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Adverse Drug Reactions Related to the
Use of Fluoroquinolone Antimicrobials
An Analysis of Spontaneous Reports and Fluoroquinolone
Consumption Data from Three Italian Regions
Roberto Leone,
1
Mauro Venegoni,
2
Domenico Motola,
3
Ugo Moretti,
1
Valentina Piazzetta,
1
Alfredo Cocci,
4
Domenico Resi,
3
Federico Mozzo,
1
Giampaolo Velo,
1
Liliana Burzilleri,
5
Nicola Montanaro
3
and Anita Conforti
1
1 Clinical Pharmacology Unit, WHO Reference Centre for Education and Communication
in International Drug Monitoring, University of Verona, Verona, Italy
2 Department of Medicine, Fatebenefratelli Hospital, Milan, Italy
3 Department of Pharmacology, Interuniversity Research Centre for Pharmacoepidemiology,
University of Bologna, Bologna, Italy
4 Pharmaceutical Unit, ASL, Cremona, Italy
5 Lombardy Centre of Pharmacovigilance, Milan, Italy
Abstract
Objective: To analyse and compare with one another and with other antibacterial
drugs the adverse drug reactions (ADRs) of the different fluoroquinolones
currently used in Italy, spontaneously reported from doctors in three northern
Italian regions.
Methods: The data on fluoroquinolones and other antibacterials were obtained
from the spontaneous reporting system database of Emilia Romagna, Lombardy
and the Veneto, which are the principal contributors to the Italian spontaneous
surveillance system. The fluoroquinolone ADRs with a causality assessment of
certain, probable or possible (according to WHO criteria), reported between Jan-
uary 1999 and December 2001, were selected and toxicity profiles of individual
drugs were described and compared with one another. The reports were also
correlated with sex and age of patients and with regional prescription data to
estimate individual fluoroquinolone reporting rate of adverse events.
Results: During the study period, 10 011 reports were received by the system (a
mean annual reporting rate of approximately 185 per million inhabitants): 1920
referred to systemic antimicrobials, of which 432 (22.5%) involved fluoro-
quinolones.
Pefloxacin was associated with the highest reporting rate (982 reports/daily de-
fined dose/1000 inhabitants/day), followed by moxifloxacin (356), rufloxacin
(221) and lomefloxacin (196). The most frequently reported reactions to
fluoroquinolones involved the skin, but their percentage (25%) was significantly
lower (p < 0.01) than those of other systemic antimicrobials (58.5%), whereas
the percentages of reactions involving the central nervous (12.2 vs 3.6%), mus-
culoskeletal (14.7 vs 0.3%) and psychiatric systems (9.3 vs 1.8%) were signifi-
ORIGINAL RESEARCH ARTICLE
Drug Safety 2003; 26 (2): 109-120
0114-5916/03/0002-0109/$30.00/0
© Adis International Limited. All rights reserved.
cantly higher (p < 0.01). We found some significant differences in the safety
profiles of individual fluoroquinolones: ciprofloxacin was more frequently
associated with skin reactions (p < 0.01), levofloxacin and pefloxacin with mus-
culoskeletal (p < 0.01), and rufloxacin with psychiatric disorders (p < 0.05).
Levofloxacin was the fluoroquinolone associated with the highest rate of se-
rious tendon disorders; phototoxic reactions were more frequent with lome-
floxacin, and toxic epidermal necrolysis and Stevens-Johnson syndrome were
seen only with ciprofloxacin.
Conclusions: The differences in the safety profiles should be taken into account
when prescribing a fluoroquinolone to individual patients.
Fluoroquinolone antimicrobials are used to treat
various infections, and the newer drugs in this class
have a broader spectrum of activity that better cov-
ers Gram-positive bacteria and even anaerobes.
On the basis of spectrum of activity, several
classifications have been proposed, distinguishing
three or four generations of fluoroquinolones.
[1-7]
First-generation fluoroquinolones (e.g. nalidixic
acid) are moderately active against Gram-negative
bacteria and used to treat urinary tract infections;
second-generation fluoroquinolones (e.g. nor-
floxacin, lomefloxacin and ciprofloxacin) have
broader Gram-negative activity that also includes
Pseudomonas and are also partially active against
Gram-positive organisms (Staphylococcus aureus
but not Streptococcus pneumoniae). Some authors
classify in a IIb-generation group agents with im-
proved Gram-positive activity such as sparfloxacin
and grepafloxacin.
[3,5]
Third-generation fluoro-
quinolones have expanded activity against S. pneu-
moniae and the common atypical organisms (e.g.
levofloxacin); the fourth generation includes agents
with significant anaerobic coverage (e.g. moxi-
floxacin and trovafloxacin, a fluoronaphthyridone
related to the fluoroquinolone antibacterials). In
some classifications, levofloxacin is considered a
second-generation
[5,7]
and moxifloxacin a third-
generation fluoroquinolone.
[1-3,5]
Adverse effects are the ‘Achilles heel’ of this
class of antimicrobials: a number of molecules
have been withdrawn from the market or their de-
velopment discontinued because of serious ad-
verse reactions. Fleroxacin was withdrawn in 1990
because of phototoxicity
[8]
and temafloxacin in
1992 (shortly after its registration) because of 95
cases of severe hypoglycaemia, hepatic and renal
dysfunction, haemolytic anaemia and anaphylaxis
(the so-called temafloxacin syndrome), some of
which were fatal.
[9]
It is interesting to note that
trials involving more than 3000 patients before its
registration indicated that temafloxacin was at
least as well tolerated as other fluoroquinolones
and had a low incidence of known class effects
such as phototoxicity.
[10]
The development of
several fluoroquinolones, such as clinafloxacin,
Bay 3118 and tosufloxacin, was stopped after the
identification of unacceptable toxicity (photo-
toxicity, hypoglycaemia, thrombocytopenia and
nephritis).
[6]
In 1999, grepafloxacin was with-
drawn from the market by the manufacturer be-
cause of cardiovascular effects, mainly prolonga-
tion of the QT interval.
[11]
In the same year,
trovafloxacin was withdrawn in Europe because
of 152 documented reports of serious liver toxicity,
including nine patients who died or required a liver
transplant.
[12]
The use of sparfloxacin was mark-
edly limited because of phototoxicity and car-
diotoxicity,
[13]
and in February 2001 the manufac-
turer withdrew the drug from the US market. The
labelling of moxifloxacin, gatifloxacin, and levo-
floxacin has been modified by adding warnings
about potential prolongation of the QT interval and
disturbances of blood glucose (this last only for
gatifloxacin).
[13]
Various studies have demonstrated a correlation
between certain adverse events and specific sites
110 Leone et al.
© Adis International Limited. All rights reserved. Drug Safety 2003; 26 (2)
and constituents around the fluoroquinolone nu-
cleus (figure 1).
[14-16]
It has been shown that posi-
tion 1 controls genetic toxicity and theophylline
interaction, which is most marked with enoxacin,
pefloxacin and ciprofloxacin.
[17]
The carboxyl in
position 3 and the keto group in position 4 are both
involved in chelation and metal binding, and so
influence the interactions of all fluoroquinolones
with antacids, milk, iron and other preparations
containing Ca
2+
and Mg
2+
. Position 7 controls γ-
aminobutyric acid (GABA)-binding activity in the
brain and is responsible for a number of CNS ad-
verse effects, particularly convulsions; it is also
involved in theophylline interactions. The fluoro-
quinolones more frequently associated with CNS
adverse reactions are fleroxacin, trovafloxacin and
grepafloxacin.
[16]
Position 8 has been shown to be
the most important in mediating phototoxicity,
with fluorine having more phototoxic potential
than chlorine or nitrogen. A high degree of pho-
totoxicity is associated with the dihalogenated
quinolones, such as lomefloxacin, sparfloxacin
and clinafloxacin. There is some suggestion that
position 5 is also important for phototoxicity and
QT prolongation.
[18]
Finally, hepatotoxicity has
been found in the presence of two or three nitro-
gens in the molecule of quinolones (e.g. trova-
floxacin).
[6]
The overall incidence of adverse events associ-
ated with fluoroquinolone use in the US and Eur-
ope varies widely among the different fluoro-
quinolones, from 4.2% for ofloxacin to 47% for
grepafloxacin.
[5]
Information concerning the true
incidence of adverse drug reactions (ADRs) can-
not be obtained by spontaneous reporting, since
the events are always under-reported. However,
when consumption data are available, comparing
the toxicity profiles of the drugs in the same ther-
apeutic class and with similar indications that are
marketed in the same country in a comparable
period of time is generally acceptable
[19]
because,
under these conditions, the under-reporting can be
assumed to be more or less of the same magnitude
for the reference drugs.
[20]
Many comparative
studies of the safety of different drugs on the
basis of spontaneous reporting data have been
published.
[21-27]
Given the particular nature of the fluoro-
quinolone market and consumption in Italy, the
aims of this study were to compare the adverse
reactions of fluoroquinolones with those of other
antibacterial drugs prescribed in three Italian re-
gions and to investigate whether the spontaneous
reporting data, correlated with sex and age of pa-
tients and with regional prescription data, reveal
differences in toxicity profiles of individual
fluoroquinolone antibacterial agents.
Methods
The data on fluoroquinolone antimicrobial
agents currently available in Italy (figure 2), and
on other systemic antimicrobials were obtained
from a database containing all of the spontaneous
reports of ADRs from the Italian regions of Emilia
Romagna, Lombardy and the Veneto. These re-
gions had an estimated population of about 18 mil-
lion inhabitants in January 2000 (about 32% of the
Italian population) and are the principal contribu-
tors to the Italian spontaneous surveillance system
(accounting for about 54% of all Italian reports).
We analysed the spontaneous reports collected be-
tween January 1999 and December 2001.
The following information was considered: re-
porter category, patient age and sex, the reporter’s
diagnosis of the ADR, the characteristics of the
underlying disease, and drug exposure (indication,
duration of treatment and dosage). The reports
were classified according to the WHO criteria for
X
8
R
5
R
7
F
N
O
CO
2
H
R
1
H
Fig. 1. The basic nucleus of the fluoroquinolones.
ADRs Related to Fluoroquinolone Antimicrobial Agents 111
© Adis International Limited. All rights reserved. Drug Safety 2003; 26 (2)
causality assessment,
[28]
and those with a certain,
probable or possible causality assessment were in-
cluded in the analysis. The drugs were categorised
using the Italian Codifa System and the anatomical
therapeutic chemical (ATC) classification. The re-
actions were coded according to the WHO Adverse
Reaction Terminology (WHOART) and classified
as serious or nonserious events on the basis of the
WHO Critical Term List.
[29]
All reports of ADRs occurring in association
with fluoroquinolones during the study period
were analysed in detail by a specially constituted
ad hoc panel of experts that included internists,
pharmacologists and pharmacists. The main task
was to check the completeness of the reports and
the terminology of the ADRs. The reports with two
or more symptoms were reviewed by the team and
a single diagnosis was formulated whenever possi-
ble. The reporting doctor was contacted if further
clinical data were necessary to reach a diagnosis.
The reports with no temporal correlation between
drug exposure and disease onset, a doubtful ADR
diagnosis or relating to events obviously due to the
underlying disease were excluded.
Fluoroquinolone consumption in the three re-
gions during the study period (figure 2) was de-
rived from the regional databases holding all of the
prescriptions of drugs (such as the fluoroquino-
lones) that are reimbursed by the Italian health sys-
tem. Figure 2 also shows national consumption
(kindly supplied by OsMed using IMS Health
data), which has a similar pattern. Age- and sex-
related consumption data (figure 3) were available
only for Lombardy, but we think they are repre-
sentative of the other two regions. Drug consump-
tion was expressed as daily defined dose (DDD)
per 1000 inhabitants per day.
For each drug the female/male reporting rate
with 95% confidence intervals was calculated on
the basis of gender distribution in the three regions.
The toxicity profiles of fluoroquinolones were
compared with one another and with other sys-
0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
DDD/1000 inhabitants/day
Regions
Whole of Italy
Enoxacin
Pefloxacin
Ofloxacin
Rufloxacin
Moxifloxacin
Lomefloxacin
Norfloxacin
Ciprofloxacin
Levofloxacin
Fig. 2. Individual fluoroquinolone consumption in the Emilia Romagna, Lombardy and the Veneto regions compared with consumption
in the whole of Italy during the study period. DDD = daily defined dose.
112 Leone et al.
© Adis International Limited. All rights reserved. Drug Safety 2003; 26 (2)
temic antimicrobials using the χ
2
test for statistical
analyses. The same test has been used to compare
the female/male reporting rate of individual
fluoroquinolones.
Results
During the study period, 10 011 reports (33%
serious) were received by the system (a mean an-
nual reporting rate of approximately 185 per mil-
lion inhabitants). A total of 1920 reports referred
to systemic antimicrobials, of which 432 (22.5%)
involved fluoroquinolones. Only seven reports
were excluded by the expert panel, mainly because
the dates of drug administration and/or reaction
onset were missing. The analysis was therefore
based on 425 reports of 621 reactions (about 1.5
per patient). In included reports, causality assess-
ment was certain in 2%, probable in 76% and pos-
sible in 22%, with no significant differences
among single fluoroquinolones.
The number of reports relating to individual
fluoroquinolones is shown in table I. The female/
male reporting rate ratio of 1.2 was lower than that
observed for all other systemic antimicrobials
(1.4); this can be explained by the higher fluoro-
quinolone consumption in males than females
(figure 3), mainly due to levofloxacin (Lombardy
data for individual drugs not shown). However, we
observed a female/male reporting rate ratio signif-
icantly higher for rufloxacin and moxifloxacin
than the other fluoroquinolones, even though their
consumption was slightly greater among male pa-
tients.
Thirty-eight percent of the reports were sent by
hospital doctors (7% by emergency rooms), 60%
by general practitioners, and the remaining 2% by
specialists and pharmacists. During the same pe-
riod, 48% of the reports regarding other antibacte-
rial drugs were reported by general practitioners
Table I. Adverse reaction reports attributed to the fluoroquinolones, available in Italy during the study period (January 1999–December 2001).
Female/male reporting rate was calculated on the basis of gender distribution in the three Italian regions
Drug No. of reports Female/male reporting rate ratio
(95% CI)
total (% serious) female/male
Levofloxacin 164 (44.5) 77/87 0.84 (0.62–1.14)
Ciprofloxacin 115 (46.1) 68/47 1.37 (0.94–1.98)
Moxifloxacin
a
42 (31.0) 30/10 2.83
b
(1.38–5.79)
Lomefloxacin 39 (51.3) 20/19 0.99 (0.53–1.86)
Norfloxacin 23 (39.1) 15/8 1.77 (0.75–4.18)
Pefloxacin 18 (35.0) 10/8 1.18 (0.47–2.99)
Rufloxacin 12 (33.3) 11/1 10.39
b
(1.34–80.45)
Ofloxacin
c
8 (44.4) 3/4 0.71 (0.16–3.16)
Enoxacin 4 (25.0) 0/4 NA
Total 425 (43.2) 234/188 1.18 (0.97–1.42)
a In two reports sex was not reported.
b Significant differences (χ
2
test, p < 0.01).
c In one report sex was not reported.
NA = not applicable.
0
2
4
6
8
10
12
DDD/1000 inhabitants/day
0−10
11
−15
16
−20
21
−30
31
−40
41
−50
51
−60
61
−65
66
−70
>70
Female
Male
Age (y)
Fig. 3. Age- and sex-related fluoroquinolone consumption in
the Lombardy population during the study period. DDD = daily
defined dose.
ADRs Related to Fluoroquinolone Antimicrobial Agents 113
© Adis International Limited. All rights reserved. Drug Safety 2003; 26 (2)
and 46% by hospital doctors (5% by emergency
rooms). On the basis of reporter categories, it was
deduced that 31% of the fluoroquinolone reports
involved inpatients and 69% outpatients. The fluoro-
quinolones were administered orally in 98% of
cases, with only 2% being parenterally administered.
The age-specific reporting rate is shown in
figure 4. The total annual reporting rate increased
with age, suggesting that the elderly are more sus-
ceptible. On the other hand, older patients con-
sumed more fluoroquinolones than younger ones
(figure 3); thus, the observed age-dependent in-
crease in reporting rate may reflect increase in drug
consumption.
The reporting rate of reactions to fluoro-
quinolones per DDD per 1000 inhabitants per day
is shown in figure 5: pefloxacin was associated
with the highest reporting rate (982), followed by
moxifloxacin (356), rufloxacin (221) and lome-
floxacin (196). Considering only the serious re-
ports, pefloxacin maintains the highest rate (382),
followed by moxifloxacin (110), lomefloxacin
(101) and ciprofloxacin (88).
Table II shows the observed ADRs according to
the involved organ systems. The most frequently
reported reactions to fluoroquinolones involved
the skin, but their percentage was significantly
lower (p < 0.01) than that of other systemic antimi-
crobials. On the contrary, the percentages of reac-
tions involving the CNS and musculoskeletal and
psychiatric systems were significantly higher (p <
0.01). The individual drugs had a different pattern:
the percentage of cutaneous reactions was signifi-
cantly higher (p < 0.01) for ciprofloxacin; the per-
centage of musculoskeletal reactions was signifi-
cantly higher (p < 0.01) for levofloxacin and
pefloxacin; and the percentage of psychiatric reac-
tions was significantly higher (p < 0.05) for
rufloxacin. No significant differences have been
found in ADRs involving the other system organ
classes.
The most frequently reported serious reactions
to fluoroquinolones were tendon disorders (16 re-
ports, with 12 Achilles tendon ruptures), halluci-
nations (15), angioedema (11) and photosensitivity
reactions (9). Eleven men and five women experi-
enced serious tendinitis (median age 72, range
0
5
10
15
20
25
(3) (3)
(29)
(57)
(53)
(56)
(41)
(40)
(143)
>70
66−70
61−65
51−60
41−50
31−40
21−30
16−20
11−15
0−10
No. of reports/million inhabitants/y
Age (y)
Fig. 4. Age-specific adverse fluoroquinolone reaction reporting
rates per million inhabitants per year in the combined Emilia
Romagna, Lombardy and the Veneto regions of Italy from
January 1999 to December 2001. Numbers in parentheses are
the numbers of reports for each specific age group.
0
250
500
750
1000
No. of reports/DDD/1000 inhabitants/day
Serious
Nonserious
Pefloxacin (18)
Moxifloxacin (42)
Rufloxacin (12)
Lomefloxacin (39)
Ciprofloxacin (115)
Levofloxacin (164)
Norfloxacin (23)
Fig. 5. Reporting rates of serious and nonserious reactions
(coded according to the WHO Critical Term List) to fluoro-
quinolones per daily defined dose (DDD) per 1000 inhabitants
per day in the combined Emilia Romagna, Lombardy and the
Veneto regions of Italy. Only drugs with at least ten reports are
included. Consumption figures are derived from regional pre-
scription data. Numbers in parentheses are the total number of
reports.
114 Leone et al.
© Adis International Limited. All rights reserved. Drug Safety 2003; 26 (2)
33–80, years); in five cases (31%), corticosteroids
were concomitant drugs. Levofloxacin is associ-
ated with the highest rate (11.4 reports/daily de-
fined dose/100 inhabitants/day) of serious tendini-
tis (figure 6). No reports on tendon disorders were
associated with enoxacin, ofloxacin, rufloxacin,
pefloxacin or moxifloxacin. The drugs with the
largest number of hallucination reports were
rufloxacin (5) and levofloxacin (5), whereas six of
the nine cases of phototoxic reactions were attrib-
uted to lomefloxacin. During the study period,
there were four cases of acute renal impairment,
two cases of toxic epidermal necrolysis and two of
Stevens-Johnson syndrome: all referred to cipro-
floxacin. Three cases of international normalised
ratio (INR) prolongation due to an interaction be-
tween warfarin and levofloxacin were also re-
ported. We found 17 reports of rhythm disorders,
mostly nonserious reactions such as tachycardia
and palpitation; no torsade de pointes, ventricular
tachycardia or atrial fibrillation were reported.
Discussion
The data emerging during the clinical develop-
ment of a new drug are not sufficient to assess its
potential toxicity when it is used in a larger patient
population.
[30]
The postmarketing period is there-
fore important for consolidating drug safety pro-
files and detecting previously unknown adverse ef-
fects.
Spontaneous reporting of ADRs has proved to
be valuable in providing information about new
drug-related adverse effects and generating early
signals, and thus maintains a primary role among
pharmacovigilance methods.
[31,32]
Through the
analysis of spontaneous reports it is not possible to
obtain the true incidence of adverse effects; how-
ever, the educational role of this type of data
should not be disregarded. In fact, when the drug
consumption data are available and the reporting
rate is acceptable, we have the opportunity to learn
more about the safety of a group of drugs, as from
studies on nonsteroidal anti-inflammatory drugs
(NSAIDs), selective serotonin reuptake inhibitors
Table II will go here
ADRs Related to Fluoroquinolone Antimicrobial Agents 115
© Adis International Limited. All rights reserved. Drug Safety 2003; 26 (2)
ADRs Related to Fluoroquinolone Antimicrobial Agents 115
© Adis International Limited. All rights reserved. Drug Safety 2003; 26 (2)
Table II. Adverse effect profiles of fluoroquinolones
a
by body system in comparison with the profiles of other systemic antimicrobials. Number of reports with, in parentheses, the
percentage of all reported reactions within each group
Organ or system Levofloxacin Ciprofloxacin Moxifloxacin Lomefloxacin Norfloxacin Pefloxacin Rufloxacin Total for all
fluoroquinolones
Total for other
systemic
antimicrobials
Skin 46 (19.9) 53 (34.9)
b
10 (13.5) 17 (27.9) 11 (36.7) 8 (25.8) 5 (23.8) 150 (25.0)
c
1074 (58.5)
Musculoskeletal 59 (25.5)
b
9 (5.9) 1 (1.4) 6 (9.8) 3 (10.0) 7 (22.6)
b
2 (9.5) 87 (14.7)
c
5 (0.3)
CNS 24 (10.4) 16 (10.5) 17 (23.0) 8 (13.1) 1 (3.3) 3 (9.7) 4 (19.0) 73 (12.2)
c
66 (3.6)
Gastrointestinal 18 (7.8) 16 (10.5) 12 (16.2) 6 (9.8) 3 (10.0) 3 (9.7) 2 (9.5) 60 (10.0) 167 (9.1)
Body as a whole 26 (11.3) 11 (7.2) 9 (12.2) 7 (11.5) 5 (16.7) 1 (3.2) 59 (9.8) 136 (7.4)
Psychiatric 15 (6.5) 13 (8.6) 9 (12.2) 7 (11.5) 3 (10.0) 4 (12.9) 6 (28.6)
d
57 (9.3)
c
33 (1.8)
Cardiovascular 7 (3.0) 7 (4.6) 8 (10.8) 2 (3.3) 3 (9.7) 1 (4.8) 28 (4.7) 64 (3.5)
Others
e
36 (15.6) 27 (17.8) 8 (10.8) 8 (13.1) 4 (13.3) 2 (6.5) 1 (4.8) 86 (14.3) 292 (15.9)
Total
f
231 (100) 152 (100) 74 (100) 61 (100) 30 (100) 31 (100) 21 (100) 600 (100) 1837 (100)
a With at least ten reports in the considered period.
b Significant differences (χ
2
test, p < 0.01) among the fluoroquinolones in the reports implicating this organ system versus the other reports.
c Significant differences (χ
2
test, p < 0.01) among total fluoroquinolones and the other systemic antimicrobials in the reports implicating this organ system versus the
other reports.
d Significant differences (χ
2
test, p < 0.05) among the fluoroquinolones in the reports implicating this organ system versus the other reports.
e None of the other organ systems involved accounted for more than 4% of the fluoroquinolone reports.
f The total number of reports is higher than that given in the text and table I because the same report may contain multiple system reactions.
and antihistamines, published in Spain, Italy, Swe-
den and the UK.
[21,22,24-26]
In the case of fluoroquinolones, spontaneous
reporting played a considerable role, as some
drugs have been withdrawn from the market on
the basis of reports of serious ADRs. The recent
‘cerivastatin case’ further emphasises that sponta-
neous reporting is able to detect different toxicity
profiles of drugs in the same chemical-therapeutic
class.
The fluoroquinolones are widely used antibac-
terial agents in Italy,
[33]
with levofloxacin ranking
first despite its recent introduction (1998). Other
peculiarities of the Italian market are the presence
of rufloxacin and the low ofloxacin consumption.
The age-related increase in reporting rates es-
sentially reflects the greater use of fluoroquino-
lones in older patients, thus confirming that the
incidence of adverse effects is not higher in the
elderly than in the younger population.
[34]
Compared with published data for other drug
classes,
[35-40]
fluoroquinolones have a lower fe-
male/male reporting rate ratio, possibly because of
their greater use (particularly levofloxacin) in male
patients aged over 60 years. It is known that
chronic obstructive pulmonary disease, one of the
main indications for fluoroquinolone use in Italy,
is more prevalent in men than in women aged over
60 years.
[41]
When adjusted for drug prescriptions, our data
suggest higher reaction rates for pefloxacin and
moxifloxacin. As moxifloxacin is the newest
fluoroquinolone on the Italian market (launched in
2000), we presume that the larger number of re-
ports is due to doctors paying particular attention
to ADRs according to the reporting guidelines. On
the contrary, the lower reporting rate for nor-
floxacin (the oldest marketed fluoroquinolone)
could be due to a drop in attention.
Adverse events involving the CNS are, after
gastrointestinal reactions, the second most fre-
quently reported form of fluoroquinolone toxicity
in the literature. Their overall incidence is 1–2%
(ranging from 0.2 to 11% for individual agents),
and they include a broad range of effects, such as
dizziness, mild headache and drowsiness, followed
by insomnia, organic psychosis and convulsions.
[42]
Our spontaneous reporting data confirm that,
unlike that of other antimicrobials, fluoroquino-
lone toxicity has the CNS as an important target
organ. The proportion of CNS-related reactions
and psychiatric disorders (generally considered to-
gether by other authors) is about 22%, very similar
to the approximately 23% found in the database of
the WHO Collaborating Centre in Uppsala (data on
file). NSAIDs or theophylline were concomitant
drugs in 12% of the patients experiencing CNS re-
actions with fluoroquinolones. Rufloxacin and
moxifloxacin were associated with a higher pro-
portion of CNS adverse reactions than other
fluoroquinolones. Clinical studies have found that
the degree of the CNS reactions induced by
moxifloxacin is similar to that of the reactions in-
duced by norfloxacin, but higher than those of the
reactions induced by ciprofloxacin, ofloxacin or
levofloxacin.
[42]
The few clinical data available for
rufloxacin confirm that CNS-related events are the
0
4
8
12
No. of reports/DDD/1000 inhabitants/day
Norfloxacin Ciprofloxacin Lomefloxacin Levofloxacin
Fig. 6. Reporting rates of serious fluoroquinolone-related tendi-
nitis per daily defined dose (DDD) per 1000 inhabitants per day
in the combined Emilia Romagna, Lombardy and the Veneto
regions of Italy. Consumption figures are derived from regional
prescription data.
116 Leone et al.
© Adis International Limited. All rights reserved. Drug Safety 2003; 26 (2)
most frequently reported.
[43]
The drug diffuses ef-
ficiently into the cerebrospinal fluid and it is likely
that the blood-brain barrier penetration of
fluoroquinolones plays an important role in CNS
toxicity.
[14]
However, some data have raised
doubts about the possibility that the CNS reactions
induced by fluoroquinolones are related to their
lipophilicity.
[43,44]
In our study, rufloxacin-related CNS events
were more frequent in women, which explains the
highest female/male reporting ratio for this agent.
Recent trovafloxacin data have shown that CNS
reactions occur more frequently in women than in
men, although the reason for this is unknown.
[42,45]
Skin reactions are the most frequently reported
clinical manifestations related to systemic antimi-
crobials in the context of our spontaneous surveil-
lance system, accounting for about 58% of all re-
ported adverse events. This may reflect the
over-reporting of skin reactions per se or the un-
der-reporting of other organ reactions, but the lat-
ter is the more likely explanation because it is eas-
ier to recognise and report cutaneous adverse
reactions than those involving other organ sys-
tems. The skin is also the main organ system in-
volved in ADRs to fluoroquinolones, but the per-
centage is lower (25%) because of their different
ADR pattern.
Clinical data show that fluoroquinolone-related
skin reactions occur in about 0.5–3.0% of patients
[46]
and that they may be mediated by an allergic reac-
tion or photosensitivity (both photoallergy and
phototoxicity).
In our analysis, the highest proportion of pho-
tosensitivity reactions was reported in association
with lomefloxacin. In animal and in vitro models,
lomefloxacin seems to be the marketed fluoro-
quinolone that has the greatest potential for induc-
ing phototoxic reactions
[47,48]
and, in a randomised
clinical trial, the frequency of photosensitivity at-
tributed to the drug was about 1%.
[49]
It has been
suggested that an evening administration strategy
could reduce the risk of inducing phototoxic ef-
fects.
[50]
The most important cardiac toxicity of fluoro-
quinolones is prolongation of the QT interval. This
has been recorded with the newer fluoro-
quinolones, and appears to be a class effect.
[51]
A
recent prescription event monitoring study of the
older fluoroquinolones confirmed this observa-
tion, by finding that ciprofloxacin was associated
with the highest number of dysrhythmic cardio-
vascular events.
[52]
In our database three serious rhythm disorders
were associated with levofloxacin, one with
moxifloxacin and one with pefloxacin; however,
the data are not sufficient to reveal any particular
differences among the individual fluoroquino-
lones in terms of cardiovascular toxicity.
Musculoskeletal adverse reactions are an im-
portant fluoroquinolone class effect. In our study,
and in line with the WHO database, a higher pro-
portion of these events was reported for levo-
floxacin and pefloxacin. In animal studies, all of
the fluoroquinolones have induced arthropathy
with cartilage erosions and noninflammatory
effusions in juvenile animals,
[53]
and so fluoro-
quinolones are not approved for paediatric use or
during pregnancy. A number of case reports and
spontaneous report studies of fluoroquinolone-
associated tendinitis have been published.
[54-65]
A
retrospective cohort study found that the adjusted
relative risk of Achilles tendinitis during fluoro-
quinolone use was 3.7 and that of other types of
tendinitis 1.3.
[66]
More than 2000 tendon disorders
have so far been reported worldwide to the WHO
Collaborating Centre in Uppsala (data on file). A
simultaneous increase in nontraumatic tendon rup-
ture (mono- or bilateral) and in fluoroquinolone
use has been observed in The Netherlands,
[67]
but
the authors only partially attributed the tendinitis
increase to fluoroquinolone use. A very recent
nested case-control study among users of fluoro-
quinolones in a UK general practice database indi-
cated that the overall excess risk of Achilles tendon
disorders is 3.2 cases per 1000 patient years. This
effect seems to be restricted to current users aged
60 years or older with a crude relative risk of 3.5
ADRs Related to Fluoroquinolone Antimicrobial Agents 117
© Adis International Limited. All rights reserved. Drug Safety 2003; 26 (2)
(95% CI 2.3–5.3).
[68]
Other possible risk factors for
tendinitis include concomitant corticosteroid use,
renal disease, haemodialysis and transplantation.
[5]
In our analysis, levofloxacin was the fluoro-
quinolone with the highest tendinitis reporting
rate, an observation that is supported by the WHO
database, in which levofloxacin ranked first for
tendinitis reports during the same period (522 in-
cluding tendon disorder and rupture). A large
number of tendinitis reports with levofloxacin
have recently been observed in France. Sub-
sequently, a ‘Dear Doctor’ letter was sent out in
France, Germany and Italy informing of the
levofloxacin-related risk of tendinitis, particu-
larly in elderly patients and those receiving con-
comitant corticosteroids.
Fluoroquinolone nephrotoxicity is uncommon
and may be a result of direct damage or a hyper-
sensitivity response. The most common renal ad-
verse effects are crystalluria, haematuria, intersti-
tial nephritis and acute renal failure, particularly
with ciprofloxacin.
[69,70]
In accordance with these
data, we received reports of four cases of acute
renal failure due to ciprofloxacin.
It has been reported that the effects of oral anti-
coagulants are enhanced by the concurrent admin-
istration of quinolones, although the mechanism
underlying this possible interaction is unknown. A
number of case reports have indicated that cipro-
floxacin prolongs prothrombin times or increases
INR in patients receiving warfarin anticoagulation
therapy.
[71-75]
It seems that ciprofloxacin-warfarin
coagulopathy is most prevalent in elderly patients
who require multiple drug therapy;
[76]
there are
also some case reports describing this interaction
in the case of norfloxacin, ofloxacin and more re-
cently levofloxacin.
[77-80]
The levofloxacin pre-
scribing information leaflet in the US indicates the
possible interaction with warfarin, but not that in
the European Union.
Conclusion
The spontaneous reporting of ADRs has proved
to be valuable in providing information about new
drug-related adverse effects and generating early
signals, thus maintaining its primary role among
pharmacovigilance methods. It does not allow the
risk associated with a given drug to be accurately
quantified because of the possibly confounding
bias and under-reporting of ADRs. Nevertheless,
when an adequate reporting rate and consumption
data are available, spontaneous reporting allows
comparison of drug toxicity profiles within the
same chemical-therapeutic class.
The analysis of the Emilia Romagna, Lombardy
and Veneto databases of spontaneous ADR report-
ing confirms that, unlike that of other systemic an-
timicrobials, the toxicity of fluoroquinolones often
involves the CNS and musculoskeletal system.
Furthermore, the individual fluoroquinolones have
different safety profiles: ciprofloxacin was more
often associated with skin reactions than other
fluoroquinolones, levofloxacin and pefloxacin
with musculoskeletal disorders and rufloxacin
with psychiatric disorders. Our spontaneous re-
porting data show that levofloxacin was the
fluoroquinolone with the highest rate of serious
tendon disorders, phototoxic reactions were more
frequent with lomefloxacin, and toxic epidermal
necrolysis and Stevens-Johnson syndrome were
were reported only with ciprofloxacin. These find-
ings should be taken into account when prescribing
a fluoroquinolone to individual patients.
Acknowledgements
We are very grateful to the Pharmaceutical Departments
of Emilia Romagna, Lombardy and the Veneto, and their
local Health Districts, for collecting the adverse reaction
forms. We also thank the WHO Collaborating Centre for
International Drug Monitoring in Uppsala, Sweden, for al-
lowing us to consult the WHO database.
This work was supported by the Health Regional Author-
ities of Emilia-Romagna, Lombardy and the Veneto. The
authors have no conflicts of interest directly relevant to the
content of this study.
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Correspondence and offprints: Dr Roberto Leone, Clinical
Pharmacology Unit, Policlinico G.B. Rossi, Piazzale L.
Scuro 10, 37134 Verona, Italy.
E-mail: rleone@sfm.univr.it
120 Leone et al.
© Adis International Limited. All rights reserved. Drug Safety 2003; 26 (2)
