Cardiotoxicity of fluoroquinolones

Ethan Rubinsteina,* and John Cammb

a Infectious Diseases Unit, Sheba Medical Center, Tel Hashomer 52621, Israel; b St George's Hospital Medical School, Cranmer Terrace, London SW17 0RE, UK

Currently marketed fluoroquinolones enjoy an admirable safety profile that is not matched by any other antibiotic group. The widespread use of fluoroquinolones in the elderly, who are susceptible to cardiac arrhythmias because of underlying heart diseases, metabolic derangement and use of anti-arrhythmic agents and other medications that prolong the QT interval, has raised the issue of the cardiac safety of the newer fluoroquinolones. This issue had been further stressed by the unexpected removal from the market of several fluoroquinolones because of safety issues, including cardiotoxic effects. A recent leading article addressed this issue, and the aim of the present article is to update the reader on this matter.1

How frequent is torsade de pointes (TdP)? A WHO report from 1983–1999 reported 761 cases, with 34 (4.8%) being fatal. Beerman, in Sweden, in a 1 month survey of 32 hospitals serving 4.2 million inhabitants, reported 68 episodes of ventricular tachycardia, of which 14 were TdP. A single case was related to antibiotics, yielding an incidence of TdP of 8.6 cases/10 million individuals. In patients with the congenital form of long QT syndrome (LQTS) the relative risk of sudden death from cardiac arrhythmia for a QTc of 440 ms is 1, for a QTc of 500 ms it is 1.4 and for a QTc of 640 ms it is 2.8.2 Females are more susceptible than males to QTc prolongation caused by drugs, because of the specific regulation by sex hormones of ion channel expression and function.3 Similarly, the elderly are more susceptible than the young.

Fifty drugs have been reported to cause TdP, the most common being: sotalol (rate 1.8–4.8%), cisapride (rate of 1 per 120 000 patients), ibutilide (rate 2–6%) terfenidine and quinidine (rate 2–8.8%).4 A QT prolongation is seen in 31% of patients receiving erythromycin (rate up to 0.4% in high risk patients who receive i.v. therapy), whereas there is only a low rate in patients taking oral erythromycin.5

Among the antimicrobials, those most commonly implicated are: the macrolides (erythromycin > clarithromycin > azithromycin), trimethoprim–sulfamethoxazole, pentamidine, the azoles and the fluoroquinolones. The frequency with which sparfloxacin has been associated with TdP—the protoype of the arrhythmias induced by fluoroquinolones—is 14.5 per million (12 FDC report),6 and the rate for grepafloxacin is 3.8 per million compared with a rate of 1 per million for ciprofloxacin, about 1 per million for levofloxacin and 3 per million for clarithromycin.7

Fluoroquinolones share the potential, as do most other agents that cause QT prolongation, to block the cardiac voltage-gated potassium channels, particularly the rapid component (IKr) of the delayed rectifier potassium current (IK). By doing so, fluoroquinolones usually, but not always, prolong the QT interval, a process that even if subdued may lead to the occurrence of arrhythmia. In addition, they have the potential to interact with other drugs that prolong the QTc interval. It has been shown that the higher the fluoroquinolone dose and serum AUCs, the higher the QT prolongation risk and subsequently the risk of TdP.

It has been shown that the radical in position 5 of the fluoroquinolone ring is responsible for QTc prolongation. Thus, a methyl group at position 5, as in sparfloxacin, is associated with a prolongation of the QTc interval of 14 ms. An amino group at position 5, as in grepafloxacin, is associated with a mean QTc prolongation of 11 ms. A proton (H) at this position is associated with a QTc prolongation of <2 ms for ciprofloxacin, 3 ms for gatifloxacin and 5–6 ms for gemifloxacin, moxifloxacin and levofloxacin.8 It should, however, be noted that only a few of the studies demonstrating these QT prolongations were comparative and performed under the same conditions.

The new fluoroquinolones differ among themselves by several orders of magnitude in their in vitro capacity to block HERG (the human-ether-a-go-go gene), responsible for the IKr, and subsequently for prolonged QT and TdP. The difference between the various members of the group may be larger compared with the effect of this antibiotic class to other drug classes.

Sparfloxacin

In earlier clinical trials (Phase I/II), in a dose-escalating study of 200–800 mg loading dose, followed by doses of 100–400 mg/day, 10% of healthy volunteers showed a QTc interval >460 ms, signalling early in the drug's development the potential for life threatening arrhythmias. In a Phase III trial of therapy of community-acquired pneumonia, QTc prolongation was observed in 2.4% of cases receiving sparfloxacin. Soon after the introduction of the antibiotic into the market, seven cases of cardiac-related adverse events were reported (three cases with ventricular tachycardia with two fatalities), all in patients with risk factors for QTc prolongation. In post-marketing studies there were 145 reports of QT-related events among 49 000 patients (FDA database).7 These clinical results paralleled the in vitro ability of sparfloxacin to inhibit HERG channels (17% inhibition at 10 µM, 35% at 30 µM and 64% at 100 µM). The IC50 IKr (the concentration that inhibits 50% of the delayed rectifier potassium current) of sparfloxacin is 0.23 µM, compared with 26.5 µM for gatifloxacin and 27.2 µM for grepafloxacin.9

Grepafloxacin

Grepafloxacin was removed from the market voluntarily in 1999 due to reports of seven cardiac-related fatalities, of which three were reported as TdP. In the anaesthetized rabbit and dog models, grepafloxacin at a dose of 30 mg/kg i.v. caused more dose-related transient arrhythmias compared with ciprofloxacin; ventricular tachycardia appeared at 300 mg/kg.10In vitro, HERG assays demonstrated a 15% inhibition of IKr channel at a concentration of 10 µM and 87% inhibition at 300 µM.

Levofloxacin

Levofloxacin has been used in >200 million prescriptions, with a remarkable safety record. Fifteen cases of QT-related ventricular arrhythmias or cardiac arrest per 10 million prescriptions have been reported, but without satisfactory details. Data reported to R.W. Johnson Pharmaceutical Research Institute and Ortho-McNeil Pharmaceuticals, the US marketer of levofloxacin, document TdP at a frequency of 1 per million prescriptions, similar to the rate of TdP associated with ciprofloxacin.11 Mean QTc prolongation was measured in 37 patients and averaged 4.6 ms (range 47–92 ms). Risk factors for QTc prolongation in these patients were electrolyte disturbances in eight patients, and in six patients co-administration of trimethoprim–sulfamethoxazole, amiodarone, cisapride or fluoxetine. The frequency of the outliers defined as QTc >60 ms from baseline or >500 ms overall was 3% (one of 37) and 11% (four of 37), respectively. Of four patients with QTc >500 ms, one patient, who took amiodarone concomitantly, developed TdP.12 These clinical data are in accord with animal experiments showing lack of prolongation of the action potential in the rabbit Purkinje fibre model at levofloxacin concentrations of 1–100 µM (12–20 times the therapeutic serum concentration in man), compared with an effect caused by sparfloxacin that became evident at a concentration of 10 µM.13 In the guinea pig isolated right ventricular myocyte model, sparfloxacin, grepafloxacin, moxifloxacin and gatifloxacin at a concentration of 100 µM prolonged the action potential duration by 13–40%, whereas ciprofloxacin, trovafloxacin and levofloxacin prolonged the duration of the action potential by 0.6–3.3%.11 In dogs with a stable idioventricular rhythm, up to 60 mg/kg of oral levofloxacin did not induce any premature depolarization, whereas 60 mg/kg of sparfloxacin administered orally caused TdP in all animals within 24 h. In the anesthetized dog model, levofloxacin 3 mg/kg increased cardiac output slightly, whereas sparfloxacin at the same dose decreased the heart rate and prolonged the effective refractory period.14

Gatifloxacin

Volunteer studies in Phase I/II revealed a mean QTc prolongation of 2.9 ± 16.5 ms. No QTc prolongation was noted in 4000 patients in Phase II/III clinical trials, who had also received agents known to prolong the QT interval, and in patients with hypokalaemia. Among some 1 300 000 patients who received gatifloxacin, TdP was reported in two cases, both occurring in patients who received concomitant sotalol15 or fluconazole (known to prolong the QT interval), and in a patient with bradycardia, hypomagnesaemia and syncope of unknown cause. In 15 752 patients with respiratory tract infection (RTI) enrolled in Phase IV trails, including 4906 patients with underlying cardiovascular diseases, no arrhythmias were reported. In a HERG assay in transfected HEK 293 cells, IKr inhibition at a concentration of 10 µM (therapeutic concentration in humans) was 3.3%, which is comparable to ciprofloxacin, and not very different at a concentration of 30 µM (8.6%), lower than that of sparfloxacin, grepafloxacin and moxifloxacin.16

Moxifloxacin

Like most other new fluoroquinolones, moxifloxacin bears a warning about use in patients with tendency to prolonged QT intervals, either as a result of cardiac disease or a metabolic condition (hypokalaemia), or as a result of use of other agents that prolong the QTc interval. Of 750 patients who had paired ECG tracings, the mean QTc interval prolongation was 6 ± 26 ms in 9.5% of the patients, compared with 9.2% for the comparators.17 Following the i.v. administration of moxifloxacin in a smaller number of patients, mean QTc prolongation was 12.1 ms. Of 6000 patients in Phase II–IV clinical trials, no cardiovascular morbidity attributable to prolongation of the QTc interval was noted. Among patients in Phase II and III clinical trials, 228 received moxifloxacin concomitantly with other agents that prolong the QTc interval (amiodarone, amitriptiline, cisapride clarithromycin, clomipramine, procainamide, quinidine, quinine, sotalol, terfenadine, etc). One patient had an arrhythmia associated with a prolongation of the QTc interval (compared with none of 199 patients who received the comparator agent). Three of 3780 patients who received moxifloxacin alone had unspecified arrhythmias. In post-marketing surveillance, of about 2 million spontaneous reports there was a single reported case of TdP in an elderly female patient with several risk factors for ventricular arrhythmia (hypokalaemia, CAD, digoxin and a pacemaker inserted for a sick sinus syndrome).

Gemifloxacin

Of 119 subjects (including populations at high risk for QT prolongation) receiving a single 320 mg standard therapeutic dose, QTc prolongation was 3.71 ms [90% confidence interval (CI) 0.04–7.38].18 Of 137 patients in clinical trials the mean QTc interval was 5 ± 25.6 ms, with two outliers in the gemifloxacin and comparator group having a QTc interval >500 ms.

BMS-284756

BMS-284756 (garenoxacin) is a des-fluoroquinolone in Phase III clinical trials. No QTc prolongation was noted following 14 days of therapy in 40 volunteers treated with doses of 100–1200 mg daily. Also, in a study with single doses 200–800 mg/day i.v., no changes were observed.19

Conclusions

What are the lessons from all these observations? While prolongation of the QTc interval seems to be a class effect of the fluoroquinolones, there are several-fold differences between the various members of this group. As a whole, the fluoroquinolones that are currently on the market or soon to be launched (excluding sparfloxacin and possibly grepafloxacin) are safe from the point of view of prolongation of the QTc interval, with a frequency of this adverse event occurring at rate of about 1 per million prescriptions. Nevertheless, special attention should be paid to the occasional outlier with an inborn prolonged QTc (LQTS), those with bradycardia (particularly if female),20 those with hypokalaemia or hypomagnesaemia, those with organic heart disease (particularly congestive heart failure), those on anti-arrhythmic agents from class Ia (particularly quinidine) and class III, possibly those with brain lesions (in particular brainstem stroke),21 and those who receive concommitantly drugs that prolong the QTc interval independently.21 In all these patients a fluoroquinolone is better avoided, or, if it is needed, it should be administered under careful and frequent ECG (and Holter monitoring) tracings. If in doubt, physicians are encouraged to consult the internet as an updated source, e.g. http://www.sads.org/ (from the Sudden Arrhythmia Death Syndrome Foundation), http://www.bielnews.ch/cyberhouse/qt/engl/drugs.html (from the LQT European Information Center21) or http://www.qtdrugs.org (from Georgetown University).

To avoid the risk of TdP appearing as a surprise late in the development of the fluoroquinolone, it seems advis-able to screen drugs for their effect on HERG, to include elderly females, and, if ethically appropriate, patients with risk factors for the development of TdP (e.g. LQTS patients, patients with congestive heart failure and on antiarrhythmic agents, and patients with hypokalaemia and hypomagnesaemia) in earlier phases in order to capture early and properly assess the occasional outlier and the risk of TdP appearance, before the marketing stage. If TdP has occurred, the best mode of action is quickly to refer the patient to a hospital in an ambulance equipped with a monitor and defibrillator. A 2 g dose of (10%) magnesium solution should be administered i.v. over a 2 min period (a dose that can be repeated twice).22 Along with magnesium, potassium should be administered i.v. as well to bring the K+ serum concentration to 4.5 mmol/L. If the patient does not respond to these measures, accelerating the pulse with ß-adrenergic stimulators (isoproterenol) or transvenous cardiac pacing might be needed.

Notes

* Corresponding author. Tel: +972-3-5345-389; Fax: +972-3-5347-081; E-mail: unit{at}netvision.net.il or Erubins{at}yahoo.com Back

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