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Antimicrobial Agents and Chemotherapy, February 1998, p. 419-424, Vol. 42, No. 2
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
In Vitro Activities of Y-688, a New 7-Substituted
Fluoroquinolone, against Anaerobic Bacteria
A. P.
MacGowan,*
K. E.
Bowker,
M.
Wootton,
H. A.
Holt, and
D. S.
Reeves
Bristol Centre for Antimicrobial Research and
Evaluation, Southmead Health Services NHS Trust and University of
Bristol, Department of Medical Microbiology, Southmead Hospital,
Westbury-on-Trym, Bristol BS10 5NB, United Kingdom
Received 23 July 1997/Returned for modification 20 September
1997/Accepted 20 November 1997
 |
ABSTRACT |
The in vitro activities of Y-688, a new 7-substituted
fluoroquinolone derivative, against 317 nonduplicate anaerobic isolates were determined. Eighty-five percent of the Bacteroides
fragilis group (n = 89) were inhibited by
2 mg
of Y-688 per liter, while 78, 100, 89, and 98% of gram-negative
bacilli (n = 135), gram-positive cocci
(n = 59), and non-spore-forming (n = 58) and spore-forming (n = 51) gram-positive bacilli,
respectively, were inhibited by
1 mg of Y-688 per liter.
 |
TEXT |
Y-688
[(S)-(+)-7-(3-aminomethyl-3-fluoromethyl-1-pyrrolidi- ny)-1-cyclopropyl-6-fluoro-1,4-dihydro8-methoxy-4-oxo-3-qui- nolinecarboxylic acid] is a new 7-substituted fluoroquinolone (Fig.
1) (7). Little work has so far
been published on its in vitro activity against anaerobes, although
Y-688 is known to have good activity against gram-positive strains,
including strains of staphylococci and enterococci resistant to
ofloxacin, tosufloxacin, or sparfloxacin (17). In this study
the in vitro activity of Y-688 was compared to those of the
fluoroquinolone levofloxacin, the napthyridone compound trovafloxacin
(4), the carbapenem meropenem, and the nitroimidazole
metronidazole against 317 nonduplicate anaerobic clinical isolates.
The anaerobic bacteria studied were from the collection held at
Southmead Hospital. Most were recent clinical isolates from the
hospital, but strains were also provided by Bristol Dental Hospital,
the Public Health Laboratory Service Anaerobic Reference Unit, Cardiff,
United Kingdom, Zeneca Pharma, Alderley Park, United Kingdom, and
D. A. Murdoch of this department. Strains were identified by
standard criteria (10, 13). The following control strains were used: Bacteroides fragilis ATCC 25285, Clostridium perfringens NCTC 1129, Peptostreptococcus
magnus ATCC 14956, Staphylococcus aureus ATCC 9144, and
Escherichia coli ATCC 10536. The antimicrobials used were
obtained from their manufacturers. They included levofloxacin (Hoechst-Marion-Roussel, Middlesex, United Kingdom), trovafloxacin (Pfizer, Sandwich, United Kingdom), meropenem (Zeneca Pharma, Cheshire,
United Kingdom), and metronidazole (P.M.U. South Devon Healthcare,
Devon, United Kingdom). Susceptibilities were determined by the
standard agar incorporation dilution method recommended by the British
Society for Antimicrobial Chemotherapy (3). Wilkins Chalgren
agar (CM619; Unipath) supplemented with 5% lysed horse blood was used,
and the antimicrobials were incorporated into the medium in a
log2 dilution series starting from 1 mg/liter. Inocula were
prepared by diluting bacterial suspensions equivalent in turbidity
to McFarland 0.5 standard 1 in 10 in saline, resulting in
approximately 104 CFU per spot when the inocula were
applied by a multipoint inoculator (Denley Instruments, Billingshurst,
United Kingdom). The plates were incubated anaerobically in an
atmosphere of 80% N2, 10% H2, and 10%
CO2 at 37°C for 40 h in an anaerobic cabinet (Don
Whitley, Shipley, United Kingdom). The MIC was read by eye and was
defined as the lowest concentration of drug to inhibit macroscopically visible colonies.
For the purposes of analysis strains were grouped into either a species
or a genus with
5 representatives, and MIC ranges, MICs at which 50%
of the isolates were inhibited (MIC50), and MIC90s were calculated. If there were
10 strains in a
particular group the percentages of strains with MIC values of
0.5,
1,
2, and
4 mg/liter were calculated for the quinolones.
Y-688 and trovafloxacin were the most active fluoroquinolones tested
against these anaerobic bacteria: the MIC90 of Y-688 was
1.0 mg/liter, compared to 8, 1, 1, and >128 mg/liter for levofloxacin, trovafloxacin, meropenem, and metronidazole, respectively (Tables 1
and 2). The high MIC90 of
metronidazole was related to the numbers of Actinomyces
spp., Lactobacillus spp., and Propionibacterium acnes isolates tested rather than to any changes in metronidazole susceptibility in other anaerobe species. However, Y-688 was two- to
fourfold less active than trovafloxacin against members of the B. fragilis group but four to eight times more active than trovafloxacin against other gram-negative rods such as
Fusobacterium and Prevotella spp. (Table 1).
Y-688 had activity similar to those of trovafloxacin, meropenem, and
metronidazole against gram-positive anaerobic cocci (Table 2).
Similarly, for either spore-forming or non-spore-forming gram-positive
bacilli Y-688 was equipotent to trovafloxacin and meropenem (Table 2).
The MIC50s for Bacteroides spp. B. distasonis, B. ovatus, B. thetaiotaomicron,
B. uniformis, and B. vulgatus and for a
Bifidobacterium species were the highest, namely, 1 mg/liter, while those for P. magnus,
Peptostreptococcus micros, and Prevotella
intermedia were the lowest, namely, 0.015 mg/liter. The MICs of
Y-688 against those genera or species for which fewer than five
representatives were tested, B. caccae (1),
B. eggerthii (3), B. ureolyticus (3), Fusobacterium necrophorum (1),
Fusobacterium sp. (1), Peptostreptococcus
prevoti (2), Porphyromonas asaccharolytica (1), Porphyromonas gingivalis (1),
Prevotella buccae (4), Prevotella
loescheii (2), and a Propionibacterium sp.
(2) (the numbers in parentheses are the numbers of isolates)
were <1 mg/liter except for a single isolate of P. buccae
(MIC, 4 mg/liter). The MICs for single strains of Clostridium
paraputrificum and Clostridium clostridioforme of
quinolones were high, and the C. paraputrificum isolate was
also resistant to metronidazole (MIC, 32 mg/liter; Table 1). The
meropenem MICs for all strains tested were <4 mg/liter except for
single strains of Actinomyces meyeri (MIC, 4 mg/liter) and
Actinomyces viscosus (MIC, 8 mg/liter) and three strains of
Lactobacillus spp. (MICs, 8, 16, and 16 mg/liter). As
expected, metronidazole MICs of
8 mg/liter were noted among Actinomyces spp. Lactobacillus spp., and
Propionibacterium spp.
There are at present a number of fluoroquinolone derivatives with
greater in vitro activity against anaerobic bacteria than ciprofloxacin
and ofloxacin (8). Perhaps the most active thus far
described is E5068, with a MIC50 and a MIC90 of
0.03 and 0.25 mg/liter, respectively, against the B. fragilis group (1). Clinafloxacin (CI960, PD 127391),
DU 6859a, and Bay y3118 have MIC90s of 0.12 to 0.5 mg/liter
for these bacteria (6, 12, 15, 16), while WIN 57273 and
clinafloxacin inhibited >95% of 300 mixed anaerobe strains
(5) at
2 mg/liter. Bay y3118 and DU 6859a also have
excellent activities against a wide range of anaerobes (11, 14,
16). However, WIN 57273 and Bay y 3118 are not being developed
because of toxicity problems.
Other fluoroquinolones are not quite as active; for example,
trovafloxacin had an MIC90 of 1 mg/liter against 400 mixed
anaerobes but is more active than CI990 (95% of strains inhibited by
16 mg/liter), sparfloxacin, or temafloxacin (2, 5). All of the above are more active than levofloxacin. Y-688 has an
MIC90 of 1 mg/liter, indicating that it has activity
similar to those of trovafloxacin and also Bay 12-8039 (9).
However, Y-688 is two- to fourfold less active than trovafloxacin or
Bay 12-8039 against the B. fragilis group, which is of
concern in view of their importance as human pathogens. Besides the in
vitro activity against anaerobes, bactericidal activity, inoculum
effect, postantibiotic effect, toxicology, and performance in in vitro
and animal models and human pharmacokinetics will have to be taken into
account prior to deciding doses and frequency of dosing for human
treatment studies and the further development of Y-688.
 |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Medical Microbiology, Southmead Hospital, Westbury-on-Trym, Bristol
BS10 5NB, United Kingdom. Phone: 0044 117 959 5652. Fax: 0044 117 959 3154. E-mail: STAFF{at}BCARE.ORG.UK.
 |
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Antimicrobial Agents and Chemotherapy, February 1998, p. 419-424, Vol. 42, No. 2
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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