The spectrum of activity, mechanisms of action and

resistance, important resistance patterns, and adverse

effects of commonly available fluoroquinolones (ie,
ciprofloxacin, levofloxacin, moxifloxacin, delafloxacin) will be
reviewed here. Detailed information on pharmacokinetics,
pharmacodynamics, and drug interactions can be found by
using the drug interactions program included within
UpToDate.

BENEFITS AND RISKS OF USE

Restriction of use for uncomplicated infections — In
general, we find that the risks of fluoroquinolone use
outweigh the benefits for the treatment of uncomplicated
infections such as acute rhinosinusitis, uncomplicated
cystitis, and acute bronchitis. Antibiotics are either not
indicated for these conditions or alternate agents with lower
toxicity profiles are usually available for their treatment. (See
"Uncomplicated acute sinusitis and rhinosinusitis in adults:
Treatment" and "Acute simple cystitis in adult and adolescent
females" and "Acute bronchitis in adults".)
This approach is in line with recommendations from the US
Food and Drug Administration (FDA) derived from their 2016
safety review, which showed that systemic fluoroquinolone
use is associated with uncommon but potentially permanent
and disabling adverse effects involving the musculoskeletal
and nervous systems [1]. (See 'Adverse effects' below.)
Use for more severe infections — When treating more
severe infections, we weigh the benefits and risks of
fluoroquinolone use in each individual patient.
For the majority, fluoroquinolones are well tolerated. The
most common adverse effects are mild and include
gastrointestinal upset, headaches, dizziness, or a transient
change in mood or sleep. Although their exact incidence is
unknown, gastrointestinal and central nervous system
adverse effects are estimated to be three times more
common with fluoroquinolones when compared with other
antibiotics [2]. The incidence of C. difficile infection also
appears to be higher with fluoroquinolone use when
compared with some other antibiotics [3,4]. Thus, when
equally efficacious and narrower spectrum options are
available, we tend to select them over fluoroquinolones.
Less common but potentially severe adverse effects include
tendinopathies and tendon rupture, peripheral neuropathy,
QT interval prolongation, and putatively aortic dissection and
rupture. Rarely, tendinopathies and neuropathies can be
permanent and/or disabling; thus, we try to avoid
fluoroquinolones in patients with known tendinopathies and
neuropathies or in those at risk. Similarly, we avoid
fluoroquinolone use in patients with prolonged QT intervals
or in patients taking other medications that prolong the QT
interval. (See 'Tendinopathy' below and 'Peripheral
neuropathy' below and 'QT interval prolongation' below.)
Aortic dissection and rupture is a putative, but potentially
devastating, adverse effect associated with fluoroquinolone
use. Although the putative risk is small, the FDA warns
against fluoroquinolone use in patients with known aortic
aneurysms and those with risk factors for aneurysm such as
Marfan syndrome, Ehlers Danlos syndrome, peripheral
atherosclerotic vascular diseases, uncontrolled hypertension,
and/or advanced age [5]. The risk-benefit ratio clearly varies
among such individuals. As an example, for an older patient
with severe community-acquired pneumonia, the benefits of
fluoroquinolone use may outweigh the small potential risk of
aortic aneurysm rupture. By contrast, the risk-benefit ratio is
likely greater for an individual with a known aneurysm and a
questionable indication for fluoroquinolone use. (See 'Aortic
aneurysm and dissection' below.)
Fluoroquinolones also interact with a variety of other drugs,
which need be taken into account when prescribing (see
'Drug interactions' below). Additional uncommon adverse
effects are also discussed below. (See 'Adverse effects'
below.)
Special populations
Pregnancy and breastfeeding — Fluoroquinolones should
generally be avoided during pregnancy and lactation unless
a safer alternative is not available. In animal models,
fluoroquinolone use during pregnancy has been associated
with cartilage and bone toxicity in developing fetuses [6-9].
While similar effects have not been observed in humans,
available data are limited and follow-up times generally do
not exceed time of birth [10,11]. Reassuringly, in one meta-
analysis of observational studies evaluating over 2800
pregnant women exposed to fluoroquinolones, no
differences in congenital malformations, spontaneous
abortion, or prematurity were detected when compared with
unexposed pregnant women [11]. While a small decrease in
the live birth rate was detected among pregnant women
exposed to fluoroquinolones when compared with controls
in this study, this appears to correlate with an increase in
elective pregnancy terminations, possibly due to a
misperceived risk to the newborn.
Children — Routine use of systemic fluoroquinolones
should be avoided in children due to the potential risk of
musculoskeletal toxicity. However, it is reasonable to use a
systemic fluoroquinolone in children when no safe or
effective alternative exists or when parenteral therapy can be
avoided by using an oral fluoroquinolone [12-17]. This
approach is consistent with recommendations from the
American Academy of Pediatrics [12]. FDA-approved uses in
children are limited and include treatment of complicated
urinary tract infections and pyelonephritis as well as
treatment and prevention of inhalation anthrax.
The concern over musculoskeletal toxicity is based on the
association between fluoroquinolones and tendinopathies as
well as studies in juvenile animals, which have demonstrated
a dose- and duration-dependent association with erosive
arthropathy in weight-bearing joints with fluoroquinolone
use [12]. Available clinical trial data suggest that adverse
musculoskeletal events are usually mild and not long term.
As an example, in a retrospective cohort study evaluating
2233 children, reports of musculoskeletal toxicity were
higher among children who received levofloxacin when
compared with a non-fluoroquinolone antibiotic (3.4 versus
1.8 percent) over a one-year period [18]. Arthralgia was the
most common musculoskeletal adverse event, reported in
over 80 percent of symptomatic children in both groups.
Children who had persisting musculoskeletal adverse events
during the first year of follow-up were requested to enroll in
four additional years of follow-up [19]. Of children identified
with a musculoskeletal adverse event during years 2 through
5 following treatment, the number that were considered
"possibly related" to drug therapy was equal for both groups
(1 of 1340 in the levofloxacin group; 1 of 893 in the
comparator group). No musculoskeletal adverse event was
considered "likely related" to levofloxacin.
Patients with myasthenia gravis — Fluoroquinolones
should be avoided in individuals with myasthenia gravis
because they have neuromuscular-blocking activity that may
precipitate myasthenic crises [20]. Postmarketing reports
have included death and respiratory failure requiring
mechanical ventilation in patients with myasthenia gravis
receiving fluoroquinolones. The label carries a boxed
warning from the FDA advising against use in this population
[21].
MECHANISM OF ACTION
Fluoroquinolones are bactericidal antibiotics that directly
inhibit bacterial deoxyribonucleic acid (DNA) synthesis
[22,23]. All fluoroquinolones bind to complexes of DNA with
each of two enzymes that are essential for DNA replication,
DNA gyrase and DNA topoisomerase IV, and this binding
generates DNA cleavage. The potency with which
fluoroquinolones inhibit one enzyme or the other varies
among bacterial species. In general, fluoroquinolone
generation of DNA cleavage complexes results in cessation of
DNA replication, DNA damage, and, ultimately, cell death.

PHARMACOKINETICS
High oral bioavailability and a large volume of distribution
are key pharmacokinetic properties of most fluoroquinolones
( table 1).
Each fluoroquinolone is absorbed from the upper
gastrointestinal tract [24-28]. Ciprofloxacin, ofloxacin,
levofloxacin, moxifloxacin, and delafloxacin all have oral and
intravenous formulations that allow direct estimates of oral
bioavailability, with values of 59 percent for delafloxacin, 70
percent for ciprofloxacin, 86 percent for moxifloxacin, and
>95 percent for ofloxacin and levofloxacin [28,29].
Norfloxacin has an oral formulation only, and its estimated
bioavailability is approximately 30 to 40 percent.
Peak concentrations in serum are usually attained within one
to three hours of administering an oral dose. Food does not
substantially reduce fluoroquinolone absorption but may
delay the time to reach peak serum concentrations [30,31].
However, dairy, antacids, multivitamins containing zinc,
certain medications (eg, sucralfate), and other sources of
divalent cations (aluminum, magnesium, calcium) can
substantially decrease absorption (presumably by formation
of cation-quinolone complexes). Concurrent use should be
avoided or these substances should be given several hours
apart from the fluoroquinolone in order to avoid their
interaction [32].
The volumes of distribution of quinolones are high and, in
most cases, exceed the volume of total body water, indicating
accumulation in some tissues. Concentrations in prostate
tissue, stool, bile, lung, and neutrophils as well as
macrophages usually exceed serum concentrations.
Concentrations in urine and kidney tissue are high for the
quinolones with a major renal route of elimination (all except
moxifloxacin). Concentrations of quinolones in saliva,
prostatic fluid, bone, and cerebrospinal fluid are usually
lower than drug concentrations in serum.
Detailed information on metabolism ( table 1), dose
adjustments, and other pharmacokinetic properties can be
found using the Lexicomp drug information monographs
included within UpToDate. (See "Ciprofloxacin (systemic):
Drug information" and "Levofloxacin (systemic): Drug
information" and "Moxifloxacin (systemic): Drug information"
and "Delafloxacin: Drug information" and "Ofloxacin
(systemic): Drug information" and "Norfloxacin (United
States: Not available): Drug information" and "Gemifloxacin
(United States: Not available): Drug information" and
"Gatifloxacin: Drug information".)

SPECTRUM OF ACTIVITY
Fluoroquinolones are broad-spectrum antibiotics with potent
activity against aerobic, enteric gram-negative bacilli and
many common respiratory pathogens. In addition, some
fluoroquinolones are active against Pseudomonas species,
selected gram-positive organisms, anaerobes, and
mycobacteria. The relative potency against specific
pathogens within these categories varies among
fluoroquinolones. Because resistance to fluoroquinolones is
common, knowledge of local epidemiology is important
when selecting an antibiotic. (See 'Antimicrobial resistance'
below.)
Fluoroquinolones are also important for the treatment of less
common infections including tuberculosis, non-tuberculous
mycobacterial infections, and anthrax.
Although some fluoroquinolones have activity against certain
gram-positive organisms and anaerobes, clinical experience
with their use for these organisms is limited and their
potency is often less than that of other antibiotics. Thus,
fluoroquinolones are generally not used as first-line agents
for susceptible organisms within these categories.
● Ciprofloxacin – Ciprofloxacin primarily targets and has
the greatest activity against aerobic, enteric gram-
negative bacilli (eg, Enterobacterales, including
Escherichia coli, Klebsiella spp, Proteus spp), as well as
Pseudomonas aeruginosa. This spectrum of activity
makes ciprofloxacin a great option for intra-abdominal
infections and other infections caused by enteric
bacteria. Although ciprofloxacin also has potent activity
 against aerobic gram-negative respiratory pathogens
(eg, H. influenzae, M. catarrhalis), it has limited to no
activity against gram-positive organisms (eg, S.
pneumoniae, Staphylococcus aureus).
● Levofloxacin – Levofloxacin has activity against gram-
positive organisms (eg, Streptococcus pneumoniae,
Staphylococcus aureus, some strains of coagulase-
negative staphylococci) and reduced, but still adequate
activity, against aerobic, enteric gram-negative
organisms and P. aeruginosa. Levofloxacin is also active
against most common respiratory pathogens, including
Streptococcus pneumoniae, Haemophilus influenzae,
Moraxella catarrhalis, and intracellular or cell wall-
deficient bacteria (ie, Legionella spp, Mycoplasma spp,
and Chlamydia pneumoniae).
● Moxifloxacin – Moxifloxacin has activity against gram-
positive organisms (eg, Streptococcus pneumoniae,
Staphylococcus aureus, some strains of coagulase-
negative staphylococci) and reduced, but still adequate
activity, against aerobic, enteric gram-negative
organisms (eg, Enterobacterales, including Escherichia
coli, Klebsiella spp, Proteus spp). Moxifloxacin is less
active than ciprofloxacin or levofloxacin against
 Pseudomonas aeruginosa, Providencia spp, Proteus spp,
and Serratia marcescens and is generally not used to
treat these organisms. Moxifloxacin is also active against
most common respiratory pathogens, including
Streptococcus pneumoniae, Haemophilus influenzae,
Moraxella catarrhalis, and intracellular or cell wall-
deficient bacteria (ie, Legionella spp, Mycoplasma spp,
and Chlamydia pneumoniae). Additionally, moxifloxacin
has activity against some anaerobes and is most active
against mycobacteria compared with other
fluoroquinolones. Given its overall spectrum of activity,
although data are limited, moxifloxacin appears to be
similarly effective as ampicillin-sulbactam for anaerobic
lung infections (eg, aspiration pneumonia or lung
abscess) [33] and is the only fluoroquinolone that has
sufficient activity against anaerobic bacteria for clinical
use. Resistance among Bacteroides species limits its use
for the treatment of intra-abdominal infections.
● Delafloxacin – Delafloxacin has activity against gram-
positive organisms (eg, Streptococcus pneumoniae,
Staphylococcus aureus, some strains of coagulase-
negative staphylococci) and reduced, but still adequate
activity, against aerobic, enteric gram-negative
 organisms (eg, Enterobacterales, including Escherichia
coli, Klebsiella spp, Proteus spp) and P. aeruginosa.
Delafloxacin is the only fluoroquinolone with reliable
activity against methicillin-resistant Staphylococcus
aureus (MRSA). However, clinical experience with
delafloxacin is limited. Delafloxacin also has activity
against anaerobes in vitro [34], but in vivo data are
lacking. (See "Anaerobic bacterial infections".)
● Other antimicrobial activity of fluoroquinolones
• Enterococci – Although some fluoroquinolones have in
vitro activity against enterococci, they are generally
not used for the treatment of enterococcal infections
because achievable serum concentrations are
frequently close to the minimum inhibitory
concentrations and efficacy data are limited. (See
"Treatment of enterococcal infections".)
• Mycobacterium tuberculosis – Fluoroquinolones also
have excellent activity in vitro against Mycobacterium
tuberculosis and are used as second-line agents in the
setting of resistance and/or intolerance to first-line
agents. In general, moxifloxacin and levofloxacin are
preferred over other fluoroquinolones because of
 their greater potency. (See "Antituberculous drugs: An
overview".)
• Nontuberculous mycobacteria – Fluoroquinolones are
also active against many nontuberculous
mycobacteria including M. fortuitum, M. kansasii, and
some strains of M. chelonae. Activity against M. avium
complex is fair to poor. Moxifloxacin and ofloxacin are
active against M. leprae. (See "Rapidly growing
mycobacterial infections: Mycobacteria abscessus,
chelonae, and fortuitum" and "Treatment of
Mycobacterium avium complex pulmonary infection in
adults" and "Leprosy: Treatment and prevention".)
• Other atypical bacteria – Fluoroquinolones are among
first-line options for the treatment of susceptible
infections caused by Bacillus anthracis, Francisella
tularensis, and Salmonella enterica Serovar Typhi
(typhoid fever). Specific recommendations vary by site
and severity of infection. (See "Treatment of anthrax"
and "Tularemia: Clinical manifestations, diagnosis,
treatment, and prevention" and "Enteric (typhoid and
paratyphoid) fever: Treatment and prevention".)
ANTIMICROBIAL RESISTANCE
Mechanisms of resistance — Resistance to quinolones may
occur via mutations in bacterial chromosomal genes or via
acquisition of resistance genes on plasmids.
Mutations in chromosomal genes occur in genes that [35]:
● Encode the subunits of DNA gyrase and topoisomerase
IV (altered target mechanism)
● Regulate the expression of cytoplasmic membrane efflux
pumps or proteins that constitute outer membrane
diffusion channels (altered permeation mechanism)
Major plasmid-mediated resistance mechanisms include [36-
42]:
● Qnr proteins, which protect DNA gyrase and
topoisomerase IV from quinolone activity
● Fluoroquinolone-modifying enzymes (encoded by an
aminoglycoside acetyltransferase variant gene [AAC(6′)-
Ib-cr]), which acetylates fluoroquinolones and reduces
their activity
● Efflux pumps (encoded by qepA and oqxAB genes),
which pump fluoroquinolones (particularly ciprofloxacin
and norfloxacin) out of the cell
Plasmid-mediated resistance mechanisms typically confer
low-level resistance. However, high-level resistance can result
when plasmid-mediated mechanisms accumulate or co-occur
with chromosomal mutations. The likelihood of developing
resistance is believed to be related to the intensity and
duration of antibiotic therapy. As an example, ≥5 days of
fluoroquinolone exposure was associated with significant
resistance in an in vitro model [43].
Plasmid-mediated resistance mechanisms can confer
resistance to other antimicrobial classes directly or because
they are linked to other drug-resistance genes encoded on
the same plasmid.
Important resistance patterns — Resistance to
fluoroquinolones is common, and rates are growing
worldwide among many targeted bacteria. Thus,
fluoroquinolone use may be precluded or limited for certain
indications unless susceptibility is documented such as the
following:
● Sexually transmitted infections, particularly with
Neisseria gonorrhoeae (see "Treatment of
uncomplicated gonorrhea (Neisseria
 gonorrhoeae infection) in adults and adolescents",
section on 'Fluoroquinolones')
● Urinary tract infections (see "Acute complicated urinary
tract infection (including pyelonephritis) in adults and
adolescents", section on 'Management' and "Acute
simple cystitis in adult and adolescent females", section
on 'Management')
● P. aeruginosa infections (see "Principles of antimicrobial
therapy of Pseudomonas aeruginosa infections")
● Typhoid and paratyphoid (see "Enteric (typhoid and
paratyphoid) fever: Treatment and prevention" and
"Enteric (typhoid and paratyphoid) fever: Treatment and
prevention", section on 'Antimicrobial resistance')
● Infections with Shigella spp and Campylobacter spp (see
"Shigella infection: Treatment and prevention in adults",
section on 'Antibiotic resistance' and "Campylobacter
infection: Clinical manifestations, diagnosis, and
treatment", section on 'Resistance')
Fluoroquinolone resistance is relatively uncommon among S.
pneumoniae, H. influenzae, and M. catarrhalis. (See
"Resistance of Streptococcus pneumoniae to the
fluoroquinolones, doxycycline, and trimethoprim-
sulfamethoxazole" and "Moraxella catarrhalis infections" and
"Epidemiology, clinical manifestations, diagnosis, and
treatment of Haemophilus influenzae".)

ADVERSE EFFECTS
General considerations — Fluoroquinolones are generally
safe and well tolerated. However, rare but severe adverse
events have been reported, leading to restrictions in their
use [1] and, in some cases, their removal from the market
[44-47].
Much of the data regarding adverse effects are derived from
passive reporting systems and observational studies, which
are prone to confounding. In some cases, uncommon side
effects were only recognized with more extensive clinical use
after regulatory approval. Because safety and tolerability are
best assessed in randomized trials, our knowledge of
adverse effects associated with fluoroquinolone use
continues to evolve.
Delafloxacin is structurally designed to have a lower adverse
effect profile, particularly for central nervous system events
and phototoxicity [48]. Randomized trial data suggest that
treatment-related adverse events may be less common with
delafloxacin when compared with other fluoroquinolones
[49]. However, only limited numbers of patients have thus far
been treated with delafloxacin, and long-term data are
lacking.
Gastrointestinal
Gastritis — The most common adverse effect associated
with fluoroquinolone use is transient and mild
gastrointestinal upset (eg, anorexia, nausea, vomiting, or
abdominal discomfort). Diarrhea is less common.
C. difficile-associated disease — Because of their broad-
spectrum, fluoroquinolones may confer greater risk of C.
difficile-associated disease when compared with some other
antibiotics [3,4]. Reductions in fluoroquinolone prescriptions
have been associated with declines in C. difficile rates both in
the community and in health care institutions [50-52].
Certain epidemic strains of C. difficile (ie, NAP1/BI/027) are
fluoroquinolone resistant; use of fluoroquinolones during
outbreaks caused by such strains has been a risk factor for
the development of C. difficile-associated disease [53]. (See
"Clostridioides difficile infection in adults: Epidemiology,
microbiology, and pathophysiology".)
Hepatoxicity — As a class, fluoroquinolones are associated
with low risk of mild elevation of aminotransferase levels.
Among commonly used fluoroquinolones (ie, ciprofloxacin,
levofloxacin, moxifloxacin), severe hepatic failure is rare but
reported [54-58].
In a population-wide propensity-matched retrospective study
of all Swedish patients aged 40 to 85 years, receipt of an oral
fluoroquinolone was associated with a higher risk of acute
liver injury compared with those who received amoxicillin
(hazard ratio [HR] 2.32, 95% CI 1.01-5.35), although absolute
incidence was only 2.98 and 1.27 per 10,000 person-years,
respectively [59]. A similar increase in risk of hepatotoxicity
has also been observed in multiple case control studies
[60,61].
Trovafloxacin warrants mention because it was removed
from the market worldwide for its association with fatal
hepatoxicity [46,47]. Gatifloxacin has the second strongest
association with hepatoxicity; it is no longer available in the
United States, and worldwide availability is limited.
Neurologic — Neurologic adverse effects are among the
most common adverse effects associated with
fluoroquinolones [2]. Most neurologic adverse effects are
mild, such as headache, dizziness, or transient change in
mood or sleep patterns. Less commonly, more serious
central nervous system adverse effects can occur, ranging
from delirium to hallucination to seizures. The peripheral
nervous system can also be affected; peripheral neuropathy
predominates.
Altered mental status — The labels of all systemic
fluoroquinolones include US Food and Drug Administration
(FDA) warnings about the risk of delirium, memory
impairment, disorientation, agitation, and disturbances in
attention. Such adverse effects have been reported after a
single fluoroquinolone dose, and the offending drug should
be stopped if they occur [62].
Peripheral neuropathy — Peripheral neuropathy is an
uncommon but well-described adverse effect of
fluoroquinolone use [63,64]. Peripheral neuropathy can
occur at any time during treatment with a fluoroquinolone
and can last for months to years after the drug is stopped or
be permanent. In reported cases, the onset of peripheral
neuropathy was rapid, often within a few days.
Symptoms of peripheral neuropathy may include pain,
burning, tingling, numbness, weakness, or a change in
sensation to light, touch, pain, temperature, or the sense of
body position. If symptoms of peripheral neuropathy develop
while receiving a fluoroquinolone, the fluoroquinolone
should be stopped, and the patient should be switched to an
antibiotic from a different class, unless the benefit of
continuing the fluoroquinolone outweighs the risk. Generally,
the management of fluoroquinolone-associated peripheral
neuropathy is similar to the management of other drug-
induced neuropathies, which includes stopping the offending
agent and providing symptomatic care. (See "Overview of
polyneuropathy", section on 'Management'.)
Although the precise incidence is unknown, in a case-control
study of men aged 45 to 80 years, current users of
fluoroquinolones were at a higher risk of developing
peripheral neuropathy than controls (rate ratio [RR] 1.83, 95%
CI 1.49-2.27) [63]. Similar findings were reported in another
nested case-control study comparing 5357 cases of
peripheral neuropathy to matched controls [65]. Risk was
highest among men and patients >60 years old; risk
increased by approximately 3 percent with each day of
exposure and persisted for 180 days. The number needed to
harm for a 10-day course was 152,083 patients (95% CI
117,742-202,778).
The exact mechanism by which peripheral neuropathy occurs
remains unknown [66]. Hypotheses include direct nerve
inflammation with or without ischemia caused by toxic
metabolite and free radical accumulation [67].
Other adverse effects — Other neurologic adverse effects
are uncommon and include:
● Seizure – Seizures are very rare complications of
fluoroquinolone use. In some cases, seizures may result
from theophylline accumulation or from the ability of
theophylline and nonsteroidal anti-inflammatory drugs
to augment fluoroquinolone-mediated displacement of
gamma-aminobutyric acid from its receptors [68-70].
(See 'Drug interactions' below.)
● Pseudotumor cerebri – Fluoroquinolone use has also
been associated with secondary pseudotumor cerebri
syndrome, as illustrated by the findings of a case-control
study evaluating health care records from over six
million patients [71]. Compared with nonuse,
fluoroquinolone use within 15 or 30 days of diagnosis
increased the risk of developing secondary pseudotumor
cerebri syndrome (adjusted rate ratios for 15 days 5.67,
95% CI 2.72-11.83). Although the overall rate of the
 disorder was low, estimated at about 2 per 100,000
overall and 1 in 166,000 due to fluoroquinolones,
clinicians should be aware of this potential risk in
patients with characteristic symptoms (eg, headache,
tinnitus, diplopia).
● Myasthenia gravis exacerbations – Fluoroquinolones
have neuromuscular-blocking activity and may
exacerbate muscle weakness in individuals with
myasthenia gravis [20]. Postmarketing reports have
included death and respiratory failure requiring
mechanical ventilation in patients with myasthenia
gravis receiving fluoroquinolones. Thus,
fluoroquinolones should be avoided in individuals with
myasthenia gravis. (See "Myasthenic crisis", section on
'Precipitants'.)
Cardiovascular
QT interval prolongation — Fluoroquinolones can prolong
the QT interval by inhibiting cardiac KCHN2 potassium
voltage-gated channels, potentially leading to torsades de
pointes (a life-threatening arrhythmia) [72]. When safe and
effective alternatives are available, we avoid fluoroquinolone
use for patients taking other QT-prolonging drugs and
patients with long QT syndromes or other significant risk
factors for arrhythmia ( table 2).
Available clinical data suggest that, among available
fluoroquinolones, moxifloxacin has the highest association
with QT interval prolongation, arrhythmia, and
cardiovascular mortality, followed by levofloxacin and then
ciprofloxacin [73-76]. Delafloxacin, which came to market in
2018, has not been associated with QT interval prolongation,
but clinical experience is limited [28,77]. Sparfloxacin,
grepafloxacin, and gatifloxacin each had strong associations
with QT interval prolongation [78]. However, these agents
have either been removed from the market or have limited
availability.
In a meta-analysis of five large observational studies and one
randomized trial evaluating >7 million patients,
fluoroquinolone use was associated with an increased risk of
arrhythmia (odds ratio [OR] 1.85, 95% CI 1.22-2.81) when
compared with either placebo or other antibiotic use [76].
Concordantly, an increased risk of cardiovascular mortality
was detected in a meta-analysis of one randomized trial and
two observational studies evaluating over three million
patients (OR 1.71, 95% CI 1.39-2.09). Based on a network
meta-analysis of clinically available fluoroquinolones, the risk
of arrhythmia was highest with moxifloxacin use followed by
levofloxacin and ciprofloxacin [76]. A similar trend was
observed for cardiovascular mortality, although the increase
in risk with moxifloxacin when compared with levofloxacin
did not reach statistical significance. Delafloxacin was not
evaluated.
Because most studies evaluating the effect of
fluoroquinolones on the QT interval are observational, they
are prone to confounding by indication (eg, fluoroquinolone
use for pneumonia carries greater baseline risk of adverse
cardiovascular effects than does amoxicillin use for acute
sinusitis). In addition, most studies do not account for
comorbidities that may augment risk of arrhythmia. (See
"Acquired long QT syndrome: Definitions, pathophysiology,
and causes" and "Acquired long QT syndrome: Clinical
manifestations, diagnosis, and management".)
Aortic aneurysm and dissection — Several observational
studies have suggested that fluoroquinolone use may be
associated with an increased risk of aortic aneurysm or
dissection [79-83]. However, the causal role of
fluoroquinolones in the development of aortic aneurysms
and dissection is unclear.
Based on these studies, the FDA issued a warning in
December 2018 highlighting this association and
recommended avoiding fluoroquinolones in patients with
known aortic aneurysms or those with risk factors for
aneurysm such as Marfan syndrome, Ehlers Danlos
syndrome, peripheral atherosclerotic vascular diseases,
uncontrolled hypertension, and/or advanced age [5]. In one
nationwide cohort study in Sweden, fluoroquinolone use
(360,088 fluoroquinolone treatment episodes) was
associated with an increased risk of aortic aneurysm within
60 days from the start of treatment when compared with
amoxicillin use (1.2 versus 0.7 cases per 1000 person-years;
HR 1.66, 95% CI 1.12-2.46) in propensity-matched controls.
The estimated absolute difference was 82 cases of aortic
aneurysm or dissection per 1 million treatment episodes [82].
The observational nature of this study leaves room for
potential confounders (eg, severity of the infection for which
the antibiotic was prescribed, smoking status, baseline blood
pressure). If a causal role for fluoroquinolones and aortic
aneurysm or dissection exists, the absolute risk is small and
likely limited to individuals with predisposing risk factors.
Whether preferentially avoiding fluoroquinolones in patients
with any risk factor for aortic aneurysm or dissection (eg,
hypertension or older age) versus those with strong risk
factors (eg, known aneurysm) provides benefit is unclear.
When considering fluoroquinolone use, we take this
uncertainty into account and weigh the overall risk-benefit
ratio in each patient.
Other adverse effects — Aortic and mitral valve
regurgitation have been associated with fluoroquinolone use
in a single large observational study [84]. However, whether
this association is causal is uncertain. In a nested case-
control study of >135,000 patients extracted from the United
States PharMetrics Plus database, current fluoroquinolone
use was associated with an increased risk of aortic or mitral
regurgitation when compared with amoxicillin (RR 2.40, 95%
CI 1.82-3.16) and azithromycin (RR 1.75, 95% CI 1.34-2.29). No
increase in risk was detected for past fluoroquinolone use.
Patients with valvular regurgitation also had higher rates of
coronary artery disease, heart failure, and atrial fibrillation,
suggesting that there may be residual confounding in the
analysis. Additional study is needed to confirm or refute
these findings.
Musculoskeletal
Tendinopathy — Fluoroquinolone use has been associated
with a broad range of tendinopathies, including tendon
rupture [85-91]. The Achilles tendon is most often affected,
although any tendon can be involved [90,92]. Thus, when
prescribing a fluoroquinolone, we advise patients to
discontinue the medication if any sign of tendinopathy
develops (ie, pain, swelling). In addition, we generally advise
patients to avoid exercise, contact their physician for
evaluation, and transition to a non-fluoroquinolone antibiotic
when appropriate. This approach is consistent with
recommendations from the FDA [90].
The incidence of tendinopathies associated with
fluoroquinolone use is not well established but is estimated
to be low (ie, approximately 3 to 4 cases per 100,000 for the
Achilles tendon) [93,94]. Most cases occur early in the course
of therapy, with a median of eight days based on case
reports [89,92,94].
In a cohort study reviewing 28,907 cases of Achilles
tendinopathy and 7685 cases of tendon rupture,
fluoroquinolone use was associated with increased risk of
tendinopathy (OR 4.3, 95% CI 3.2-5.7) and tendon rupture
(OR 2.0, 95% CI 1.2-3.3) when compared with other
antibiotics [91]. Risk appeared to be higher among persons
>60 years old (OR 8.3 versus 1.6), nonobese (OR 7.7 versus
2.4), and those using oral glucocorticoids (OR 9.1 versus 3.2).
Kidney, heart, and lung transplantation have been identified
as potential additional risk factors [90].
It is unclear whether any one fluoroquinolone confers
greater risk of tendinopathy over another, although one
study demonstrated a higher risk of tendon ruptures with
levofloxacin [67,92,95].
The mechanisms of fluoroquinolones’ effects on connective
tissues are not well understood. Data suggest that tenocyte
toxicity is due to local boosting of metalloprotease activity
and magnesium chelation from high concentrations of
fluoroquinolone accumulated in tendons and possibly other
connective tissues [96,97].
Arthropathy — Arthropathy with cartilage erosions and
noninflammatory effusions occurs in the weight-bearing
joints of juvenile animals given quinolones. Experience with
use of quinolones in children has increased, particularly in
children with cystic fibrosis given ciprofloxacin. These
children and others receiving nalidixic acid and norfloxacin
have only uncommonly had joint symptoms, which have
been reversible [13,98]. Studies to identify subclinical
cartilage damage by magnetic resonance imaging of joints of
treated children have also been negative [99]. (See 'Children'
above.)
Other adverse effects
Dysglycemia — Fluoroquinolones have been associated
with both hypoglycemia and hyperglycemia in both diabetic
and nondiabetic patients [100-105]. In July 2018, the FDA
strengthened its warning about the risk of hypoglycemia
associated with systemic fluoroquinolone use, particularly for
older adults and those with diabetes mellitus [62].
Among moxifloxacin, levofloxacin, and ciprofloxacin,
moxifloxacin appears to confer the highest risk of both
hyperglycemia and hypoglycemia among diabetic patients
[100]. Gatifloxacin was withdrawn from the market in the
United States and Canada in June 2006 because it was
associated with a greater frequency of symptomatic
hypoglycemia and hyperglycemia when compared with other
fluoroquinolones, including some fatal cases [101-103].
Retinal detachment — Retinal detachment has been
reported with fluoroquinolone use; however, a causal
relationship has not been established. Several large
observational studies have attempted to assess whether an
association between fluoroquinolone use and retinal
detachment exists, with conflicting results [79,106-110].
A nationwide registry-based cohort study from Denmark that
controlled for potential confounders found that neither
recent nor current fluoroquinolone use was associated with
an increased risk of retinal detachment [107]. Similarly, in a
large population-based study in the United States,
fluoroquinolone use was not associated with an increased
risk of rhegmatogenous retinal detachment or symptomatic
retinal breaks [108]. In contrast, a nested case-control study
of patients in Canada who visited an ophthalmologist found
an increased rate of retinal detachment in patients who were
currently receiving an oral fluoroquinolone (3.3 percent of
cases versus 0.6 percent of controls; aOR 4.5, 95% CI 3.6-5.7)
[106]. The absolute increase in the risk of retinal detachment
was 4 per 10,000 person-years. In a case-crossover study
using French health care databases that included 27,540
patients with retinal detachment, there was an increased risk
for retinal detachment during the 10-day period after being
prescribed a fluoroquinolone (aOR 1.46, 95% CI 1.15-1.87)
[109]. The risk was increased for both rhegmatogenous (full-
thickness; aOR 1.41, 95% CI 1.04-1.92) and exudative (aOR
2.57, 95% CI 1.46-4.53) retinal detachment.
Considering all the data above and other reports, the FDA
issued an update in May 2017 stating that available data do
not support a causal association between fluoroquinolones
and retinal detachment [111]. If an association exists, the risk
of retinal detachment attributable to fluoroquinolone use is
likely small and may be limited to individuals with additional
predisposing risk factors.
Phototoxicity — Some fluoroquinolones carry a small risk
of phototoxicity [47]. The effect seems to be most
pronounced with older-generation fluoroquinolones (eg,
lomefloxacin, sparfloxacin) due to their chemical structures
[112]. The risk is lessened with most presently available
fluoroquinolones and may be absent for delafloxacin, which
is designed to avoid this adverse effect [113]. Sunscreen
containing UVA blockers may offer some protection [114],
although this has not been systematically studied.
Hypersensitivity reactions — Delayed-onset
maculopapular rash is the most common type of
hypersensitivity reaction to fluoroquinolones, occurring in
approximately 2 to 3 percent of patients. Immediate
reactions (eg, urticaria, pruritus, angioedema, wheezing,
anaphylaxis) are less common but can be life-threatening. In
clinical trials, an unusually high occurrence of maculopapular
rash (14 percent) was reported in young women receiving
gemifloxacin for seven or more days; biopsies showed no
evidence of vasculitis [115]. Persons with a gemifloxacin-
associated rash had a higher rate of rash to subsequent
ciprofloxacin (5.9 percent) than those having received
placebo [116]. Acute interstitial nephritis also occurs
infrequently and has been associated with eosinophiluria but
generally not crystalluria [117]. Hypersensitivity reactions to
fluoroquinolones are discussed in greater detail separately.
(See "Hypersensitivity reactions to fluoroquinolones".)
Persistent multisystem adverse effects — Persistent
multisystem symptoms (termed fluoroquinolone-associated
disability) have been reported following fluoroquinolone use
[118,119]. However, whether fluoroquinolones are causal of
such symptoms and what the potential mechanism of action
may be is unclear.
In 2015, the FDA reviewed its database for all serious adverse
events reported in previously healthy persons taking a
fluoroquinolone for acute bronchitis, urinary tract infection,
and acute rhinosinusitis between 1997 and 2015 [120].
Among 1122 reports, 178 met criteria for events involving
two or more body systems and lasting for ≥30 days after
stopping the fluoroquinolone. There was an unusually high
proportion of direct patient reports for fluoroquinolones
when compared with other drugs (85 versus 2 to 6 percent).
Three-quarters of reported cases occurred in females and
those aged 30 to 59. Almost all had musculoskeletal
symptoms; two-thirds each had neuropsychiatric or
peripheral nervous system symptoms. Patterns of symptoms
and the extent of association were similar among the three
most commonly reported (and used) fluoroquinolones,
levofloxacin, ciprofloxacin, and moxifloxacin. Given the large
numbers of fluoroquinolone prescriptions over the study
period, the risk of the fluoroquinolone disability syndrome is
likely exceedingly low.

DRUG INTERACTIONS
Fluoroquinolones interact with a variety of other drugs. This
section will review the most important or frequent
interactions. A complete listing is provided separately for
each fluoroquinolone (see appropriate drug information
topic reviews by searching on the drug name). In addition,
details about specific interactions can be found using the
drug interactions program included within UpToDate.
● Most fluoroquinolones prolong the QT interval and
should not be given in combination with other QT-
prolonging medications. (See 'QT interval prolongation'
above.)
● Ciprofloxacin inhibits hepatic cytochrome P450
isoenzyme 1A2, which can impair the elimination of
substrate drugs (eg, clozapine, erlotinib, ibrutinib,
ropinirole, tizanidine, theophylline, caffeine, and
methylxanthines) [121,122]. Generally, ciprofloxacin
should be avoided for patients taking these medications;
if coadministration is unavoidable, dosing of substrate
drugs should be reduced or levels monitored.
Norfloxacin can also increase theophylline levels, but it is
unclear if this is due to cytochrome P450 isoenzyme
inhibition. Other fluoroquinolones do not inhibit or
induce cytochrome P450 enzymes or xanthine
metabolism to a clinically relevant extent ( table 1).
● Nonsteroidal anti-inflammatory drugs (NSAIDs) may
augment the central nervous stimulant effects of
fluoroquinolones by displacing neurotransmitter
gamma-aminobutyric acid from its receptors, potentially
lowering the seizure threshold [69]. The extent to which
concurrent use of quinolones with NSAIDs results in
 central nervous system toxicities is unclear, but patients
receiving both classes of drugs should be cautioned
about and monitored for these adverse effects.
● Rifampin and the long-acting rifamycin, rifapentine,
lower the plasma concentration of moxifloxacin
[123,124]. This interaction is potentially an important
consideration when formulating treatment regimens for
tuberculosis and other mycobacterial infections.
Other drug interactions have been studied less extensively.
Ciprofloxacin has had effects on the pharmacokinetics of
cyclosporine. Enoxacin and ciprofloxacin have been shown to
reduce the clearance of the less active R-enantiomer of
warfarin but have no clinically important effect on the more
active S-enantiomer [125].

SUMMARY
● Characteristics of fluoroquinolones −
Fluoroquinolones are bactericidal antibiotics with broad
spectrum antimicrobial activity and many advantageous
pharmacokinetic properties including high oral
bioavailability and large volume of distribution
 ( table 1). (See 'Introduction' above and 'Mechanism of
action' above and 'Pharmacokinetics' above.)
● Spectrum of activity − The spectrum of activity includes
aerobic, enteric gram-negative bacilli (eg, Escherichia
coli) and many common respiratory pathogens,
including atypical bacteria. Some fluoroquinolones are
also active against Pseudomonas species, selected gram-
positive organisms, anaerobes, and mycobacteria. (See
'Spectrum of activity' above.)
• Ciprofloxacin primarily targets gram-negative bacilli,
including Pseudomonas aeruginosa.
• Levofloxacin, moxifloxacin, and delafloxacin have
increased activity against gram-positive organisms
(eg, Streptococcus pneumoniae) and reduced activity
against P. aeruginosa when compared with
ciprofloxacin.
• Moxifloxacin additionally has activity against some
anaerobes and is most active against mycobacteria
compared with other fluoroquinolones.
• Delafloxacin (the newest fluoroquinolone) also has
activity against anaerobes and is the only
fluoroquinolone with reliable activity against
 methicillin-resistant Staphylococcus aureus (MRSA).
However, clinical experience with delafloxacin is
limited.
● Antimicrobial resistance − Resistance to
fluoroquinolones is growing worldwide and is commonly
reported in most target bacteria, with the exceptions of
S. pneumoniae, Haemophilus influenzae, and Moraxella
catarrhalis. Resistance mechanisms can be
chromosomally encoded or plasmid mediated. Plasmid-
mediated mechanisms are almost always associated with
resistance to other antibiotics. (See 'Antimicrobial
resistance' above.)
● Reserving use for complicated infections − Because of
rising resistance rates, growing knowledge of potentially
serious adverse effects (including Clostridioides difficile
infection), and drug interactions, use of fluoroquinolones
is generally reserved for complicated infections in which
the benefits of use clearly outweigh the risks. (See
'Benefits and risks of use' above.)
● Avoiding use in children and pregnant and lactating
women − Fluoroquinolones should generally be avoided
in pregnant women, lactating women, and children,
 unless a safer alternative is not available. This avoidance
is due to the potential for musculoskeletal toxicity in
developing fetuses and children. (See 'Pregnancy and
breastfeeding' above and 'Children' above.)
● Adverse effects − The most common adverse effects are
mild and involve the gastrointestinal tract (eg, nausea)
and central nervous system (eg, headache and
dizziness). Less common but potentially severe adverse
effects include QT interval prolongation, tendinopathies,
dysglycemia, and putatively retinal detachment and
aortic aneurysm or dissection. (See 'Adverse effects'
above.)
● Drug interactions − Fluoroquinolones interact with
multiple other medications. Additional detail can be
found in the Lexicomp database and drug interactions
program included within UpToDate.
• Coadministration of other medications that prolong
the QT interval should be avoided because of the risk
of potentially fatal arrhythmias ( table 2).
• Dairy, antacids, multivitamins containing zinc, certain
medications (eg, sucralfate), and other sources of
divalent cations can substantially decrease oral
 absorption. Concurrent use should be avoided or
these substances should be given several hours apart
from the fluoroquinolone in order to avoid their
interaction.

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