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Antimicrobial Agents and Chemotherapy, December 1998, p. 3141-3145, Vol. 42, No. 12
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Photosensitivity Reactions Caused by Lomefloxacin
Hydrochloride: A Multicenter Survey
Jirô
Arata,1,*
Takeshi
Horio,2
Rinzo
Soejima,3 and
Kenji
Ohara4
Department of Dermatology, Okayama University
Medical School, Okayama,1
Department of
Dermatology, Kansai Medical University, Osaka2
Department of Medical Welfare, Kawasaki Medical Welfare
University, Kurashiki,3 and
Drug
Information Department, Shionogi & Co., Ltd.,
Osaka,4 Japan
Received 28 January 1998/Returned for modification 25 July
1998/Accepted 10 September 1998
 |
ABSTRACT |
The photosensitivity effect of lomefloxacin hydrochloride (LFLX)
was investigated in terms of patient background factors (sex, age,
underlying disease, complications, history, occupation, and residential
condition, etc.), treatment factors (daily dosage of LFLX, duration of
treatment, total dose, concomitant drugs, and previous medication,
etc.), and correlations among them. In 100 institutions throughout
Japan, 4,284 patients were enrolled over a period of 2 years, beginning
in October 1991, avoiding the accumulation of patients in any specific
season. Since 8 patients did not visit again after enrollment, the
clinical records of 4,276 patients were analyzed. Photosensitivity in
44 patients was found (1.03%), but the symptoms in most patients were
not severe and improved after discontinuation of LFLX treatment. The photosensitivity reaction was more prevalent in patients who were 60 years of age and older with concomitant diseases and complications, in
patients treated with a total amount of 20 g and more of LFLX for
30 days or longer, and in patients with a history of previous treatment
with quinolone drugs. Although the incidence and degree of the
photosensitivity reaction vary significantly among new quinolone drugs,
every quinolone drug is potentially phototoxic. In particular,
long-term use of LFLX should be avoided, and patients taking LFLX
should be advised to abstain from prolonged exposure to sunlight.
| |
INTRODUCTION |
Lomefloxacin hydrochloride (LFLX) is
a difluoroquinolone with two fluorine atoms at positions 6 and 8 on the
quinolone ring. LFLX is characterized by a relatively long half-life of
6 to 8 h in circulation and good penetration into tissues after
oral administration (17). During the clinical trials of LFLX
before its commercial release, only one case of a
photosensitivity reaction among 4,488 subjects was reported
(24). After LFLX was first marketed in April 1990, Tozawa et
al. (19) reported a frequent occurrence of photosensitivity
reaction in patients on this drug. To determine the exact incidence of
photosensitivity induced by LFLX, a nationwide, multicenter survey was
performed during a period of 2 years. The present study presents the
analysis of clinical records of 4,276 patients treated with LFLX.
| |
MATERIALS AND METHODS |
Patients.
One-hundred institutions in a nationwide
distribution participated in this study. Patients with various
infections were enrolled during the period from October 1991 to October
1993. The patients were informed of the potential of LFLX to lead to
phototoxicity. Based on the assumption that the photosensitivity
reaction occurs according to a Poisson distribution, with a true
prevalence of 0.3%, approximately 4,000 patients were needed to record
at least 10 events of photosensitivity reaction with a test power of
0.90. The present study was performed in eight divided districts in Japan (Kyushu-Okinawa, Chugoku-Shikoku, Kinki, Tokai-Hokuriku, South
Kanto, North Kanto, Tohoku, and Hokkaido). The number of patients
allotted to each district was based on the amount of LFLX sold in each
district. The average number of patients enrolled in each institution
was set at 60 throughout the study and at approximately 5 per month to
avoid a seasonal bias. Patients with a history of allergy against LFLX
and other quinolones; patients with severe cardiac, hepatic, or renal
dysfunction; pregnant patients; pregnancy-expecting patients; lactating
women; and children (patients who were less than 16 years old) were not
enrolled. Main clinical indications for lomefloxacin included various
cutaneous infections, acute and chronic respiratory tract infections,
bile duct infections, bacterial enteritis, complicated and
uncomplicated urinary tract infections, various oral cavity infections,
various ocular infections, various gynecologic infections, otitis
media, and others.
Drug and administration procedure.
Lomebact capsules
containing 100 mg of LFLX (Shionogi & Co., Ltd., Osaka, Japan) were
used. The drug was administered at a daily dose of 100 or 200 mg, two
or three times daily. The patients were informed of the potential of
LFLX to induce phototoxicity. The duration of LFLX treatment depended
on the disease being treated and the judgment of the attending
physicians. The period of follow-up after the end of the treatment was
not regulated. The patients were advised to return to the prescribing
physicians if they had a photosensitivity reaction.
Judgment.
At the start of administration, skin color (light,
usual, or dark), hobby, occupation, and residential district of each
patient were recorded. Usual skin color in Japanese means a color
between white and dark, i.e., slightly yellowish to slightly brownish. When photosensitive skin lesions developed, severity, involved site of
the body, season, situation of exposure to sunlight, relation to LFLX,
treatment, and outcome were recorded. The case file, including
photographs of the skin lesions, etc., of each patient was checked by
the evaluation committee (members, Jirô Arata, Takeshi Horio, and
Rinzo Soejima). The dermatologic diagnosis of photosensitivity reaction
was based on the distribution of lesions (face, neck, arm, and upper
chest, etc.) and the nature of the eruption. Photosensitivity reactions
included unusually intense sunburn and various types of acute
dermatitis on exposed areas.
Data analysis.
Case records were analyzed by the Drug
Information Department and Data Analysis Center of Shionogi & Co.,
Ltd., under the supervision of the evaluation committee. Factors
correlating with a photosensitivity reaction were divided into patient
background factors (sex, age, distinction between in- and outpatient,
infectious disease being treated, other concomitant disease,
complication, history, skin color, hobby, occupation, and residential
district, etc.) and treatment factors (daily dosage of LFLX, daily
frequency of administration, duration of administration, total dose,
previous medication, concomitant drugs, and previous quinolone
administration) and were statistically analyzed.
On the basis of the contingency table categorizing presence or absence
of a photosensitivity reaction, patient background factors, and
treatment factors, the hypothesis that patient background factors or
treatment factors are independent of the development of a
photosensitivity reaction was tested for each factor.
When a factor had a natural order categorically, the Wilcoxon rank sum
test was used. When a factor was not categorized by order, the
chi-square test or the direct-probability calculation method was used.
To visually evaluate and interpret the relationship among factors
affecting the development of a photosensitivity reaction, the
chi-square automatic interaction detection method (CHAID)
(5) was used. Specifically, analysis was performed by using
the presence or absence of a photosensitivity reaction as the response
and patient background factors or treatment factors as the explanatory
variables. The results were summarized with P values. In the
interpretation of P values, the significance level was set
at less than 0.05%.
| |
RESULTS |
At the outset of the study, 4,284 patients were enrolled. The
numbers of patients recruited by each center varied from 2 to 120. Because 8 patients did not visit again, 4,276 patients were evaluated.
The numbers of patients varied from 127 to 1,145, according to
districts. A histogram of enrollment by month is shown in Fig. 1. The patient background factors are
presented in Table 1. The dosages and
durations of LFLX treatment are shown in Table
2.
A photosensitivity reaction was found in 44 patients (1.03%).
The severity was mild in 17 patients (38.6%), moderate in 25 patients (50.8%), and severe in one patient. The eruption disappeared after discontinuation of LFLX in 41 patients. One patient developed a
postinflammatory pigmentation. One was lost to follow-up.
Photosensitivity reactions in patients at 22 of 100 participating
institutions were observed. The 22 institutions were widely located
from Hokkaido to Okinawa. The numbers of patients with photosensitivity
reactions among the 22 institutions were 1 each in 8 institutions, 2 each in 10 institutions, 3 each in 3 institutions, and 7 in 1 institution. During the 2 years of this survey, two to six cases of
photosensitivity were observed monthly. The incidences were 1.34% (28 of 2,086 cases) in April through September and 0.73% (16 of 2,190 cases) in October through March. The incidence was slightly higher in
spring and summer (P = 0.0498).
The incidence of photosensitivity reactions according to the category
of patient background factors is shown in Table
3. Photosensitivity occurred in 31 males
(1.4%) and in 13 females (0.6%), the incidence being significantly
higher in males (P = 0.0096). Age distribution was as
follows: 3 (0.3%) patients younger than 40 years of age, 3 (0.2%)
patients from 40 to 59 years old, and 38 (2.1%) patients 60 years and
older. The incidence was significantly higher in patients who were 60 years of age and older (P = 0.00005). Seven (0.3%)
patients had no concomitant disease, and 37 (1.7%) patients had some
concomitant systemic disease. The incidence was significantly
higher in patients with some concomitant systemic disease
(P = 0.00005). By occupation, photosensitivity was
observed in 9 (5.8%) of 156 agricultural workers, in 5 (1.5%) of 338 other outdoor workers, in 25 (1.2%) of 2,171 patients without jobs, and in 5 (0.4%) of 1,329 indoor workers. The incidence among
agricultural workers was significantly higher (P < 0.00005). The incidence of photosensitivity reaction classified by
treatment factors is shown in Table 5. Photosensitivity was found in 21 (0.7%) of the patients without any previous medication and in 23 (2.1%) of the patients with previous medication. The incidence in
patients with some previous medication was significantly higher
(P = 0.0001). A history of previous quinolone
administration was found in 8 (3.6%) of 44 patients who
developed photosensitivity. The incidence was significantly
higher in patients with a history of previous quinolone
administration (P = 0.0001).
First, the result of analysis of the influence of the factors on the
incidence of photosensitivity and of the interaction among the factors
when patient background factors were used as explanatory variables is
shown in Fig. 2. Among background
factors, the age factor most strongly affected the development of
photosensitivity, and the incidence in subjects who were 60 years of
age and older was high. Among patients who were 60 years of age and
older, the incidence of a photosensitivity reaction was influenced by
occupation and underlying disease, but these factors did not affect the
incidence in patients who were less than 60 years of age. In
consideration of these interactions, a profile based on background
factors was prepared, and an image of patients who are more disposed to
develop photosensitivity under LFLX treatment was determined. The
profiles and their incidence based on the background factors in
patients with a high incidence included patients 60 years of age and
older and outdoor workers in 13 cases (6.2%); and patients 60 years of
age and older, patients who were indoor workers or not working, patients with concomitant diseases, and those living in hilly districts
in 15 cases (3.8%).
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FIG. 2.
Influence of background factors of patients on incidence
of photosensitivity to lomefloxacin. *, incidence (number of
photosensitivity cases/number of evaluated cases).
|
|
The influence of treatment factors was analyzed (Fig.
3). Among treatment factors, the duration
of treatment was most often associated with the occurrence of a
photosensitivity reaction. The incidence was high when patients were
treated with NFLX for 30 days or more. In patients who were treated for
fewer than 15 days or for 15 to 29 days, the incidence of
photosensitivity was related to previous quinolone medication. This
relationship was not found, however, in patients who were treated for
30 days or more.
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FIG. 3.
Influence of treatment factors on incidence of
photosensitivity to lomefloxacin. *, incidence (number of
photosensitivity cases/number of evaluated cases).
|
|
Because the age of patients and the duration of treatment were most
associated with the incidence of a photosensitivity reaction, the
incidence was assessed by combining the following factors: a
contingency table dividing the patients by age into 60 years and older
and into less than 60 years and by treatment duration into the groups
30 days and more and fewer than 30 days was prepared, and the incidence
of a photosensitivity reaction in each cell was calculated (Table
4). The incidence in patients who were 60 years of age and older and took LFLX for more than 30 days was the
highest, i.e., 6.43% (18 of 280). The incidence in patients who were
60 years of age and older but took LFLX for fewer than 30 days was
1.30% (20 of 1,533), and that in patients who were aged fewer than 60 years who took LFLX for 30 days and more was 0% (0 of 140).
| |
DISCUSSION |
Since norfloxacin was first marketed in 1984, several new
quinolones have been developed and are widely used. Their safety, however, has not yet been fully established. Quinolone-specific adverse
reactions have become common, such as toxicity in young animals,
dizziness and insomnia, and convulsion when administered concomitantly
with nonsteroidal antiinflammatory drugs. A photosensitivity reaction
caused by quinolones was first reported for nalidixic acid (2, 3,
11). As new quinolones have become widely used, photosensitivity
due to new quinolones has become prevalent. However, the actual
incidence has not yet been established.
During the clinical trials of lomefoxacin before its commercial
release, only one case of a photosensitivity reaction among 4,488 subjects (0.02%) was reported (24). In this case, a patient on lomefloxacin developed a severe sunburn after ocean fishing. After
this drug had been marketed, however, photosensitivity reactions were
reported from several institutions (6, 25, 26). Tozawa et
al. (19), Department of Urology, Anjo Kosei Hospital,
reported a high incidence, i.e., 5.6% (19 of 338 patients). Therefore, in addition to the follow-up investigation at this institution, a
nationwide survey of the incidence of photosensitivity due to lomefloxacin was performed.
Among a total of 56,285 patients treated with lomefloxacin during
development of this drug and during a period of 3 years in a
postmarketing survey, photosensitivity was found in only 20 patients
(0.04%) (15). Later, Tozawa et al. (20) reported that when the dosage of LFLX was limited to 400 mg daily in two divided
doses for fewer than 14 days, a photosensitivity reaction developed in
only 1 of 324 patients (0.3%).
There are many reports of photosensitivity due to new quinolones. Using
mice in vivo, Wagai et al. (22) reported phototoxicity of
nalidixic acid, enoxacin, ofloxacin, lomefloxacin, and levofloxacin; Maruya et al. (8) reported phototoxicity of ciprofloxacin, lomefloxacin, ofloxacin, enoxacin, and norfloxacin; and Sanchez et al.
(14) reported phototoxicity of pefloxacin, norfloxacin, and
ciprofloxacin. Using rats, Masuoka et al. (10) found
phototoxicity of sparfloxacin and nalidixic acid. Aoki et al.
(1) also observed phototoxicity of lomefloxacin, enoxacin,
ofloxacin, norfloxacin, ciprofloxacin, tosufloxacin, nalidixic acid,
sparfloxacin, and fleroxacin in guinea pigs.
Wagai et al. (21), Maruya et al. (8), and
Robertson et al. (13) reported independently that active
oxygens are produced upon UVA irradiation of quinolones and that these
active oxygens, but not photodegradation products, are involved in
phototoxicity. In photoallergy due to quinolone antibacterial drugs,
Yamada et al. (23) demonstrated that ENX can be
photoallergic by the adjuvant and strip method. Horio et al.
(4) developed a photoallergic reaction to lomefloxacin and
nalidixic acid in guinea pigs under maximizing conditions with
cyclophosphamide pretreatment.
Clinically, photosensitivity from all new quinolones has been reported,
although the incidence is markedly different among drugs. In the
postmarketing survey of recently sold sparfloxacin and fleroxacin,
photosensitivity was found in 53 of 10,024 patients (0.53%) taking
sparfloxacin and in 94 patients taking fleroxacin, although the total
number of patients treated with fleroxacin is not known. For both
drugs, the incidence in patients who were 60 years of age and older and
treated for 2 or more weeks was high (for fleroxacin, Megalocin report
issued by Kyorin Pharmaceutical Co., Ltd. in 1995; for sparfloxacin,
internal postmarketing survey document by Dainippon Pharmaceutical Co.,
Ltd.). Photosensitivity was observed in 4 of 190 patients (2.1%)
treated with Y-26611 (16), a drug for which development for
clinical use was discontinued during clinical trials. The U.S. product
labeling (Maxaquin) for lomefloxacin reports a photosensitivity rate of
2.4%. This incidence is higher than that from our present study. This
difference may be attributed to different skin types and different life
styles. Matsumoto et al. (9) and Marutani et al.
(7) reported that photostability was greatly improved and
that phototoxicity was reduced by introducing a methoxy group at
position 8 of the quinolone ring. Cytotoxicity of the hydrogen and
halogen also decreased. On the basis of these results, it is possible
that the photosensitivity reaction is easily caused by new quinolone
drugs such as lomefloxacin, sparfloxacin, fleroxacin, and Y-26611 that
have a fluorine atom at position 8 of the quinolone ring.
The reasons for the higher incidence in patients who were 60 years of
age and older are not clear. Because blood levels of ofloxacin,
lomefloxacin, enoxacin, and fleroxacin reportedly increase with age
(12, 18), a higher concentration in the skin due to this
increase might partially explain a higher incidence of photosensitivity
in elderly persons. Elderly persons may stay longer in the sunshine
while walking slowly or sitting on benches. Longer treatment may
increase the probability of sun exposure. Because quinolones are
potentially phototoxic substances, intense exposure to UV light could
induce phototoxic skin reactions in patients taking these agents.
Patients with a history of receiving a new quinolone may have acquired
photoallergy to the new quinolone. In the present study,
photosensitivity was more associated with patients with a history of
previous quinolone treatment when the duration of the present treatment
with lomefloxacin was shorter than 30 days in comparison to when it was
30 days or longer. It is difficult to determine, however, whether the
photosensitivity observed in patients taking lomefloxacin was
photoallergic or phototoxic. Patients taking lomefloxacin should be
advised to avoid excessive exposure to sunlight. Moreover, the duration
of lomefloxacin treatment should be short.
| |
ACKNOWLEDGMENT |
We thank the physicians in the 100 participating institutions for
their kind cooperation in this survey.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Dept. of
Dermatology, Okayama University Medical School, Shikata-cho 2-5-1, Okayama, 700-8558, Japan. Phone: 81-86-235-7277. Fax: 81-86-235-7283. E-mail: ropin{at}cc.okayama-u.ac.jp.
| |
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Antimicrobial Agents and Chemotherapy, December 1998, p. 3141-3145, Vol. 42, No. 12
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
