Postgraduate Medicine

ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20

Macrolide and fluoroquinolone mediated

cardiac arrhythmias: clinical considerations and
comprehensive review

Elyse Cornett, Matthew B. Novitch, Alan D. Kaye, Chris A. Pann, Harish

Siddaiah Bangalore, Gregory Allred, Matthew Bral, Preya K. Jhita & Adam M.
Kaye

To cite this article: Elyse Cornett, Matthew B. Novitch, Alan D. Kaye, Chris A. Pann,
Harish Siddaiah Bangalore, Gregory Allred, Matthew Bral, Preya K. Jhita & Adam M.
Kaye (2017) Macrolide and fluoroquinolone mediated cardiac arrhythmias: clinical
considerations and comprehensive review, Postgraduate Medicine, 129:7, 715-724, DOI:
10.1080/00325481.2017.1362938

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 POSTGRADUATE MEDICINE, 2017
VOL. 129, NO. 7, 715–724
https://doi.org/10.1080/00325481.2017.1362938

CLINICAL FEATURE
REVIEW

Macrolide and fluoroquinolone mediated cardiac arrhythmias: clinical

considerations and comprehensive review
Elyse Cornetta, Matthew B. Novitchb, Alan D. Kayec, Chris A. Pannd, Harish Siddaiah Bangaloree, Gregory Allredf,
Matthew Bralf, Preya K. Jhitag and Adam M. Kayeh
a
Departments of Anesthesiology and Pharmacology, Toxicology & Neuroscience, LSU Health Shreveport, Shreveport, LA, USA; bMedical College of
Wisconsin, Wausau, WI, USA; cDepartment of Anesthesiology, LSU-Health Science Center-New Orleans, New Orleans, LA, USA; dDepartment of
Molecular & Cellular Biology, College of Science & Mathematics, California Polytechnic State University, San Luis Obispo, CA, USA; eDepartment of
Anesthesiology, LSU Health Shreveport, Shreveport, LA, USA; fDepartment of Anesthesiology, LSU Health Shreveport, Shreveport, LA, USA; gLSU
Health Shreveport, Shreveport, LA, USA; hThomas J. Long School of Pharmacy and Health Sciences, University of the Pacific, Stockton, CA, USA
Downloaded by [University of New England] at 08:07 09 December 2017

ABSTRACT ARTICLE HISTORY

While there is evidence for cardiac arrhythmias associated with macrolide and fluoroquinolone anti- Received 13 April 2017
biotics, there is still debate among health care providers as to whether this risk of arrhythmia is Accepted 31 July 2017
overstated. A joint panel of the US Food and Drug Administration suggested that macrolide and KEYWORDS
fluoroquinolone labels need much stronger warnings regarding the possible serious adverse cardiac Macrolides;
effects associated with these antibiotics, especially since they are so widely prescribed. And while health fluoroquinolones; cardiac
care providers may differ on the pertinence of the cardiac risks associated with antibiotic use, they can arrhythmias; delayed
undoubtedly minimize the cardiac effects that are associated with these antibiotics by paying attention rectifier potassium channels
to the cardiac risk factors and drug history associated with the patient. Relevant studies for our review
were identified from a PubMed search using keywords and combined word searches involving macro-
lides, fluoroquinolones, and cardiac arrhythmias. We attempted to include as many recent (>2015)
articles as possible. We included case reports, randomized, controlled trials, observational studies, case-
control studies, systematic reviews, and retrospective studies. Underlying cardiac issues can predispose
patients to harmful cardiac side effects that can be exacerbated in the presence of antibiotics. The
health care provider should rule out any risk factor associated with antibiotic-induced cardiac arrhyth-
mia in the event that a patient does need a macrolide or fluoroquinolone antibiotic. Rigorous patient
evaluation and a detailed patient history, including short and long term medication use, is the likely key
to reducing any risk of cardiac arrhythmias associated with macrolides and fluoroquinolones. Clinicians
should be cautious when prescribing macrolide and fluoroquinolone medications to patients with risk
factors that may lead to antibiotic-induced cardiac arrhythmias, including a slow heart rate and those
that are taking medications to treat arrhythmias.

1. Introduction
In 2014, one million courses of antibiotics were dispensed in the
USA, which translates to >5 prescriptions written for every six
people in the USA [1]. Interestingly, of these one million written
prescriptions, 30% those were prescribed in an outpatient setting,
meaning the antibiotic was not required or appropriate to treat
the condition [1]. The increase in patient demand for antibiotics to
treat conditions such as a cold or bronchitis, which are viral, not
bacterial, has led to epidemic antibiotic resistance according to
the Centers for Disease Control (CDC) and Food and Drug
Administration (FDA) [2]. Now more than ever, healthcare profes-
sionals see increased incidences of complex side effects associated
with antibiotics, including cardiac arrhythmia and cardiac death
[3]. These side effects are especially associated with macrolide and
fluoroquinolone antibiotics. According to a recent analysis of the
FDA Adverse Event Reporting System (FAERS) from 2004 to 2011,
over 200 reports of azithromycin-associated arrhythmias and sud-
den cardiac deaths resulted in a total of 65 fatalities [2]. A meta-
analysis involving 20,779,963 patients analyzed the risk of death
and cardiac death compared to the survival benefit of antibiotics
revealed that macrolide antibiotics cause 36 additional sudden
cardiac deaths per million treatment courses [4]. Furthermore,
1:8,500 patients will develop a serious arrhythmia or irregular
heartbeat and 1:30,000 will die because of antibiotic treatment [4].
The US FDA suggested that macrolide and fluoroquinolone
labels need much stronger warnings about the possible ser-
ious adverse events of taking a course of these medications
(see Table 1 for the cardiac effects associated with both classes
of drugs). Currently, prolongation of the QTc interval (cor-
rected QT interval, which adjusts the QT interval correctly for
heart rate extremes) is the most serious, especially in those
with prior cardiac pathology, followed by peripheral neuropa-
thy, tendonitis, and tendon rupture. FDA Panel members
called for stronger warnings in 2015, with some even suggest-
ing the risks be called out with a black box warning. Last, the
panel also voted that the benefits and risks of the use of

CONTACT Elyse Cornett ecorne@lsuhsc.edu LSU Health Shreveport, 1501 Kings Highway, Shreveport, LA 71103
© 2017 Informa UK Limited, trading as Taylor & Francis Group
 716 E. CORNETT ET AL.
Table 1. Cardiac side effects associated with each antibiotic discussed in this
manuscript.
Antibiotic Cardiac effect
Macrolides
Azithromycin TdP, QTc prolongation, ventricular tachycardia
Clarithromycin TdP, QTc prolongation, myocardial infarction
Erythromycin IV: delay in repolarization, TdP, QTc prolongation. Oral:
sudden cardiac death
Fidaxomicin None
Telithromycin None. Black-box warning for liver failure.
Fluoroquinolones
Cifprofloxacin Paroxysmal atrial fibrillation, QTc prolongation
Ofloxacin QTc prolongation
Norfloxacin QTc prolongation
Temafloxacin Withdrawn from market (death)
Grepafloxacin Withdrawn from market (death)
Levofloxacin QTc prolongation, polymorphic tachycardia
Sparfloxacin QTc prolongation
Trovafloxacin Restricted use (hepatic eosinophilia)
Moxifloxacin Ventricular arrhythmia, cardiovascular death, QTc
prolongation
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Sparfloxacin QTc prolongation, TdP
fluoroquinolone courses do not justify the currently labeled
indications for the treatment of acute bacterial sinusitis, acute
bacterial exacerbation of chronic bronchitis, chronic obstruc-
tive pulmonary disease, or uncomplicated urinary tract
infection.
However, a 2016 population-based retrospective cohort
study involving older adults (age >65 yr) report by Trac
et al., suggested that the risk of cardiac arrhythmia from
macrolide antibiotic use may have been overstated [5]. The
study included >600,000 seniors who received a new pre-
scription of azithromycin, erythromycin, or clarithromycin
and reported that these patients had no greater increase in
ventricular arrhythmia or cardiac death in the following
30 days after treatment compared to patients who were
prescribed amoxicillin, levofloxacin, or ceftriaxone. The PI
on this study, Dr. Amit Garg, released a statement; ‘we
would recommend the FDA carefully consider all available
evidence, including the findings from this study, to decide
if a change in its warning on macrolide antibiotics and the
risk of ventricular arrhythmia is warranted’ [6]. Moreover, a
2016 bi-national cohort study investigating patients from
Denmark and Sweden found only 66 instances of arrhyth-
mia in 900,000 fluoroquinolone antibiotic courses, which
was equal to the rate of arrhythmia observed in individuals
who were treated with penicillin [7].
Given that both macrolide and fluoroquinolone antibio-
tics have evidence both for and against cardiac effects, we
sought to review the current literature involving macrolide
and fluoroquinolone antibiotics and cardiac side effects.
We conducted a PubMed search using keywords and com-
bined word searches involving macrolides and/orfluoroqui-
nolones, and the following terms in various combinations:
cardiac arrhythmias, cardiac morbidity, cardiac mortality,
antibiotics, genetic factors, elderly, female, QTc prolonga-
tion, history, case study, epidemiology, pathophysiology,
etiology, prevention, and treatment. In this review, we
will outline the cardiac risk factors associated with macro-
lides and fluoroquinolones, how these cardiac effects are
occurring and treatment options that are available. We
included case reports, randomized, controlled trials, obser-
vational studies, case–control studies, systematic reviews,
and retrospective studies. We attempted to use as many
recent (2015) articles as possible, however, if older articles
contained pertinent and useful information they were also
included.
2. Cardiac arrhythmias
An arrhythmia is an abnormal heart rhythm. The four types of
arrhythmias include extra beats, bradyarrhythmias, supraven-
tricular tachycardias, and ventricular arrhythmias [8].
Arrhythmias are classified by rate (tachycardia or bradycardia),
mechanism (triggered, re-entry or automaticity), duration (iso-
lated premature beats, couplets or runs), or by the site of origin
(atrial, junctional, ventricular, or heart blocks) [8]. When a
patient presents with an arrhythmia, an electrocardiogram
(ECG or EKG) will record and plot the electrical activity of the
heart so it can be visualized. The ECG recordings are repre-
sented as a graph of voltage vs. time. Each beat of the heart
will produce a distinct ECG tracing that is labeled at different
peak points with the letters P, Q, R, S, T. In short, the P repre-
sents atrial repolarization, QRS represents ventricular depolar-
ization, and ST represents ventricular repolarization [9]. Most
macrolide and fluoroquinolone-induced arrhythmias affect the
QTc interval. When the QTc interval becomes prolonged, this
can result in a fatal form of polymorphic ventricular tachycardia,
also known as torsades de pointes (TdP) [10]. TdP is the most
common form of heart arrhythmia that is associated with these
antibiotics.
A normal QTc interval for males is 400–440 ms and for
females is 400–460 ms [11]. Abnormal QTc range in males is
450+ms and in females is 470+ms. The FDA’s regulatory gui-
dance states that if a drug results in QTc prolongation of
greater than 10 ms above baseline, it may be of clinical
significance. The FDA also states that if the drug causes QTc
prolongation greater than 20 ms above baseline, there is a
high likelihood that the drug might be pro-arrhythmogenic.
Discontinuation of a drug is recommended if the QTc interval
is prolonged for more than 60 ms above the baseline.
3. Antibiotic-induced cardiac arrhythmia mechanism
of action
Macrolides and fluoroquinolones prolong the QTc interval
via blockade of the rapid component of the delayed rectifier
potassium channel IK (IKr) [12,13]. This channel is important
for regulating ventricular electrical repolarization. The block-
ade occurs through interactions of the drug with the alpha
subunit amino acid residues. These amino acid residues are
indistinct binding sites as there are no specific receptors for
these antibiotics. The gene human ether-a-go-go-related
gene (hERG)1 encodes for IKr and mutations in hERG1 lead
to the type 2 form of congenital long QTc syndrome, LQT2
[13–15].
The IKr regulates the outward flow of potassium ions from
ventricular myocytes, particularly the midmyocardial cells (M
cells). Potassium current flows from the intracellular fluid into
the extracellular fluid and stimulates ventricular repolarization.

However, by obstructing and reducing the outward flow of
potassium, intracellular potassium concentrations are
increased causing an electrical heterogeneity across the ven-
tricular wall [16]. The net outward current prolongs action
potential duration. This delays myocyte repolarization along
with QTc prolongation. Prolongation of the QTc interval leads
to prolongation of the action potentials of ventricular myo-
cytes. This net reduction of outward current and increase of
inward currents occurs during phases II and III of the action
potential [16].
Membrane instability that is predisposed by the diminished
outward net current during repolarization may abruptly halt,
reverse, and depolarize brokering the formation of early-after-
depolarization (EAD) and second action potentials. EADs com-
monly occur in the M cells and Purkinje cells [16]. EAD occurs
by reactivating L-type calcium channel current and sodium-
calcium exchange during the action potential [17]. The second
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action potential (EAD) may excite and induce the surrounding
ventricular myocytes to produce extrasystoles like premature
ventricular complexes (PVC). If this aberrant pathway persists,
it may incite multiple series of EADs via reentry and if the
pathway is fast paced and sustained it may result in poly-
morphic ventricular arrhythmias (TdP) [14,18].
4. Genetic factors and risk factors
Variations of QTc interval function can result from one of the
thousands of inherited genetic mutations [19,20]. In fact, drug-
induced TdP that is not induced by antiarrhythmic drugs is
more likely to occur as a result of gene mutations when
compared to patients that have multiple risk factors [21].
Mutations in the genes that encode the IKr channel subunits,
KCNH2 and KCNQ1, are the most common mutations asso-
ciated with a genetic susceptibility to drug-induced QTc pro-
longation [22,23]. However, not every patient with this
mutation experiences a prolonged QTc interval after taking a
course of antibiotics. This suggests that additional patient-
specific variables are important in the occurrence of arrhyth-
mias [24]. Furthermore, although macrolides and fluoroquino-
lones can cause arrhythmia, they are relatively weak IKr
blockers and therefore, when young patients with no high-
risk factors present with QTc prolongation or antibiotic-
induced TdP, there is evidence that a subclinical disease may
be present [25,26].
Another genetic risk factor for QTc prolongation and
arrhythmia is female sex [25]. Interestingly, 86.5% of women
with antibiotic-induced TdP also have other risk factors for
arrhythmias and women are prescribed more drugs associated
with QTc prolongation than men [25,27]. Moxifloxacin and
levofloxacin also induce greater QTc prolongation in women
compared to men [28]. A 2014 review of 29 cases (22 women,
7 men) involving erythromycin, QTc prolongation and TdP
showed that there was no significant relationship between
dose and QTc duration, but there was a significant relationship
between erythromycin-induced QTc and TdP with female sex,
heart disease, and old age, particularly when comorbid with a
severe illness, and substrates or inhibitors of CYP3A [29]. There
were similar risk factors cited for clarithromycin-induced QTc
prolongation and TdP [30].
POSTGRADUATE MEDICINE 717
Finally, most drug-induced arrhythmias are associated with
at least one risk factor for TdP [25]. A retrospective review of
249 cases of TdP associated with the administration of fluor-
oquinolones reported 96% of patients had at least 1 predis-
posing factor for TdP, and 71% had at least 2 risk factors,
including electrolyte abnormalities, bradycardia, cardiovascu-
lar disease, female sex, administration of another fluoroquino-
lone [31]. Furthermore, 74.3% of TdP cases have two or more
risk factors, with structural heart disease (heart failure and left
ventricular hypertrophy) being the most frequent-acquired
risk factor in antibiotic-induced TdP cases [25]. Antibiotic-
induced arrhythmias are also increased by the co-administra-
tion of Type Ia or III antiarrhythmic agents or with other drugs
that prolong the QTc interval or have competitive metabolic
routes [32]. Additionally, electrolyte disturbances, hypokalemia
(low potassium), and hypomagnesia (low magnesium) [31] can
also increase the risk of arrhythmias [32,33]. A summary of
these risk factors can be found in Table 2.
5. Antibiotic dose duration
There is evidence to suggest that cardiac side effects can
develop independently of the duration of the course of anti-
biotic. A 2015 case report review of the cardiac effects of
azithromycin (4 studies) and levofloxacin (2 studies) all had a
treatment duration of 1–10 days, with one study up to 35 days
[3]. Of the azithromycin case reports, two reported cardiovas-
cular death, one reported cardiac arrhythmia [34] and one
reported any cardiovascular event including heart failure,
myocardial infarction, and cardiac arrhythmia. The levofloxacin
studies reported cardiovascular death and cardiac arrhythmia.
All of these cases were short-term (i.e. ~30 days) treatment
with antibiotics except for the study with 35 days of treat-
ment. There is also a case report involving an elderly female
patient who presented with a fever and 3–4 days of feeling
unwell, was taking 40mg daily citalopram, and had a subse-
quent diagnosis of pneumonia. The patient died several days
after being switched to a course of azithromycin and ceftriax-
one antibiotics [35] and the death was likely due to prolonged
QTc syndrome secondary to citalopram and azithromycin.
Table 2. Risk factors associated with macrolide and fluoroquinolone-induced
arrhythmias and possible course of action.
Risk factor Course of action
Antiarrhythmic medication therapy Detailed patient history, antibiotic
with least risk
Bradycardia IV isoproterenol or a transvenous
pacemaker
Cardiovascular disease Detailed patient history, antibiotic
with least risk
Electrolyte abnormalities Salinated IV fluids
Female sex Detailed patient history, antibiotic
with least risk
Genetic mutation (IKr channel subunit Macrolide>Fluoroquinolone
mutations)
Hypokalemia Serum magnesium and potassium
Hypomagnesia Serum magnesium and potassium
Long-term antibiotic therapy No additional antibiotics
Old age Detailed patient history, antibiotic
with least risk
Structural heart disease (congenital) Detailed patient history, antibiotic
with least risk
 718 E. CORNETT ET AL.
There is limited information on the effects of long-term
antibiotic treatment and arrhythmia. A 2015 case report pre-
sented a male patient who took levofloxacin for up to
3 months, which was beyond the duration of the prescription.
The patient developed a sudden onset of palpitations and
shortness of breath that dissipated upon discontinuation of
the antibiotic [36]. It has also been suggested that cystic
fibrosis patients on long-term azithromycin therapy be mon-
itored throughout their course of treatment for potential QTc
prolongation [37]. Precaution should be taken with both short-
term antibiotic use, even as short as one day of treatment with
an antibiotic, and long-term antibiotic use, especially if the
patient has any of the aforementioned risk factors.
6. Specific cardiac effects of macrolides
Macrolide antibiotics are polyketides that are used to treat
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tonsillitis, pneumonia, psoriasis that has become infected, gin-
givitis, and sexually transmitted infections such as chlamydia.
Macrolides can be used preventatively against certain bacterial
infections, for example, after a splenectomy and are also use-
ful as an alternative antibiotic in those patients who are
allergic to penicillin. We will discuss the US FDA-approved
macrolides and their cardiac side effects, or conflicting views
in the section below. A full list of commonly prescribed macro-
lides can be found in Table 3.
6.1. Azithromycin
6.1.1. Cardiac effects
In 2013, the FDA warned that azithromycin was related to ‘abnor-
mal changes in the electrical activity of the heart that may lead to
a potentially fatal irregular heart rhythm’ and highlighted that
those with a previous diagnosis of general heart pathology,
especially arrhythmia, were at particularly increased risk. These
included histories of QTc interval prolongation, slower than nor-
mal heart rate, low blood levels of potassium or magnesium, and
those who use drugs to treat abnormal heart rhythms [38]. The
FDA’s Adverse Event Reporting System (AERS) included azithro-
mycin associated TdP in approximately 20 different reports [39].
In the January 2013, a randomized, placebo-controlled parallel
trial by Pfizer examined 116 healthy controls receiving 1000 mg
of chloroquine alone or in combination with increasing doses of
azithromycin (500, 1000, and 1500 mg daily). Coadministration of
azithromycin increased QTc interval, and there was a perfect
correlation between azithromycin dose and QTc interval increase
in the dose range 500 mg (10 ms) to 1500 mg (14 ms) [40]. A
separate study by Ray et al., described below, reported up to a
Table 3. List of commonly prescribed macrolides in the USA.
FDA approved Non-FDA approved
Azithromycin Carbomycin A
Clarithromycin Josamycin
Erythromycin Kitasamycin
Fidaxomicin Midecamycin
Telithromycin Oleandomycin
Roxithromycin
Solithromycin
Spiramycin
Troleandomycin
4% increase in the risk of arrhythmia-related death when taking
azithromycin [41]. Additionally, several articles report instances
of previously healthy patients with normal QTc intervals that had
azithromycin-related adverse cardiac effects, including pro-
nounced QTc interval prolongation, ventricular tachycardia in
the absence of QTc interval prolongation, and TdP [42–44].
Ray et al. 2012 examined a Tennessee Medicaid patient cohort
during 5 days of therapy with either azithromycin, no antibiotics
(control) or alternative antibiotics such as amoxicillin, ciprofloxa-
cin, or levofloxacin. The study reported that 5 days of azithromycin
therapy was associated with a small increase in cardiovascular
deaths (47 additional cardiovascular deaths per 1 million courses
of treatment) especially among patients with high risk of cardio-
vascular disease when compared to amoxicillin [41]. This was
comparable to the risk with levofloxacin use. The same study
concluded that the use of amoxicillin and ciprofloxacin did not
increase the risk of cardiovascular deaths in elderly. This study
received considerable media and internet coverage, including an
article in the New York Times® [45], since azithromycin is a widely
prescribed antibiotic for respiratory and urinary tract infections in
young and elderly patients. Similarly, a case report from the ISMP
Canada Safety Bulletin involving an elderly female patient who
presented with a 3–4-day fever was taking 40 mg daily citalopram,
and a subsequent diagnosis of pneumonia, died one day after
being switched to a course of azithromycin and ceftriaxone anti-
biotics [35]. The death was likely due to prolonged QTc syndrome
secondary to citalopram and azithromycin.
6.1.2. No cardiac effect
Interestingly, a subsequent nationwide historical cohort study
by Svanstrom et al. and the Danish Medical Research Council
found no evidence of increased risk of cardiovascular deaths
with azithromycin compared to penicillin [46]. Another pro-
spective study by Strle et al. did not find any increased risk of
cardiovascular events with azithromycin use nor any associa-
tion of QTc prolongation with azithromycin use [47]. Patients
in the study done by Ray et al. and the majority of case report
patients were elderly with multiple comorbidities such as
heart failure, hypertension, diabetes, and were taking multiple
medications. The studies by Svanstrom et al. and Strle
included healthier younger patients who had fewer comorbid-
ities and were on fewer medications.
6.2. Clarithromycin
6.2.1. Cardiac effect
A 2013 case report review of 15 women, 5 men, and 1 boy
investigated the relationship between clarithromycin, pro-
longed QTc, and TdP [30]. Among the 17 adults that devel-
oped TdP, there was no significant relationship between
clarithromycin dose and QTc interval duration. Eight adult
subjects had three major risk factors including female sex,
old age, and heart disease. 14 of the 20 adults had at least
two major risk factors. All patients that developed TdP had at
least two risk factors, and three patients in this study were
diagnosed with congenital long QT syndrome [30]. This study
suggests that risk factors associated with QTc prolongation are
important in determining if a patient will develop an antibio-
tic-induced arrhythmia.

A population-based study comparing the cardiovascular
outcomes of adults aged 18+ in Hong Kong receiving oral
clarithromycin or amoxicillin reported an increased risk of
myocardial infarction, arrhythmia, and cardiac mortality in
the clarithromycin-treated group [48].
6.2.2. No cardiac effect
A 2017 retrospective cohort study of patients >35 years in the
UK found that the cardiovascular risk associated with clarithro-
mycin used to treat respiratory infections was no greater than
any other antibiotics [49].
6.3. Erythromycin
Erythromycin has different cardiac effects when administered
orally vs. IV, although both can result in cardiac side effects.
The recommended dosages of erythromycin rarely induce a
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significant IKr blockade. However, a rapid intravenous infusion
can cause a significant delay in repolarization [50]. A 2002 FDA
report showed that erythromycin caused nearly 50% of the
macrolide-induced TdP [51] and of these cases more than half
were administered via intravenous injection. Oral administra-
tion of erythromycin is linked to sudden cardiac death [52]. A
separate cohort study of 1,249,943 person-years of follow-up
and 1476 confirmed cases of sudden cardiac death reported a
twofold increase in the risk of cardiac death in patients taking
erythromycin compared to patients not taking antibiotics [52].
They reported a fivefold increase in the risk of sudden cardiac
death when patients were coadministered with erythromycin
and a CYP3A4 inhibitor and that IV administration of erythro-
mycin is more likely to cause QTc prolongation and TdP than
oral administration.
6.4. Fidaxomicin
Fidaxomicin is a novel macrolide antibiotic and is FDA
approved to treat diarrhea in adults. A 2012 safety report
review of clinical trials and nonclinical studies reported that
neither fidaxomicin nor its primary metabolite (OP-1118) had
an inhibitory effect on the hERG channel current [53,54]. They
also reported no significant changes in ECG patterns, no QTC
interval modifications and no association between QTc inter-
val prolongation and fidaxomicin level.
6.5. Telithromycin
Telithromycin is a novel ketolide antimicrobial used to treat
pneumonia [54]. A 2003 double-blind, placebo-controlled,
crossover study investigated 17 men and 17 women to assess
the effect of various oral doses of telithromycin on QT inter-
vals. The study reported no difference between placebo and
telithromycin, even up to 2400 mg which was three times the
clinical therapeutic dose [55]. Similarly, a 2005 two-period,
double-blind, randomized study investigated 24 women that
received either sotalol (antiarrhythmic agent) + placebo or
sotalol + telithromycin to measure the effect of this drug
combination on QTc interval prolongation [56]. Compared to
sotalol alone, the mean QTc interval decreased in subjects
taking sotalol + telithromycin. There did not appear to be a
POSTGRADUATE MEDICINE 719
synergistic effect of sotalol and telithromycin on QTc interval
prolongation. And while these noncardiac effects of telithro-
mycin seem promising, the FDA has issued a black-box warn-
ing against telithromycin due to liver failure as a side
effect [57].
7. Specific cardiac effects of fluoroquinolones
Fluoroquinolones are a class of synthetic broad-spectrum anti-
biotics that belong to the quinolone family [58]. Quinolones
are effective at preventing bacterial DNA from unwinding and
replicating, thus exerting an antibacterial effect against bron-
chitis, pneumonia, urinary tract infections, sinusitis, gynecolo-
gical infections, bacterial gastroenteritis, and pelvic
inflammatory disease. A list of commonly prescribed fluoro-
quinolones can be found in Table 4.
In healthy individuals, fluoroquinolones prolonged QTc
intervals from 0 to 17.8 ms [59,60]. In patients with the risk
factors mentioned earlier in this manuscript, cardiovascular
mortalities are more likely to occur, specifically with grepa-
floxacin. Grepafloxacin and sparfloxacin delay repolarization
more than gatifloxacin, levofloxacin, and moxifloxacin.
Ciprofloxacin and ofloxacin have the least effect on the IKr
channel and thus, QTc prolongation [61].
Unlike macrolides, fluoroquinolones are divided into four
categories, first, second, third, and fourth generation. For each
generation, we will discuss important information about the
each category as a whole and discuss specific drugs of impor-
tance when necessary.
7.1. First-generation fluoroquinolones
These fluoroquinolones have largely been replaced by fourth-
generation fluoroquinolones. The first-generation quinolones
tend to have low bioavailability and achieve minimum serum
levels [62].The newer fluoroquinolones (second, third, and
fourth generations) have broad-spectrum bactericidal activity,
are safely tolerated, and good oral bioavailability. These first-
generation fluoroquinolones also need frequent dosing.
Because of this need for frequent dosing, there is also an
increased risk of the development of bacterial resistance,
which is another concern of the use of antibiotics [63]. If
these drugs are prescribed, it is usually to treat a noncomplex
urinary tract infection [62]. Cinoxacin, in particular, is discon-
tinued for use in the USA and the UK. Since these drugs are
rarely prescribed, there is limited information regarding the
Table 4. A list of common fluoroquinolones prescribed in the USA. Second-
generation fluoroquinolones are the most commonly prescribed.
First generation Second generation Third generation Fourth generation
Cinoxacin Ciprofloxacin Balofloxacin Clinafloxacin
Nalidixic acid Enoxacin Grepafloxacin Gatifloxacin
Oxolinic acid Fleroxacin Levofloxacin Gemifloxacin
Piromidic acid Lomefloxacin Pazufloxacin Moxifloxacin
Pipemidic acid Nadifloxacin Sparfloxacin Sitafloxacin
Rosoxacin Norfloxacin Temafloxacin Trovafloxacin
Ofloxacin Tosufloxacin Prulifloxacin
Pefloxacin
Rufloxacin
 720 E. CORNETT ET AL.
cardiac effects of these drugs. Furthermore, none are listed on
the QTdrugs lists maintained by CredibleMeds® [64].
7.2. Second-generation fluoroquinolones
These medications have increased gram-negative and sys-
temic activity. Compared to the first-generation medications,
these drugs have broader clinical applications including urin-
ary tract infections, sexually transmitted infections, skin infec-
tions, and some types of pneumonias [62]. Both ciprofloxacin
and ofloxacin are the most widely used second-generation
fluoroquinolones [62]. Ofloxacin and norfloxacin are both on
the CredibleMeds® QTdrugs list [64], indicating they are asso-
ciated with QT prolongation. Ciprofloxacin has been asso-
ciated with paroxysmal atrial fibrillation in a 61-year-old male
being treated for a urinary tract infection [65] and acquired
long QT syndrome in a 70-year-old female patient on antiar-
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rhythmic therapy [66].
7.3. Third-generation fluoroquinolones
These drugs have broad gram-positive and atypical pathogen
activity, as well as some broad gram-negative bacteria cover-
age. Of the third-generation drugs, grepafloxacin and tema-
floxacin are associated with the most cardiovascular side
effects. Temafloxacin was withdrawn from the US market in
1992 after causing death in three patients [67]. Grepafloxacin
was also withdrawn from the market due to severe cardiovas-
cular effects that developed after broad clinical use including
QT prolongation and sudden cardiac death [68]. Additionally,
levofloxacin and sparfloxacin are listed on the CredibleMeds®
QTdrugs list [64]. Levofloxacin is associated with QT prolonga-
tion and polymorphic tachycardia [69].
7.4. Fourth-generation fluoroquinolones
These drugs have significant anaerobic activity and have simi-
lar indications to first-, second-, and third-generation fluoro-
quinolones (except urinary tract infections and pyelonephritis)
including intra-abdominal infections, pelvic infections, and
nosocomial pneumonia [62]. Trovafloxacin use was halted
after widespread side effects including hypoglycemia and
hepatic eosinophilia [70]. Therefore, the USA and Canada
have restricted the use of trovafloxacin to serious or life-threa-
tening infections [71]. Moxifloxacin is associated with
increased risk of ventricular arrhythmia and cardiovascular
death compared to amoxicillin-clavulanate treatment in a
2015 population-based study of 10,684,100 Taiwanese
patients [72]. A separate 2001 study investigated a clinical
trial and post-marketing data for moxifloxacin [73]. This
study included over ten million patients and reported three
cases of TdP. All three cases had known risk factors for anti-
biotic-induced arrhythmia including old age, female sex, com-
plex cardiological and pharmacological history, cardiac disease
and contaminant medications (Bayer AG®) [73]. The same
group presented a research abstract that included over 2600
patients in clinical trials that had a mean QTc prolongation of
6 ms, which is considered to be significant [74]. Of all the
fluoroquinolones, moxifloxacin has the greatest association
with QTc prolongation. It should be used with extreme cau-
tion in patients with risk factors for TdP [75].
Sparfloxacin has also been associated with cardiac effects.
A phase I/II clinical trial dose-escalation study of 200–800
loading dose followed by 100-400 mg daily dose, reported
that 10% of healthy volunteers developed heart arrhythmia
that was preceded by a QT interval of >460 ms [76]. It has also
been recommended that sparfloxacin not be administered to
patients with known QTc interval prolongation or to patients
receiving simultaneous pharmacotherapy that might induce
bradycardia or promote Torsade de pointes [77]. Finally, an
analysis of 605,127 patients receiving fluoroquinolone treat-
ment for infections of the respiratory system reported that
1838 cases resulted in a serious arrhythmia [78]. The rate of
serious arrhythmia was elevated with current fluoroquinolone
use, with gatifloxacin being the highest relative risk (7.38)
while moxifloxacin and ciprofloxacin both had increased rela-
tive risks (3.3 and 2.15) although smaller than gatifloxacin.
Surprisingly, levofloxacin (third generation) was the only fluor-
oquinolone that did not increase the rate of serious arrhyth-
mia, which is contradictory to previous reports in this
manuscript which suggest that levofloxacin does increase
risk of cardiac arrhythmia.
7.4.1. No cardiac effect
As mentioned in the introduction, a 2016 cohort study com-
paring 909,656 courses of fluoroquinolones to 909,656 courses
of penicillin did not show an increase in the fluoroquinolone
group compared to the penicillin group for serious arrhythmia
[7]. Most patients in the fluoroquinolone group were taking
ciprofloxacin (83%), a second-generation fluoroquinolone,
which has been previously shown to have a lesser risk of
serious arrhythmias in other studies [61]. Therefore, it is pos-
sible that the observed risk was lower than the actual value
with other fluoroquinolones. Overall, there is evidence both
for cardiac effects and lack thereof with macrolides, whereas
with fluoroquinolones most second-, third-, and fourth-gen-
eration medications have some risk of cardiac effects (Table 5).
8. Overall treatment
Treatment for acute antibiotic-induced TdP in a patient that is
hemodynamically unstable is prompt nonsynchronized elec-
tric defibrillation [79,80]. If the patient is hemodynamically
stable and the QTc interval prolongation has only begun to
emerge on the EKG, the healthcare provider should discon-
tinue the offending drug(s). If the patient is on several QTc
prolonging medications the medications most associated with
QTc prolongation should be discontinued first. Next the
healthcare provider should correct the electrolyte abnormal-
ities and administer intravenous magnesium sulfate 1–2 g over
~15 min [81]. Other drugs that are known to prolong the QTc
interval should also be discontinued immediately [81]. Serum
magnesium and potassium should be replaced if the patient is
hypokalemic or hypomagnesemic [82]. If patients do not
respond to IV magnesium, IV isoproterenol or a transvenous
pacemaker (to induce rapid overdrive pacing) may be used,
especially if the TdP is induced by bradycardia [83,84].
 POSTGRADUATE MEDICINE 721

Table 5. A synopsis of all the major manuscripts and studies that were discussed in this review.
Authors Year Type of study Drug Treatment duration Cardiovascular complications
Lu et al. 2015 Case report review Azithromycin na Yes
Levofloxacin na Yes
Okeahialam B 2015 Case report Levofloxacin 3 months Yes
ISMP Canada 2014 Safety Bulletin Azithroycin + several days Yes, death
Ceftiraxone
Hancox et al. 2013 Randomized, placebo-controlled parallel trial Azithromycin daily Yes
Ray et al. 2012 Cohort study Azithromycin 5 days Yes
Amoxicillin 5 days No
Cifprofloxacin 5 days No
Svandstrom et al. 2013 Nationwide historical cohort study Azithromycin na No
Strle et al. 2002 Prospective Azithromycin na No
Vieweg et al. 2013 Case report review Clarithromycin na Yes
Wong et al. 2016 Population-based study Clarithromycin na Yes
Amoxicillin na No
Berni et al. 2017 Retrospective cohort study Clarithromycin na No
Shaffer et al. 2002 Review of FDA report Erythromycin na Yes
Ray et al. 2004 Cohort study Erythromycin na Yes, sudden cardiac death
Weiss et al. 2012 Safety report of clinical trials Fidaxomicin na No
Hagberg et al. 2003 Double-blind, placebo-controlled, crossover Telithromycin na No (liver failure)
study
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Demolis et al. 2005 Two-period, double-blind, randomized study Telithromycin na No (liver failure)
Noel et al. 2003 Clinical trial Moxifloxacin na Yes
Anderson et al. 2001 In Vitro Ciprofloxacin & na No
Ofloxacin
CredibleMeds 2014 Report Ofloxacin and na Yes
norfloxacin
World Health 1999 Report Grepafloxacin na Yes, death
Organization
Samaha FF 1999 Letter to the Editor Levofloxacin 500/day for Yes
5 days
Chou et al. 2015 Population-based study Moxifloxacin na Yes
Iannini et al. 2001 Clinical trial and post marketing data review moxifloxacin na Yes, use with extreme
caution
Owens RC. 2001 Phase I/II clinical trial dose-escalation study Sparfloxacin na Yes
Ball P. 2000 Review Sparfloxacin na Yes
Lap et al. 2012 Population-based study Gatifloxacin na Yes
Inghammer et al. 2012 Cohort study Ciprofloxacin na No
Cardiovascular complications are noted with either a ‘yes’ or ‘no’ and if any pertinent additional information is necessary we have included that as well (e.g. death).

9. Clinical considerations
There are several suggestions regarding how to decrease the
potential risk for cardiac arrhythmia in the general and high-risk
populations while taking a course of these medications.
Obtaining an ECG on patients solely with high-risk factors may
efficiently reduce the risk of serious cardiac arrhythmia [85,86].
One group examined the rates of serious cardiac arrhythmia and
cardiovascular death while taking azithromycin, combined with
excluding patients who had histories of episodes of hypokale-
mia, a family history of long QTc syndrome, evidence of heart
failure, and use of other medications known to prolong the QTc
interval. The result was an exclusion of 113 of the 1,577 subjects
in their trial outright. With this method, after 1 year of the use of
azithromycin, only one cardiovascular death occurred in each
treatment group (0.18%) where total mortality was 3.1% in sub-
jects with azithromycin, and 3.5% in the placebo group [87,88].
This screening method is cost effective, as taking a patient
history is a routine procedure done at each medical exam.
Healthcare providers may also consider choosing a com-
pound that has a lower association with cardiac arrhythmia. As
previously discussed, gatifloxacin and moxifloxacin have been
found to have moderate effects, while sparfloxacin and grepa-
floxacin have the most potent inhibitory effects on potassium
channels [77,89]. Some fluoroquinolones are associated with
less of a relative risk for arrhythmias including ciprofloxacin
and in some cases, levofloxacin, although most reports sug-
gest that levofloxacin increases risk of arrhythmia [89–91].
Some other important drug interactions that healthcare pro-
viders should be wary of include most antipsychotics and
amiodarone, with amiodarone being the most frequently
reported accompanying drug in antibiotic-related arrhythmia
reports [27,92]. Several explanations have been offered for
these sorts of interactions, particularly the metabolic pathways
for most of these medications meeting in the liver by the
cytochrome P450 system, and also having metabolites that
are active potassium channel inhibitors [93]. Other drugs that
directly inhibit CYP3A, such as nitroimidazole antifungals, dil-
tiazem, verapamil and troleandomycin should also be avoided
as the risk of sudden cardiac death is five times higher with
these drugs in the presence of erythromycin (oral erythromy-
cin and the risk of sudden death from cardiac causes).
Last, implementation of consistent automated alerts in
electronic prescribing systems would likely help prevent
the overprescription of antibiotics to patients. This alone
could stop patients from trying to access drugs from multi-
ple doctors and not following drug compliance [94].
Overall, with the many conflicting studies about QTc prolon-
gation and antibiotic use, it is recommended that healthcare
providers exercise caution when prescribing macrolides or fluor-
oquinolones to patients with following characteristics [95,96]:
 722 E. CORNETT ET AL.
(1) History of known congenital long QTc syndrome, TdP,
bradyarrhythmias,
(2) Electrolyte abnormalities (hypomagnesemia,
hypokalemia)
(3) Heart failure or history of heart disease
(4) Patient has a history of antiarrhythmic drugs (quinidine,
procainamide, amiodarone, ibutilide)
(5) Patients taking drugs which are known to prolong QTc
interval (chloroquine, terfenadine, droperidol, haloper-
idol, methadone, ciprofloxacin, levofloxacin, erythromy-
cin, moxifloxacin)
10. Conclusions
Although some research is confounding, there is a definite
Downloaded by [University of New England] at 08:07 09 December 2017
relationship between macrolide and fluoroquinolone antibiotics
and cardiac side effects. The prevention of cardiac effects starts
with the healthcare provider. Before prescribing a macrolide or
fluoroquinolone, it should be determined if the patient is taking
a drug which possesses QTc prolongation or has any of the risk
factors discussed in this manuscript. While new technology,
including pharmacy prescription drug databases, can help to
prevent the overprescription or unnecessary prescription of
antibiotics, it should remain the priority of the health care
provider to be aware of these side effects and to educate their
colleagues, staff, and patients of the potentially serious effects.
Prescreening patients, taking a detailed patient history and tak-
ing the time to talk with the patient will help to prevent unne-
cessary prescription of antibiotics and being aware of the onset
of cardiac arrhythmia in the presence of these antibiotics.
Funding
This paper was not funded.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
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