Review
Cardiology 2011;120:103–110
DOI: 10.1159/000334441
QT Prolongation and Torsade de Pointes Induced
by Fluoroquinolones: Infrequent Side Effects from
Commonly Used Medications
Alexandros Briasoulis a Vikram Agarwal a Walter J. Pierce b
a
Department of Medicine and b Al-Sabah Arrhythmia Institute, St. Luke’s Roosevelt Hospital Center,
Columbia University College of Physicians and Surgeons, New York, N.Y., USA
Key Words
Arrhythmia ⴢ Fluoroquinolones ⴢ Moxifloxacin ⴢ
QT prolongation ⴢ Torsade de pointes
Abstract
Although very useful agents, fluoroquinolones are associ-
ated with a number of adverse events, some with consider-
able clinical significance. Prolongation of the QT interval, for
example, is an adverse effect associated with the use of fluo-
roquinolones. Fluoroquinolones prolong the QT interval by
blocking voltage-gated potassium channels, especially the
rapid component of the delayed rectifier potassium current
IKr, expressed by HERG (the human ether-a-go-go-related
gene). According to the available case reports and clinical
studies, moxifloxacin carries the greatest risk of QT prolon-
gation from all available quinolones in clinical practice and
it should be used with caution in patients with predisposing
factors for Torsades de pointes (TdP). Although gemifloxa-
cin, levofloxacin, and ofloxacin are associated with a lower
risk of QT prolongation compared with moxifloxacin, they
should also be used with caution in patients at risk for QT
prolongation. Ciprofloxacin appears to be associated with
the lowest risk for QT prolongation and the lowest TdP rate.
The overall risk of TdP is small with the use of fluoroquino-
lones. Clinicians can minimize that risk by avoiding prescrip-
tions of multiple medications associated with QT-interval
prolongation, especially in high-risk patients.
Copyright © 2011 S. Karger AG, Basel
© 2011 S. Karger AG, Basel
0008–6312/11/1202–0103$38.00/0
Fax +41 61 306 12 34
E-Mail karger@karger.ch Accessible online at:
www.karger.com www.karger.com/crd
Received: August 26, 2011
Accepted after revision: October 10, 2011
Published online: December 13, 2011
Introduction
Cardiac toxicity can occur as an unintended conse-
quence of drug therapy and is considered to be an in-
creasingly important adverse drug reaction.
Torsades de pointes (TdP), a potentially fatal polymor-
phic ventricular tachyarrhythmia (fig. 1), often occurs in
association with a prolonged QT interval or a heart-rate-
corrected QT interval (QTc), and it may present as sudden
death, syncope, dizziness, palpitations, seizures, ventric-
ular tachycardia, or not at all (asymptomatic) if the dura-
tion of TdP is relatively short and terminates spontane-
ously. The incidence of TdP in the general population has
been reported to be 8.6 cases per 10 million people [1].
The QT interval (420–440 ms in males and 440–460
ms in females) encompasses both the depolarization
phase and the repolarization phase of the action poten-
tial. In the absence of intermittent intraventricular con-
duction delays (e.g. intermittent or variable bundle
branch block), changes in the QT interval reflect changes
in cardiac repolarization.
QT prolongation has traditionally been separated into
two general categories: (i) inherited long QT syndrome
(LQTS) and (ii) acquired LQTS, which can be associated
with drug-related risk factors, electrolyte and metabolic
abnormalities, and structural heart disease.
Several antiarrhythmic and non-cardiovascular drug
therapies, including psychotropics, antihistamines, and
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Alexandros Briasoulis, MD
Department of Medicine
St. Luke’s Roosevelt Hospital Center
515 West 59th Street, New York, NY 10019 (USA)
Gazi Üniversitesi
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Tel. +1 212 523 4000, E-Mail alexbriasoulis @ gmail.com, ab3347 @ columbia.edu
Fig. 1. ECG monitoring showing TdP after
a single intravenous dose of moxifloxacin
in a 70-year-old female with coronary ar-
tery disease and 1st degree atrioventricu-
lar block.

Influence phototoxicity and

Metal binding and chelation
genetic toxicity (CH3 > H > H2),
controls interaction with antacids, milk,
cardiotoxicity (NH2 > CH3 > H)
iron; divalent cations
R5 O
Effect of F atom on side
effect profile has not
been reported F COOH

No side effects associated

R7 X8 N R2 with this position

Controls GABA binding,

Fig. 2. Chemical structure of fluoroquino- theophylline interaction Controls R1
lones with structural side effect relation- phototoxicity
Controls theophylline interaction and
ships (reproduced with permission from (C-8 F > C-8 C1
genetic toxicity
> N-8 > C-8 H
the Canadian Journal of Infectious Diseas-
> C-8 OMe)
es and Medical Microbiology).

antimicrobial agents, have been implicated as the causes
for QT-interval prolongation and TdP. Most of the drugs
that have been associated with a prolonged QT interval
or TdP development can also block the rapidly activating
component of the delayed rectifier potassium current
(IKr) in ventricular cardiomyocytes. QT-interval prolon-
gation is a class effect among the fluoroquinolones. Flu-
oroquinolones are among the drugs of choice for the
treatment of common bacterial infections due to their
wide spectrum against respiratory, gastrointestinal, and
genitourinary pathogens. QT prolongation is a class ef-
fect of fluoroquinolones, but there are great differences
between the various members of this group in their pro-
arrhythmic potential. The proarrhythmic side effect of
these antimicrobial agents is receiving more and more
attention since the withdrawal of grepafloxacin and
sparfloxacin from the market due to adverse cardiac
events [2]. Grepafloxacin has been withdrawn because of
prolongation of the QT interval and resultant TdP, and
sparfloxacin because of phototoxicity and QT prolonga-
tion at rather low doses, thus increasing the risk for se-
vere arrhythmia.
The quinolone nucleus consists of a bicyclic ring struc-
ture (fig. 2). There are fluoroquinolone structure-activity
relationships and structure-adverse effect relationships
based on constituents found at specific sites on the qui-
nolone nucleus. All drugs in the class possess a carboxyl
group at position 3, a keto group at position 4, a fluorine
atom at position 6, and either a piperazinyl group or a
methylpiperazinyl group at position 7. No significant in-
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mV
60 Phase 1 (ICa)
Phase 2 (ICa, IKr, IKs)
0
Phase 3 (IKr, IK1)
Phase 0 (INa)
–100
0 100
Fig. 3. Cardiac action potential.
teractions have been associated with positions 1, 2, 3, 4,
6, 7, and 8. Position 5 controls activity against gram-pos-
itive microorganisms and the potential for photosensitiv-
ity and QT prolongation following fluoroquinolone ad-
ministration [3].
It has been suggested that a methyl (grepafloxacin) or
amino (sparfloxacin) substituent located at position 5 on
the quinolone nucleus is associated with greater prolon-
gation of the QT interval than hydrogen atoms at the
same position (ciprofloxacin, gatifloxacin, moxifloxacin,
and levofloxacin; fig. 3) [2]. In vitro studies demonstrated
that sparfloxacin, grepafloxacin, moxifloxacin, and gati-
floxacin blocked HERG (human ether-a-go-go-related
gene) channel currents with clinically relevant IC50 (half-
maximal inhibitory concentration) values, while levo-
floxacin, ciprofloxacin, and ofloxacin required much
higher concentrations to create blockade [4]. The predis-
posing factors to QTc prolongation with fluoroquino-
lones are female gender, structural heart disease, admin-
istration of another QT-interval-prolonging medication
at the same time, reduced drug elimination (due to drug
interaction, renal, or hepatic dysfunction), electrolyte ab-
normalities (hypokalemia, hypomagnesemia, bradycar-
dia, prolonged QTc interval before therapy, and congeni-
tal LQTS (caused by mutations that produce the loss of
function of different K+ currents or gain of function of
Na+ currents). In a recent study, 96% of the 249 previ-
ously published cases of TdP associated with non-cardiac
drugs had at least 1 concomitant risk factor for TdP and
71% had at least 2 predisposing factors [5]. In the present
paper, we will review the current literature on the QT-
interval-prolonging effect of fluoroquinolones based on
the results of case reports, observational studies, and
clinical trials.
Moxifloxacin and Torsade de Pointes
Contribution of Cardiac Potassium Channels to the
Formation of Cardiac Action Potentials
In addition to inward sodium and calcium currents, 5
potassium currents are primarily involved in the genera-
tion of cardiac action potentials [6]: The inward-rectifier
background current (IK1), the rapidly activating and in-
activating transient outward current (Ito), and the ultra-
Phase 4 (IK1)
rapid (IKur), rapid (IKr), and slow (IKs) components of de-
200 ms
layed rectifier currents. IK1 transmits the background po-
tassium current that stabilizes the resting membrane
potential and is responsible for determining the thresh-
old potential for the initial depolarization and final repo-
larization of the action potential (late phase 3). Ito consists
of at least 2 components carrying fast (Ito,f ) and slow (Ito,s)
transient outward currents. They are differentiated on
the basis of the rate of inactivation and its recovery, and
are variably expressed in the myocardium and form the
transmural gradient of repolarization timing. Finally, de-
layed rectifier currents (IK) play a key role in determining
the duration of action potentials and comprise at least 3
components: IKur, IKr, and IKs. They are easily distin-
guished from each other by their pharmacological or bio-
physical properties. IKur is expressed mainly in the atrium
and not in the ventricle, and therefore does not help de-
termine the QT interval [7]. IKr activates rapidly but is
easily inactivated on stronger depolarization (showing a
strong inward rectification). In contrast, IKs activates very
slowly on depolarization compared with other potassium
currents, and therefore its net repolarizing currents can
accumulate, especially at higher heart rates (because of a
shorter diastolic phase) and are greatest at phase 3 of the
action potential [8]. The pore-forming subunit of the
voltage-gated channel has been shown to contain at least
2 highly conserved components: the voltage-sensing part
that surrounds the central pore and the pore domain it-
self. Voltage-gated potassium channels consist of a tetra-
mer of ␣-subunits, each having 6 transmembrane-span-
ning segments [9]. Mutations in these regions may cause
cardiac ion channel diseases by altering channel gating
and ion permeability. KCNH2 encodes the ␣-subunit of
the IKr channel, and membrane depolarization induced
by strong inward currents produces a sequence of confor-
mational changes within the channel that allows potas-
sium ion influx [10].
IKr is rapidly activated by depolarization during the
action potential and thereafter participates in repolariza-
tion during phase 3 of the action potential. IKr is carried
by HERG K+ channel proteins coded by the KCNH2 gene
[11]. The blockade of the HERG-encoded IKr current re-
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sults in the accumulation of potassium within the myo-
cyte, which, in return, delays cardiac repolarization.
Electrical instability that occurs during the repolariza-
tion phase may abruptly reverse its course and depolarize
to produce an early afterdepolarization (EAD) that in
turn may trigger a second action potential. The second
afterdepolarization occurs if the EAD reaches a critical
voltage threshold. If the second action potential excites
the rest of the ventricle, a premature ventricular complex
will appear on the ECG. This pathophysiological process
may be repetitive and self-sustaining, thereby giving rise
to a series of afterdepolarizations that result in a poly-
morphic ventricular arrhythmia referred to as TdP. If
sustained and rapid, TdP can be life-threatening [4].
Pharmacovigilance: Reporting and Monitoring
Drug-Induced QT Prolongation
The exact incidence of specific adverse events is often
impossible to assess, although clues are gathered from
multiple sources. Initial evidence of safety and tolerabil-
ity is obtained from preclinical testing of animals and
from data collected in phase 1–3 clinical studies. After the
approval of an agent for general use, the incidence of spe-
cific adverse events may be gathered from phase 4 post-
marketing studies and from reports to the US Food and
Drug Administration of unusual and serious events.
However, there are many difficulties in collecting accu-
rate safety data. For postmarketing studies, safety moni-
toring is less stringent than it is in phase 1–3 trials, and
data such as laboratory values or electrocardiograms are
not collected as often [12]. In addition, for evaluations of
spontaneous adverse events reported to central databas-
es, reports infrequently contain all of the information
necessary to determine causality, and the reporting of
older agents is usually far less frequent [12].
The mechanism of fluoroquinolone-induced QT-in-
terval prolongation is the reduction in the rapid compo-
nent of the delayed rectifier K+ current (IKr). In the past,
specific studies to determine the proclivity of a drug to
block this current have lacked a uniform methodology
and model, and studies may not have been conducted
prior to the approval of a drug. The International Con-
ference on Harmonization S7B Document has been
developed to provide standards for QT-interval testing
[13]. Published in February 2002, the draft document
recommends that new drugs undergo 3 preclinical tests:
(i) HERG studies, to examine the effect on the IKr current;
(ii) canine Purkinje fiber studies, to determine the effect
106 Cardiology 2011;120:103–110
on the action potential, and (iii) in vivo testing in the ro-
dent model, to establish the effect of the drug on the ECG.
Because the currently marketed quinolones have been ap-
proved before the availability of this consensus docu-
ment, preclinical and clinical studies of QT prolongation
and TdP have not been available, creating concern among
clinicians.
Drug-Induced QT Prolongation
The mechanism by which drugs cause QT prolonga-
tion is almost always blockade of the rapid component of
the delayed rectifier potassium current, IKr [14]. The
KCNH2 channel is blocked by drugs with diverse struc-
tures encompassing many different drug classes. Despite
the important roles of the mutations within KCNQ1,
KCNH2, and SCN5A genes (LQTS1, LQTS2, and LQTS3,
respectively), which account for approximately 90% of ge-
netically defined cases of congenital LQTS, these chan-
nels encoded by those genes are far less susceptible to
block by drugs. Drugs block the KCNH2 channel from its
inner mouth and three mechanisms unique to this chan-
nel probably explain why it is particularly susceptible to
block [14]. (i) The presence of two polar amino acids
(Thr623 and Ser624) in the pore region and two aromat-
ic amino acids (Tyr652 and Phe656) with side chains ori-
ented toward the large central cavity of the pore region
provide high-affinity binding sites for a wide range of
compounds. (ii) The absence of the prolines restricting
access to the drug binding site in KCNH2 is thought to
allow the pore to accommodate channel blockers [15].
(iii) Prolonged exposure to certain medications at thera-
peutic level disrupt KCNH2 channel protein trafficking
resulting in reduced cell surface expression of otherwise
functional channels [16]. IKr block alone is not sufficient
to result in TdP. In experimental settings, prolongation of
repolarization in Purkinje fibers can lead to the develop-
ment of EADs. These represent inward currents and are
thought to result from opening of either L-type calcium
channels or sodium channels. EADs may result in ectopic
beats if the amplitude of the EAD reaches a critical thresh-
old and occurs in a large region of the heart [17]. Trig-
gered upstrokes from EADs in tissue in which repolariza-
tion is sufficiently disturbed are the likely initiating
mechanism for TdP. The development of the EAD and
the triggered activity reflect enhanced inward current
through additional arrhythmogenic mechanisms; most
experiments suggest that these late arrhythmogenic cur-
rents are carried through either L-type calcium channels
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or the sodium-calcium exchanger [18]. Further, abnor-
malities in intracellular calcium handling, such as those
seen in heart failure, can enhance such arrhythmogenic
inward current [19].
The combination of multiple risk factors predisposes
individuals to developing TdP. In the normal ventricle,
there exists virtually no potential for TdP to develop; this
is principally because of the purpose of the repolarizing
currents, particularly the IKr and the slow component of
the IKr, in maintaining a large ‘repolarization reserve’
that encourages electrical stability. However, when mul-
tiple TdP risk factors accumulate [20], the ‘repolarization
reserve’ becomes exhausted, resulting in electrical insta-
bility within the ventricle. TdP risk factors are (i) age and
sex; (ii) underlying cardiac disease; (iii) electrolyte abnor-
malities; (iv) renal and hepatic function impairment, and
(v) IKr blocker or CYP3A4 co-administration.
Although all fluoroquinolones are IKr antagonists, the
potency of IKr blockade and QT prolongation varies in a
dose-dependent fashion. Furthermore, Kang et al. [21]
showed that levofloxacin, ciprofloxacin, and ofloxacin
were found to be significantly less potent inhibitors of
KCNH2 channels compared with sparfloxacin, grepa-
floxacin, moxifloxacin, and gatifloxacin. In a study using
patch clamp electrophysiology, all of the fluoroquino-
lones tested (levofloxacin, sparfloxacin, ciprofloxacin,
gatifloxacin, ofloxacin, grepafloxacin, and moxifloxacin)
were found to inhibit the HERG channel in a dose-depen-
dent manner, although the potencies of each agent dif-
fered markedly. Importantly, even at the high end of clin-
ically inhibitory concentrations, most of the currently
marketed quinolones only minimally inhibit KCNH2
channels. Most HERG IC50 values were far in excess of
typically achievable plasma concentrations for quino-
lones in humans [22]. Moreover, agents that only weakly
inhibited the HERG channel (levofloxacin, ciprofloxa-
cin, and ofloxacin) all lack C5 substituents, whereas spar-
floxacin and grepafloxacin do have such substituents.
Based on the HERG inhibition, the potency of the fluo-
roquinolones in terms of QT-interval prolongation has
the following rank order: sparfloxacin 1 grepafloxacin 1
moxifloxacin 1 gatifloxacin 1 levofloxacin 1 ciprofloxa-
cin 1 ofloxacin [23].
Furthermore, the average QT-interval prolongation
caused by fluoroquinolones (approximately 3–6 months)
has little clinical significance against the normal QT in-
terval [24]. It is thought to be the patients with excessive
QT prolongation (1 440 ms in males, 1 460 ms in females)
who are at most risk of developing TdP. Some fluoroquin-
olones have been withdrawn because of their prolonga-
Moxifloxacin and Torsade de Pointes
tion of the QT interval. Sparfloxacin prolonged QTc by a
mean of 10 ms, but there were no associated clinically
significant cardiac arrhythmias. Because of reported in-
cidents of TdP detected after marketing, sparfloxacin was
withdrawn [25]. Grepafloxacin also prolonged QTc by a
mean of 10 ms and was subsequently withdrawn [26].
Drug-related cardiac events (prolonged QT interval at
low doses) were reported in !1% of patients for both
drugs, increasing the risk for severe arrhythmia.
Pharmacokinetics of Fluoroquinolones
A substrate or inhibitor of cytochrome P450 (CYP) iso-
forms may significantly influence drug exposure under
certain conditions and potentially lead to TdP (for drugs
associated with QT prolongation). CYP3A4 is currently
the most important isoform for serious drug interactions
since it is responsible for metabolism of 150% of all drugs
[27].
Fluoroquinolones do not inhibit CYP3A4, 2C9, and
2C19 cytochromes and are not characterized by nonlin-
ear pharmacokinetics, which differentiates them from
most macrolides, ketolides, and azole antifungal agents.
Ciprofloxacin, which inhibits CYP1A2, is the only excep-
tion [28]; however, this interaction is not associated with
a QT-interval prolongation. All of the currently available
quinolones, regardless of intravenous or oral administra-
tion, produce similar peak concentrations. Thus, unlike
the macrolides, the route of administration is an unlikely
contributor to the development of TdP, unless the intra-
venous formulation is administered too rapidly. In the
case of erythromycin, clarithromycin and azithromycin,
the moderate-to-poor absorption may contribute to the
observed difference in the TdP incidence between intra-
venous and oral formulations of the same drugs.
Clinical Studies Examining the Effect of
Fluoroquinolones on QT-Interval Prolongation
The available evidence from retrospective and ran-
domized prospective studies is inconclusive about the as-
sociation of fluoroquinolones with QT prolongation and
TdP (table 1). A retrospective database analysis evaluat-
ing the reported rates of TdP in patients who received
fluoroquinolones in the USA for the period 1996–2001
showed that 25 TdP cases were associated with fluoroquin-
olone administration during this period. Moxifloxacin
was not associated with any case, whereas levofloxacin
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Table 1. Prospective studies of the effects of fluoroquinolones on QT prolongation and TdP incidence

Study Design n Sample Treatment/dose/route TdP Effects on QTc

characteristics (time after initiation of treatment)

Demolis Randomized 18 healthy Mox. 400 mg p.o. once or none +394 8 33 ms for 400 mg Mox. vs.
et al. [30] controlled volunteers Mox. 800 mg p.o. once vs. +396 8 28 ms for 800 mg Mox. vs.
cross-over trial placebo +379 8 24 ms for placebo p = 0.05 (24 h)
Tsikouris Randomized 13 healthy Mox. 400 mg p.o. once vs. Lev. none ciprofloxacin and Lev. had no effect
et al. [31] open-label volunteers 500 mg p.o. once vs. on QTc, +421 8 19 ms for Mox.
cross-over trial ciprofloxacin 500 mg p.o. twice p = 0.003 (7 days)
Noel Double-blind 47 healthy Mox. 800 mg p.o. once vs. none 16.3–17.8 ms (p < 0.001) for Mox. vs.
et al. [32] randomized, volunteers Lev. 1,000 mg p.o. once vs. 3.5–4.9 ms (p < 0.05) for Lev. vs.
cross-over, four- ciprofloxacin 1,500 mg p.o. 2.3–4.9 ms (p < 0.05) for ciprofloxacin
sequence trial vs. placebo (24 h)
Noel Double-blind 47 healthy single-dose Lev. none no effect with 500 mg Lev., 1.5–3.9 ms
et al. [33] randomized, volunteers 500, 1,000 or 1,500 mg p.o. (p ≤ 0.05) with 1,000 mg Lev., 6.4–7.7 ms
cross-over, four- (p ≤ 0.001) for 1,500 mg Lev., (24 h)
sequence trial
Morganroth Randomized 387 (192 CAP patients Mox. 400 mg i.v./p.o. once vs. Mox.: 0 +6.4 8 23.2 ms for Mox. vs.
et al. [34] controlled on Mox., >65 years with Lev. 500 mg i.v./p.o. once Lev.: 1 –2.5 8 22.9 ms for Lev.
trial 195 on Lev.) cardiac risk patient p = 0.04 (3 days)
factors
Makaryus Randomized 38 CAP or UTI ciprofloxacin 250 mg p.o. twice none no effects (48 h)
et al. [35] controlled patients >65 vs. Lev. 500 mg p.o. once
trial years without
risk factors

CAP = Community-acquired pneumonia; Lev. = levofloxacin; Mox. = moxifloxacin; UTI = urinary tract infection.

was associated with 13 TdP cases, gatifloxacin with 8 cas-
es, ciprofloxacin with 2 cases, and ofloxacin with 2 cases.
Levofloxacin and gatifloxacin were associated with sig-
nificantly higher rates of TdP compared with ciprofloxa-
cin [29].
Prospective randomized studies have shown that
moxifloxacin is related to greater risk of QT prolonga-
tion. In a study conducted in healthy volunteers (n = 18),
a single dose of moxifloxacin 400 mg was shown to pro-
long the QT interval, although the association with TdP
was low [30]. Another study of healthy volunteers also
revealed an association between moxifloxacin intake
and prolongation of the QT interval. In this study, 7-day
treatment with moxifloxacin 400 mg/day was associated
with a significant increase from baseline in the heart-
rate-corrected QT interval (QTc) of 6 ms [31]. In contrast,
neither levofloxacin nor ciprofloxacin were associated
with any changes in the QTc interval. A randomized pro-
spective study conducted by Noel et al. [32] examined the
effect of higher doses of these medications (800 mg mox-
ifloxacin, 1,000 mg levofloxacin, and 1,500 mg cipro-
floxacin) and showed that although all medications in-
creased the QTc interval compared with placebo therapy,
moxifloxacin caused the greatest QT prolongation. In
addition, among 228 patients who received moxifloxacin
concomitantly with other medications that prolong the
QTc interval in phase II and III clinical trials, 1 patient
had an arrhythmia associated with QTc-interval prolon-
gation. A study conducted in healthy volunteers (n = 50)
also failed to show any effect of levofloxacin 500, 1,000,
or 1,500 mg on the QT interval 4 h after treatment, al-
though levofloxacin was associated with dose-depen-
dent increases in heart rate. This study suggests that any
increase in the QT interval with levofloxacin is likely to
be mediated by an effect on heart rate rather than pro-
longation of ventricular repolarization, as seen with oth-
er drugs associated with prolongation of the QT interval.
Notably, in this study, only the 1,500-mg dose was asso-
ciated with a statistically significant effect on the QTc
interval [33].
However, not all studies have shown an association of
moxifloxacin with QT prolongation, with a randomized
controlled trial failing to show any difference in cardiac
rhythm safety between moxifloxacin and levofloxacin in
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elderly patients [34]. It should be noted that this study ex-
cluded patients with known QTc prolongation or those
receiving class IA or III antiarrhythmics.
Overall, neither levofloxacin nor ciprofloxacin appear
to be associated with a clinically significant risk of any
clinically significant increases in QT interval. For exam-
ple, in a prospective study of 38 patients receiving levo-
floxacin or ciprofloxacin at standard doses, average
changes in the longest QT interval of 0.01 and –0.01 s
were seen [35].
Multiple case reports have associated moxifloxacin
with prolonged QT and TdP. Interestingly, previously re-
ported cases of TdP have been induced by intravenous
rather than oral moxifloxacin. However, objective data
are lacking [36–38]. In other case reports, the administra-
tion of levofloxacin concomitant with other medications
that may prolong the QT interval, such as fluoxetine or
fluconazole, caused QTc prolongation and TdP in pa-
tients with multiple risk factors [39–41].
Finally, gemifloxacin, a less commonly prescribed
fluoroquinolone, also caused a slight prolongation of the
QT interval among 6,775 patients who received the rec-
ommended oral dose of this medication (320 mg once
daily) [42].
Ciprofloxacin remains the safest quinolone to date in
terms of TdP risk. A single case of TdP has been reported
to occur in association with ciprofloxacin administration
[43]. When moxifloxacin, levofloxacin, or gemifloxacin
are used, class Ia and III antiarrhythmic agents should be
avoided. In addition, patients with diagnosed forms of
congenital LQTS should avoid the aforementioned fluo-
roquinolones. Since patients with diagnosed LQTS or
those receiving class Ia or III antiarrhythmics are at
greatest risk, careful evaluation of risks versus therapeu-
tic benefits is warranted in selecting an antibiotic with
prolonged QT liability.
Concluding Remarks
Although there is enough evidence regarding the ef-
fect of various fluoroquinolones on QT prolongation, the
sample size of the randomized trials is small and there is
lack of evidence on concomitant use of other medications
that prolong QT in high-risk populations. Based on the
current evidence from preclinical and clinical studies, it
appears that of all the currently available fluoroquino-
lones, including ciprofloxacin, levofloxacin, and moxi-
floxacin, are associated with the greatest risk of develop-
ing QTc prolongation and TdP. However, the overall risk
of TdP is small with the use of fluoroquinolones.
In conclusion, physicians should be aware of the risk
of TdP while prescribing moxifloxacin, particularly in pa-
tients with prolonged baseline QTc intervals and/or mul-
tiple risk factors for the development of TdP. Therefore,
moxifloxacin administration in such patients should be
monitored closely and, if possible, an alternative drug that
does not interfere with the QTc interval should be chosen.
ECG monitoring during initiation of quinolone therapy is
necessary only if there are underlying conditions that pre-
dispose the patient to TdP, or in those patients receiving
concomitant medications that might prolong the QT inter-
val. Finally, more studies are required to identify possible
combinations of fluoroquinolones with medications that
have the greatest proarrhythmic effect, especially medica-
tions that are widely prescribed to high-risk patients.

References
1 Viskin S: Long QT syndromes and torsade de
pointes: Lancet 1999;354:1625–1633.
2 Dupont H, Timsit JF, Souweine B, Gachot B,
Wolff M, Regnier B: Torsades de pointe prob-
ably related to sparfloxacin. Eur J Clin Mi-
crobiol Infect Dis 1996;15:350–351.
3 Domagala JM: Structure-activity and struc-
ture-side-effect relationships for the quino-
lone antibacterials. J Antimicrob Chemother
1994;33:685–706.
4 Kang J, Wang L, Chen XL, Triggle DJ, Rampe
D: Interactions of a series of fluoroquinolone
antibacterial drugs with the human cardiac
K+ channel HERG. Mol Pharmacol 2001; 59:
122–126.
5 Zeltser D, Justo D, Halkin A, Prokhorov V,
Heller K, Viskin S: Torsade de pointes due to
noncardiac drugs: most patients have easily
identifiable risk factors. Medicine 2003; 82:
282–290.
6 Papazian DM, Schwarz TL, Tempel BL, Jan
YN, Jan LY: Cloning of genomic and comple-
mentary DNA from Shaker, a putative potas-
sium channel gene from Drosophila. Science
1987;237:749–753.
7 Nattel S, Yue L, Wang Z: Cardiac ultrarapid
delayed rectifiers: a novel potassium current
family of functional similarity and molecu-
lar diversity. Cell Physiol Biochem 1999; 9:
217–226.
8 Snyders DJ, Tamkun MM, Bennett PB: A
rapidly activating and slowly inactivating
potassium channel cloned from human
heart: functional analysis after stable mam-
malian cell culture expression. J Gen Physiol
1999;101:513–543.
9 Trudeau MC, Warmke JW, Ganetzky B,
Robertson GA: HERG, a human inward rec-
tifier in the voltage-gated potassium channel
family. Science 1995;269:92–95.
10 Jiang Y, Lee A, Chen J, Cadene M, Chait BT,
MacKinnon R: The open pore conformation
of potassium channels. Nature 2002; 417:
523–526.
194.27.18.18 - 5/1/2015 5:55:39 AM

Moxifloxacin and Torsade de Pointes Cardiology 2011;120:103–110 109

Gazi Üniversitesi
Downloaded by:
11 Sanchez-Chapula JA, Ferrer T, Navarro-Po-
lanco RA, Sanguinetti MC: Voltage-depen-
dent profile of human ether-a-go-go-related
gene channel block is influenced by a single
residue in the S6 transmembrane domain.
Mol Pharmacol 2003;63:1051–1058.
12 Shaffer D, Singer S, Korvick J, Honig P: Con-
comitant risk factors in reports of torsades de
pointes associated with macrolide use: re-
view of the United States Food and Drug Ad-
ministration Adverse Event Reporting Sys-
tem. Clin Infect Dis 2002;35:197–200.
13 Safety pharmacology studies assessing the
potential for delayed ventricular repolariza-
tion (QT interval prolongation) by human
pharmaceuticals. International Conference
on Harmonization S7B Document. Wash-
ington, US Food and Drug Administration,
2002.
14 Mitcheson JS, Chen J, Lin M, Culberson C,
Sanguinetti MC: A structural basis for drug-
induced long QT syndrome. Proc Natl Acad
Sci USA 2000;97:12329–12333.
15 Sanchez-Chapula JA, Ferrer T, Navarro-Po-
lanco RA, Sanguinetti MC: Voltage-depen-
dent profile of human ether-a-go-go-related
gene channel block is influenced by a single
residue in the S6 transmembrane domain.
Mol Pharmacol 2003;63:1051–1058.
16 Cordes JS, Sun Z, Lloyd DB, Bradley JA, Op-
sahl AC, Tengowski MW, Chen X, Zhou J:
Pentamidine reduces hERG expression to
prolong the QT interval. Br J Pharmacol
2005;145:15–23.
17 January CT, Riddle JM: Early afterdepolar-
izations: mechanism of induction and block.
A role for L-type Ca 2+ current. Circ Res 1989;
64:977–990.
18 Szabo B, Sweidan R, Rajagopalan CB, Laz-
zara R: Role of Na+:Ca 2+ exchange current in
Ca+-induced early afterdepolarizations in
Purkinje fibers. J Cardiovasc Electrophysiol
1994;5:933–944.
19 Wu Y, Roden DM, Anderson ME: Calmodu-
lin kinase inhibition prevents development
of the arrhythmogenic transient inward cur-
rent. Circ Res 1999;84:906–912.
20 Roden DM: Taking the ‘idio’ out of ‘idiosyn-
cratic’: predicting torsades de pointes. Pac-
ing Clin Electrophysiol 1998; 21:1029–1034.
110 Cardiology 2011;120:103–110
21 Kang J, Wang L, Chen XL, Triggle DJ, Rampe
D: Interactions of a series of fluoroquinolone
antibacterial drugs with the human cardiac
K+ channel HERG. Mol Pharmacol 2001; 59:
122–126.
22 Bischoff U, Schmidt C, Netzer R: Effects of
fluoroquinolones on HERG currents. Eur J
Pharmacol 2000;406:341–343.
23 Lannini PB, Circiumaru I: Gatifloxacin-in-
duced QTc prolongation and ventricular
tachycardia. Pharmacotherapy 2001;21:361–
362.
24 Rubinstein E, Camm J: Cardiotoxicity of
fluoroquinolones. J Antimicrob Chemother
2002;49:593–596.
25 Rubinstein E: Safety profile of sparfloxacin
in the treatment of respiratory tract infec-
tions. J Antimicrob Chemother 1996;37(sup-
pl A):145–160.
26 Wagstaff AJ, Balfour JA: Grepafloxacin.
Drugs 1997;53:817–824.
27 Dresser GK, Spence JD, Bailey DG: Pharma-
cokinetic-pharmacodynamic consequences
and clinical relevance of cytochrome P450
3A4 inhibition. Clin Pharmacokinet 2000;
38:41–57.
28 Owens RC Jr: QT prolongation with antimi-
crobial agents: understanding the signifi-
cance. Drugs 2004;64:1091–1124.
29 Frothingham R: Rates of torsades de pointes
associated with ciprofloxacin, ofloxacin, le-
vofloxacin, gatifloxacin, and moxifloxacin.
Pharmacotherapy 2001;21:1468–1472.
30 Demolis JL, Kubitza D, Tenneze L, Funck-
Brentano C: Effect of a single oral dose of
moxifloxacin (400 and 800 mg) on ventricu-
lar repolarization in healthy subjects. Clin
Pharmacol Ther 2000;68:658–666.
31 Tsikouris JP, Peeters MJ, Cox CD, Meyerrose
GE, Seifert CF: Effects of three fluoroquino-
lones on QT analysis after standard treat-
ment courses. Ann Noninvasive Electrocar-
diol 2006;11:52–56.
32 Noel GJ, Natarajan J, Chien S, Hunt TL,
Goodman DB, Abels R: Effects of three fluo-
roquinolones on QT interval in healthy
adults after single doses. Clin Pharmacol
Ther 2003;73:292–303.
33 Noel GJ, Goodman DB, Chien S, Solanki B,
Padmanabhan M, Natarajan J: Measuring
the effects of supratherapeutic doses of levo-
floxacin on healthy volunteers using four
methods of QT correction and periodic and
continuous ECG recordings. J Clin Pharma-
col 2004;44:464–473.
34 Morganroth J, Dimarco JP, Anzueto A, Nie-
derman MS, Choudhri S, CAPRIE Study
Group: A randomized trial comparing the
cardiac rhythm safety of moxifloxacin vs.
levofloxacin in elderly patients hospitalized
with community-acquired pneumonia.
Chest 2005;128:3398–3406.
35 Makaryus AN, Byrns K, Makaryus MN, Na-
tarajan U, Singer C, Goldner B: Effect of cip-
rofloxacin and levofloxacin on the QT inter-
val: is this a significant ‘clinical’ event? South
Med J 2006;99:52–56.
36 Badshah A, Janjua M, Younas F, Halabi AR,
Cotant JF: Moxifloxacin-induced QT pro-
longation and torsades: an uncommon effect
of a common drug. Am J Med Sci 2009; 338:
164–166.
37 Dale KM, Lertsburapa K, Kluger J, White
CM: Moxifloxacin and torsade de pointes.
Ann Pharmacother 2007;41:336–340.
38 Sherazi S, DiSalle M, Daubert JP, Shah AH:
Moxifloxacin-induced torsades de pointes.
Cardiol J 2008;15:71–73.
39 Samaha FF: QTC interval prolongation and
polymorphic ventricular tachycardia in as-
sociation with levofloxacin. Am J Med 1999;
107:528–529.
40 Gandhi PJ, Menezes PA, Vu HT, Rivera AL,
Ramaswamy K: Fluconazole- and levofloxa-
cin-induced torsades de pointes in an inten-
sive care unit patient. Am J Health Syst
Pharm 2003;60:2479–2483.
41 Nykamp DL, Blackmon CL, Schmidt PE,
Roberson AG: QTc prolongation associated
with combination therapy of levofloxacin,
imipramine, and fluoxetine. Ann Pharma-
cother 2005;39:543–546.
42 Ball P, Mandell L, Patou G, Dankner W, Til-
lotson G: A new respiratory fluoroquino-
lone, oral gemifloxacin: a safety profile in
context. Int J Antimicrob Agents 2004; 23:
421–429.
43 Prabhakar M, Krahn AD: Ciprofloxacin-in-
duced acquired long QT syndrome. Heart
Rhythm 2004;1:624–626.
194.27.18.18 - 5/1/2015 5:55:39 AM
Briasoulis /Agarwal /Pierce
Gazi Üniversitesi
Downloaded by: