Journal of Antimicrobial Chemotherapy (2002) 49, 593–596

JAC
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 impli-
cated are: the macrolides (erythromycin  clarithromycin
 azithromycin), trimethoprim–sulfamethoxazole, penta-
midine, the azoles and the fluoroquinolones. The fre-
quency with which sparfloxacin has been associated with
TdP—the protoype of the arrhythmias induced by fluoro-
quinolones—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 asso-
ciated 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 demon-
strating 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

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

593
© 2002 The British Society for Antimicrobial Chemotherapy
 Leading article
interval 460 ms, signalling early in the drug’s develop-
ment the potential for life threatening arrhythmias. In a
Phase III trial of therapy of community-acquired pneumo-
nia, 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 chan-
nels (17% inhibition at 10 M, 35% at 30 M and 64% at
100 M). The IC50 IKr (the concentration that inhibits 50%
of the delayed rectifier potassium current) of sparfloxacin
is 0.23 M, compared with 26.5 M for gatifloxacin and
27.2 M 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 com-
pared with ciprofloxacin; ventricular tachycardia appeared
at 300 mg/kg.10 In vitro, HERG assays demonstrated a 15%
inhibition of IKr channel at a concentration of 10 M and
87% inhibition at 300 M.
Levofloxacin
Levofloxacin has been used in 200 million prescrip-
tions, 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, docu-
ment 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 pro-
longation 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 amio-
darone 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 M
594
(12–20 times the therapeutic serum concentration in man),
compared with an effect caused by sparfloxacin that
became evident at a concentration of 10 M.13 In the
guinea pig isolated right ventricular myocyte model, spar-
floxacin, grepafloxacin, moxifloxacin and gatifloxacin at a
concentration of 100 M 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 idioventricu-
lar 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 spar-
floxacin at the same dose decreased the heart rate and pro-
longed 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 con-
comitant sotalol15 or fluconazole (known to prolong the
QT interval), and in a patient with bradycardia, hypo-
magnesaemia 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 M (therapeutic concentration in
humans) was 3.3%, which is comparable to ciprofloxacin,
and not very different at a concentration of 30 M (8.6%),
lower than that of sparfloxacin, grepafloxacin and moxi-
floxacin.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, com-
pared 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
 Leading article
trials, 228 received moxifloxacin concomitantly with
other agents that prolong the QTc interval (amiodarone,
amitriptiline, cisapride clarithromycin, clomipramine, pro-
cainamide, quinidine, quinine, sotalol, terfenadine, etc).
One patient had an arrhythmia associated with a pro-
longation of the QTc interval (compared with none of
199 patients who received the comparator agent). Three of
3780 patients who received moxifloxacin alone had unspeci-
fied 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 thera-
peutic dose, QTc prolongation was 3.71 ms [90% con-
fidence interval (CI) 0.04–7.38].18 Of 137 patients in clinical
trials the mean QTc interval was 5  25.6 ms, with two out-
liers 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 grepa-
floxacin) 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 inde-
595
pendently.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 Foun-
dation), 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 anti-
arrhythmic 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
β-adrenergic stimulators (isoproterenol) or transvenous
cardiac pacing might be needed.
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