新しいニューキノロン系抗菌剤, temafloxacinのヒト腸内細菌叢に及ぼす

Effect of Temafloxacin
VOL.41
on Intestinal
Flora
273
S-5
INFLUENCE OF A NEW-QUINOLONE ANTIBACTERIAL AGENT,
TEMAFLOXACIN, ON NORMAL HUMAN INTESTINAL MICROFLORA
Junko Watabe, Jun Mizutani, Hiromi Suzuki and Koichi Wada
Intestinal Flora Laboratory, Calpis Food Industry Co. Ltd,
11-10, 5-chome, Fuchinobe, Sagamihara, Kanagawa 229, Japan
Kunitomo
Watanabe
and Kazue Ueno
Institute of Anaerobic Bacteriology, School of Medicine, University
The effect of temafloxacin
(TMFX), a newly synthesized
quinolone
of Gifu,
antibacterial
agent,
given orally for 7 days to five healthy male volunteers, on intestinal microflora was
investigated. Faecal specimens were cultured quantitatively
for aerobic and anaerobic
bacteria before, during
Marked suppressions
and after administration.
of Enterobacteriaceae
and Streptococcus, including Enterococcus,
were observed during TMFX administration.
The anaerobic bacteria, Bacteroides, Eubac-
terium, Bifidobacterium, Veillonella and Gram-positive
cocci were also reduced by TMFX
administration in most subjects. Lecithinase-positive
Clostridium was eliminated, though,
lecithinase-negative Clostridium was not affected. Recovery of the levels and composition
of the intestinal
microflora
Key words: Intestinal
was not delayed.
flora; Quinolone; Temafloxacin
Introduction
volunteers
Temafloxacin (TMFX) (Abbott Laboratories,
is a newly developed quinolone antibacterial
USA)
agent,
which has good activity against a broad-spectrum of
microorganisms including
anaerobic
bacteria4,6,8).
Therapy with broad spectrum
antimicrobial
agents
induces changes in the intestinal
flora2) These
changes in the faecal microflora may induce diarrhea,
were admitted
to the clinical study units
during the period of TMFX use.
2. Treatments
A dose of 300 mg of TMFX was given orally to five
subjects followed by subsequent
12 h intervals for 7 days.
3.
Microbiological
Faecal samples
doses of 300 mg at
studies
were collected
before administra-
overgrowth of Clostridium difficile")
and fungi, and
tion of TMFX, on the fourth day of treatment and then
impairment of colonization resistance
in the digestive
on one day (day 8), one week (day 14), 2 weeks (day
21) and 4 weeks (day 35) after cessation of treatment.
tract9).
The present study was performed
to investigate
The faecal samples
the influence of TMFX on intestinal
microflora
(BBL, Microbiology Systems, Cockeysville, Md. USA)
and transported
to the laboratory immediately after
healthy male volunteers
under steady
state
in
condi-
tions.
1.
were put into Gaspak
defecation into sterile plastic containers.
Materials
Subjects
and Methods
Five healthy male volunteers , aged 30-43
years,
were studied. None of the volunteers had taken any
antimicrobial drugs or experienced gastrointestinal
disorders for at least
Written informed
1 month before
consent
was
the study .
obtained and the
stool was transferred
pouches
One gram of
to 9 ml of prereduced
phos-
phate buffered saline with 0.1 per cent agar, serial
10-fold dilutions were made and 0.05 ml volumes
were seeded on various media for detection of intestinal bacteria.
bacteria
scribed
The media for detection of intestinal
and the incubation
previously"
method
Non-selective
have been demedia for total
CHEMOTHERAPY
274
aerobes
and
total
bacteria,
Enterobacteriaceae,
phylococcus,
Pseudomonas
Lactobacillus,
fragilis
group,
selective
with
10-6,
lated
at
10-7
48•`72
h
in
Different
media
and
10_8
on
agar101
differentiation
teriaceae,
and
Enterococcus
No.
STREPT
1
(Eiken
Negler
and
level
20A
Neomycin
Tokyo,
for
Japan).
Enterobac-
were
counted
biochemically
La
(Analytab
by
perfringens
Tokyo,
Product,
API
level
morphology.
Bacteroides
Kagaku,
(Analytab
France)
cell
on
media
species
for
non-selective
Seiyaku,
and
to
or
genus
and
selective
inocu-
cultures.
Clostridium
(Nissui
on
identified
Biotest
to
with
strip
colonies
were
anaerobic
and
strains
identified
inoculated
cultures
identified
characteristics
were
Different
for
10-1,
samples.
Plates
aerobic
selective
and
Lecithinase-positive
faecal
were
dilution.
jars
counted
selective
with
the
predominant anaerobic bacteria, Eubacterium,Grampositive anaerobic cocci and Bifidobacteriumwere
eliminated during antibacterial agent intakes in all
subjects. In subject A, Eubacterium and Bifidobacterium decreased markedly, and in subject B, Eubacterium and Gram-positive anaerobic cocci decreased
,
and in subject C, Gram-positive anaerobic coccidecreased. Veillonella also decreased on the fourth day
of treatment, but increased from 7 days to 28 days
after treatment in all subjects. Lecithinase positive
Clostridium was detected in faeces of 3 subjects before treatment and the levels of these organismswere
decreased below the lowest detectable level during
and after treatment. However, lecithinase negative
Clostridium was not affected by TMFX administration. The major anaerobic bacteria had returnedto
F'usobacter-
non
bacteria
h for
anaerobic
stain
of
total
24-48
colonies
were
Gram
for
for
and
and
inoculated
dilution
media
37°C
were
10-7
Bacteroides
difficile
media
aerobes
and
Non
C.
Selective
total
10-5
Clostridium,
Bacteroides,
Veillonella,
for
10-3,
albicans,
positive
Balme
pretreatment levels by one day after treatment.
TMFX eliminated Escherichia coli that was detected
in faeces of most subjects before treatment and
enumerated Enterobacteriaceae other than E. coliby
7 days after the last dose of TMFX. E. coli had
returned to the pretreatment levels by 14 days after
treatment (Table 2). During the TMFX administration
with
Japan),
API
Les
product),
Grottes,
respective-
ly.
Results
Microbiological
teer
during
ment
are
listed
of
5
in
were
after
were
Table
volunteers
and
day
bacteriaceae
and
during
fourth
subject
C,
days
2.3
after
creased
subject
logs
A.
the
In
day
the
day
decreases
cus
Enterococcus,
of
the
B. fragilis
of treatment.
The
in
of
of
returned
In
7
Bacteroides
treatment
in
viable
count
group,
increased
caused
to
detectable
administration,
also
Entero-
treatment.
deall
of
but
Bacteron
the
of TMFX
Enterobacteriaceae,
and
3
markedly
was
numbers
in
pretreatment
had
after
aeruginosa
A,
anaerobes
levels
and
days
The
subject
induced
and
TMFX
P.
the
The
one
treatment
decreased
7
fourth
especially
fourth
of
treatment.
on
oides,
of
by
of
to
Enterococcus
levels
total
and
Total
day
treatment.
administration
pretreatment
treat-
general,
treatment
returned
after
volun-
after
In
treatment.
the
of each
and
1-2.
during
of
on
faeces
use
1-1,
eliminated
cessation
one
the
agent
suppressed
levels
in
antibacterial
aerobes
day
changes
Streptococa
decrease
1993
anaerobes including the B. fragilis group, Eubacterium, Bifidobacteriumand Gram-positive cocci.However, the levels of total bacteria and total aerobesreturned to the same level as before administrationone
day and 7 days after treatment, respectively. Other
for
Sta-
Candida
lecithinase
used.
media
Streptococcus,
Eubacterium,
were
medium
selective
aeruginosa,
yeast,
Bifidobacterium,
ium
and
Enterococcus,
DEC.
in
period, the level of Enterococcusdecreased markedly
and had returned to normal by one week after cessation of treatment. There was no significant increasein
Enterococcus(Table 3). The composition of Bacteroides
species in the faeces of each subject varied duringthe
period of this study.
B. ruminicola was detected dominantly in faecesof
subjects B, D and E before treatment and decreased
markedly during TMFX use (data not shown).
C. difficile was not recovered from the faecesof any
of the volunteers.
Discussion
Intestinal flora can be influenced by antimicrobial
agents, especially by drugs which are excreted extensively in the bile. The altered gastrointestinal microflora may permit potentialiy invasive pathogensto
overgrow5) or lead to a diminution in colonization
resistance to exogenous microorganisms91.TMFXhas
Effect of Temafloxacin
VOL.41
on Intestinal
Flora
S-5
275
been reported to be excreted mainly in the urine3,8).
However, the concentrations of TMFX in faeces might
Bacteroides more markedly than did sparfloxacin 10),
Although the antibacterial activity of TMFX against
be sufficient to affect both aerobes and anaerobes
faecal aerobes
in
was almost same as those of other
the intestine. None of volunteers complained of abdominal pain, nausea or diarrhoea.
quinolone drugs, the levels of faecal anaerobes, especially the B. fragilis group, decreased during TMFX
In vitro, TMFX was more active against, the B.
use and recovered promptly after administration.
Thus, TMFX administration
might not evoke side
fragilis group than other new quinolone agents such
as ciprofloxacin, ofloxacin and enoxacin 6) With in
vivo human testing, TMFX decreased the level of
reactions
such as diarrhoea.
Taken together, these results show that TMFX is
Table 1-1. Counts* of microorganisms in faecal flora of subjects A, B and C receiving 300 mg of temafloxacin
orally at 12 h intervals for 7 days
*Counts
are expressed
―: Do organisms
as log
10 per gram
of<
2
detected(counts
wet faeces.
10910 per gram)
.
Table 1-2. Counts* of microorganisms in faecal flora of subjects D and E receiving 300 mg of temafloxacin
orally at 12 h intervals for 7 days
*Counts
are expressed as
―: no orgahisms
detected
log
lo per gram
(counts
of<2
wet faeces,
log 10 per gram)
.
CHEMOTHERAPY
276
DEC.
Table 2. Levels* of Enterobacteriaceae
in faeces of volunteers
orally at 12 h intervals for 7 days
*Counts
of
d血ferent
colonies
on
Enterobacteriaceae
selective
receiving 300 mg of temafloxacin
medium (DHL)expressed
as
log
lo per
―:
no
organisms
detected
(counts
of<
2
log 10 per
gram)
gram
wet
faeces.
.
Table 3. Levels* of Enterococcus spp. in faeces of volunteers receiving 300 mg of temafloxacin
orally at 12 h intervals for 7 days
*Counts
of
different
colonies
on
enterococci
selective
medium
expressed
as log
10 per
―:
no
organisms
detected
(counts
of<
2
log 10 per
gram).
gram
wet
faeces.
1993
Effect of Temafloxacin
VOL.41
active
rods,
against
after
aerobic
Enterococcus
Microbial
on Intestinal
and
and
levels
anaerobic
were
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CHEMOTHERAPY
278
新しいニューキノロン系抗菌剤,
temafloxaCinのヒト腸内細菌叢に及ぼす影響
渡部怐子.水
谷
潤・鈴木宏美・和田光一
カルピス食品工梁株式会社腸内フローララボラトリー*
渡辺邦友・上野一恵
岐阜大学医学部附属嫌気性菌実験施般
新しく合成されたキノロン系抗菌剤であるtemafloxacinを5人の健常成人男子に経口で7日間
投与し,腸内細菌叢への影騨を綱べた。投与前,投与中および投与終了後の糞便サンプルを培
養し,糞便中の好気性菌及び嫌気性菌の菌数を測定したところ,投与期間中,大腸菌群および
腸球菌の著しい減少が観察された。バクテロイデス,ビフィドバクテリウムおよびユウバクテ
リウム等の腸内優勢嫌気性菌も,投与期間中多くの被験者で減少した。レシチナーゼ陽性クロ
ストリジウムも減少したが,レシチナーゼ陰性クロストリジウムの菌数に変化はなかった。菌
数および菌叢の構成は投与終了後すみやかに回復した。
*〒229相
模原市淵野辺5-11-10
DEC.
1993

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