial Agents, p 421-440. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch26
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Figures

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Figure 1

(A) Self-limiting TdP. (B) TdP leading onto ventricular fibrillation.

Citation: Yap Y, Camm A. 2003. QT Prolongation with Quinolone Antimicrobial Agents, p 421-440. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch26
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Image of Figure 2
Figure 2

Cardiac ionic currents and their relationship to action potential. Modified from reference .

Citation: Yap Y, Camm A. 2003. QT Prolongation with Quinolone Antimicrobial Agents, p 421-440. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch26
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Image of Figure 3
Figure 3

Alteration in action potential with individual blockade of some potassium channels.

Citation: Yap Y, Camm A. 2003. QT Prolongation with Quinolone Antimicrobial Agents, p 421-440. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch26
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Figure 4

Arrhythmogenic mechanism of torsades de pointes.

Citation: Yap Y, Camm A. 2003. QT Prolongation with Quinolone Antimicrobial Agents, p 421-440. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch26
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Image of Figure 5
Figure 5

blockade by quinolones (voltage-clamp study) showing voltage dependence of blockade with sparfloxacin being the most potent blocker, followed by grepafloxacin (equipotency as gatifloxacin) and moxifloxacin. Adapted from reference .

Citation: Yap Y, Camm A. 2003. QT Prolongation with Quinolone Antimicrobial Agents, p 421-440. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch26
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Figure 6

QT prolongation with quinolones (rabbit arrhythmia model) showing sparfloxacin is the most potent in prolonging the QT interval, followed by grepafloxacin (equipotency as gatifloxacin) and moxifloxacin. °, QT; •, QTc. *, < 0.05 of baseline (both QT and QTc). Adapted and modified from reference .

Citation: Yap Y, Camm A. 2003. QT Prolongation with Quinolone Antimicrobial Agents, p 421-440. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch26
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Figure 7

The effects of 10 fluoroquinolone antimicrobial agents at a concentration of 100 µM on action potential duration at 90% repolarization (ADP ) of action potentials recorded from isolated guinea pig right ventricular myocardia ( = 4 to 6; mean ADP in each group shown). This study showed the difference in the potency to prolong QT intervals among various fluoroquinolones. Modified from reference with permission.

Citation: Yap Y, Camm A. 2003. QT Prolongation with Quinolone Antimicrobial Agents, p 421-440. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch26
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Image of Figure 8
Figure 8

The effects of various quinolones on the blockade, action potential prolongation, QT prolongation, and TdP.

Citation: Yap Y, Camm A. 2003. QT Prolongation with Quinolone Antimicrobial Agents, p 421-440. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch26
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Image of Figure 9
Figure 9

The electrocardiogram of a female patient with congenital long QT syndrome with a QTc interval of 573 ms.

Citation: Yap Y, Camm A. 2003. QT Prolongation with Quinolone Antimicrobial Agents, p 421-440. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch26
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Image of Figure 10
Figure 10

Acquired long QT syndrome in a patient with severe hypokalemia (26 mmol/liter). Note the prolonged QT interval of 639 ms and abnormal bizarre TAJ wave.

Citation: Yap Y, Camm A. 2003. QT Prolongation with Quinolone Antimicrobial Agents, p 421-440. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch26
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Figure 11

The preclinical and clinical stages for testing the safety of new active substances (NAS) proposed in the CPMP document. Summary from reference .

Citation: Yap Y, Camm A. 2003. QT Prolongation with Quinolone Antimicrobial Agents, p 421-440. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch26
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Tables

Generic image for table
Table 1

Drugs that can prolong QT interval and TdP

Citation: Yap Y, Camm A. 2003. QT Prolongation with Quinolone Antimicrobial Agents, p 421-440. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch26
Generic image for table
Table 2

Drugs, food, and conditions that can inhibit hepatic cytochrome P450 CYP3A4 enzymic activity

Citation: Yap Y, Camm A. 2003. QT Prolongation with Quinolone Antimicrobial Agents, p 421-440. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch26
Generic image for table
Table 3

Contents in St. George's Hospital advice leaflet on long QT syndrome and websites for checking QT-prolonging drugs

Citation: Yap Y, Camm A. 2003. QT Prolongation with Quinolone Antimicrobial Agents, p 421-440. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch26

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