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In-vitro Activity of BMS-284756 (T-3811ME), a des-F(6)-Quinolone,
Against Organisms Collected in the SENTRY (2000) European Susceptibility Study
Poster #713
ABSTRACT
Background: BMS-284756, is a des-F(6)-quinolone that has shown good
activity against a wide variety of bacteria.
Methods: The in-vitro activities of BMS-284756, ciprofloxacin and
levofloxacin were determined by the broth dilution method (R.N.Jones,
Iowa) on 6582 isolates collected in the SENTRY 2000 survey. No NCCLS
breakpoint for susceptibility to BMS-284756 has been defined, so for this
report we have used that of levofloxacin (2 µg/ml).
Results: BMS, with a mode MIC of 0.03 µg/ml, was the most active of
the quinolones tested against both Staphylococcus aureus (96% of 973
isolates susceptible) and coagulase-negative staphylococci (90% of 470
isolates susceptible). With a mode MIC of 0.06 µg/ml and all isolates
susceptible, it was also the most active against the 693 isolates of
Streptococcus pneumoniae and the 151 other streptococci tested.
BMS-284756 was less active against enterococci (mode MIC 0.25 µg/ml,
61% susceptible) but was more active than the other quinolones. All the
quinolones were highly active against Haemophilus influenzae (739
isolates) and Moraxella catarrhalis (295 isolates); all isolates were
susceptible and the mode MIC of BMS-284756 was 0.03 µg/ml. With
a mode MIC of 0.03 µg/ml and 86% of 2293 isolates susceptible,
BMS-284756 had similar activity to the other quinolones against
Enterobacteriaceae; Serratia and Proteae were less susceptible than
other enterobacteria. BMS-284756 (mode MIC >4 µg/ml, 55%
susceptible) was less active than ciprofloxacin (mode MIC 0.25 µg/ml,
66% susceptible) against the 670 isolates of Pseudomonas aeruginosa. It
also had poor activity against Stenotrophomonas maltophilia (51 isolates,
mode MIC 2 µg/ml, 61% susceptible) and Acinetobacter (247 isolates,
mode MIC >4 µg/ml, 31% susceptible).
Conclusion: BMS-284756 has very promising in-vitro activity that merits
further studies to determine its clinical role.
Staphylococci
Enterobacteriaceae
BMS-284756 was more active than levofloxacin or ciprofloxacin against Staphylococcus aureus (Figure 1). There was a bimodal distribution
of BMS-284756 MICs, with those of resistant isolates straddling the tentative breakpoints (Figure 1). Isolates were usually either susceptible
to both oxacillin and BMS-284756 (and other quinolones) or resistant.
BMS-284756, levofloxacin and ciprofloxacin had broadly similar activity against Enterobacteriaceae (Figure 6). At a concentration of 0.5 µg/ml,
79% of isolates were inhibited by BMS-284756 compared to 85% by levofloxacin and ciprofloxacin. Proteae and Serratia spp. were less
susceptible than other genera (Figure 6a)
BMS-284756 was also more active than levofloxacin or ciprofloxacin against coagulase-negative staphylococci (Figure 2).
BMS-284756
Percent
60
Isolates were sent to the central testing laboratory at the University of Iowa RN Jones,
College of Medicine, Iowa City, IA) where antimicrobial MICs were determined by
microbroth dilution as described previously (Jones et al., 2000). The NCCLS breakpoints
were used, except for BMS-284756 for which which we used the levofloxacin
breakpoints: susceptible 2 µg/ml; intermediate 4 µg/ml, resistant 8 µg/ml.
BMS-284756
20
Levofloxacin
20
BMS-284756
40
20
60
60
Ciprofloxacin
(>2)
40
20
Levofloxacin
40
(>2)
20
<0.03
0.125
0.5
2
FIG 6a. In-vitro activity of BMS-284765 against Enterobacteriaceae
40
60
Levofloxacin
40
Ciprofloxacin
BMS-284756 was less active than levofloxacin and ciprofloxacin against Pseudomonas aeruginosa (Figure 7). At 0.5 µg/ml, only 8% were
inhibited by BMS-284756 compared to 47% by levofloxacin and 62% by ciprofloxacin
20
60
Center
CHU de Lille
National University of Athens Medical School
The Chaim Sheba Medical Center
University Hospital Virgen de la Macarena
Hospital de Bellvitge
Hospital Ramon y Cajal
Hacettepe Universitesi Tip Fakultesi
Marmara Universitesi Tip Fakultesi
Universita degli Studi di Genova
Universita degli Studi di Catania
Policlinico Agostino Germelli
Hopital Erasme-Université Libre de Bruxelles
Unité de Bacteriologie CHU Lausanne
Heinrich-Heine Universitat
J.-W.-Goethe Universitat
University Hospital, Linkoping
Sera and Vaccines Central Research Lab
St Thomas Hospital
Pseudomonas aeruginosa
FIG 6. In-vitro activity of quinolones against 2267 isolates of
Enterobacteriaceae
Percent
60
40
<0.03
>4
MICs (µg/ml)
0.125 0.5
MICs (µg/ml)
2
Ciprofloxacin
>4
Streptococci and enterococci
Percent
80
60
40
20
Percent
60
E. coli
30
(1095 isolates)
60
Citrobacter spp.
30
(62 isolates)
Enterobacter spp. 60
30
(278 isolates)
60
Klebsiella spp.
30
(504 isolates)
60
Proteus mirabilis
30
(145 isolates)
60
Other Proteae
30
(70 isolates)
60
Serratia spp.
30
(113 isolates)
80
60
40
20
80
60
40
20
(>2)
<0.25
<0.03
0.125
0.5
2
>4
 BMS-284756 is highly active in-vitro (and usually more active than
ciprofloxacin and levofloxacin) against against S. pneumoniae and
other streptococci, Haemophilus influenzae and Moraxella catarrhalis,
and methicillin-susceptible staphylococci, with modal MICs of 0.03 0.06 µg/ml. Methicillin-resistant staphylococci have higher MICs but
usually <4 µg/ml.
>4
FIG 7. In-vitro activity of quinolones against 670 isolates of
Pseudomonas aeruginosa
The quinolones were less effective against the enterococci, especially E. faecium, but BMS-284756 had the highest activity (Figure 5).
 BMS-284756 is less active against enterococci (and E. faecium
[modal MIC >4 µg/ml is even less susceptible than E. faecalis [modal
MIC 0.25 µg/ml]). Nevertheless, it is more effective than ciprofloxacin
and levofloxacin against these organisms.
Percent
FIG 3. In-vitro activity of quinolones against 693 isolates of
pneumococci (blue boxes, penicillin MICs <0.12 µg/ml; red boxes,
penicillin MICs >0.25 µg/ml)
BMS-284756
Percent
80
60
40
20
BMS-284756
50
40
30
20
10
Levofloxacin
50
40
30
20
10
Ciprofloxacin
50
40
30
20
10
FIG 4. In-vitro activity of quinolones against 151 isolates of
streptococci (blue boxes, a- or non-haemolytic, 70 isolates; red
boxes, b-haemolytic, 81 isolates)
Percent
60
BMS-284756
40
20
80
60
40
20
Levofloxacin
80
60
40
20
Ciprofloxacin
60
40
20
60
 BMS-284756 has generally similar activity to levofloxacin and
ciprofloxacin against Enterobacteriaceae. Amongst this group,
Proteae and Serratia spp. were less susceptible than other genera
(modal MICs of 0.5 - 2.0 µg/ml compared with 0.06 µg/ml for E. coli).
0.06
0.25
MICs (µg/ml)
1
>2
0.125 0.5
MICs (µg/ml)
2
>4
0.125 0.5
MICs (µg/ml)
2
>4
2
>4
 BMS-284756 is a promising new quinolone which deserves further
clinical investigation.
Other Gram-negative bacilli
BMS-284756 was slightly less active than levofloxacin or
ciprofloxacin against pseudomonads (53%, 63% and 73%
of isolates susceptible, respectively). It was slightly less
active than levofloxacin against Stenotrophomonas
maltophilia (61% and 91% of isolates susceptible,
respectively), but more active than ciprofloxacin
(31% susceptible).
None of the quinolones had good activity against
Acinetobacter spp. (Figure 8), and there was
little
difference in activity between them.
<0.03
0.5
MICs (µg/ml)
FIG 5. In-vitro activity of quinolones against 328 isolates of
Enterococcus faecalis (blue boxes, 234 isolates) and Enterococcus
faecium (red boxes, 94 isolates)
(>2)
0.125
(>2)
<0.03
Percent
50
BMS-284756
40
30
20
10
50
Levofloxacin
40
30
20
10
50
Ciprofloxacin
40
30
20
10
P. aeruginosa, and none of these three quinolones has reliable activity
against Acinetobacter spp (modal MICs >2 µg/ml).
<0.25
40
<0.016
 BMS-284756 is less active than ciprofloxacin or levofloxacin against
(>2)
<0.03
20
Country
France
Greece
Israel
Spain
Spain
Spain
Turkey
Turkey
Italy
Italy
Italy
Belgium
Switzerland
Germany
Germany
Sweden
Poland
UK
CONCLUSIONS
<0.03 0.125
0.5
2
BMS-284756 MICs (µg/ml)
MICs (µg/ml)
Streptococcus pneumoniae, alpha-haemolytic, non-haemolytic and beta-haemolytic streptococci were all highly susceptible to BMS-284756
(Figures 3 & 4); levofloxacin and ciprofloxacin were slightly less active.
Ciprofloxacin
The 18 hospitals participating in the European SENTRY study in 2000 were in Belgium,
France, Germany, Greece, Israel, Italy, Poland, Spain, Sweden, Switzerland, Turkey and
the U.K. (Table 1)
FIG 2. In-vitro activity of quinolones against 470 isolates of
coagulase-negative staphylococci (blue boxes, oxacillin MICs <2
µg/ml; red boxes, oxacillin MICs >4 µg/ml)
FIG 1. In-vitro activity of quinolones against 973 isolates of
Staphylococcus aureus (blue boxes, oxacillin MICs <2 µg/ml; red
boxes, oxacillin MICs >4 µg/ml)
INTRODUCTION
METHODS AND MATERIALS
TABLE 1: List of the participating
centers in Euro SENTRY 2000
RESULTS
Levofloxacin
BMS-284756 is a novel des-fluoro(6) quinolone which lacks the 6-position fluorine typical
of other members of the group. It is active against many aerobic bacteria, including some
ciprofloxacin-resistant strains (Takahara et al., 1999; Fung-Tomc et al 2000, Jones et al.,
2001). We have compared its activity to that of other quinolones and other antimicrobial
agents against aerobes collected in the European SENTRY Antimicrobial Surveillance
Program in 2000.
G. L. French
Department of Infection, Guy’s, King’s and St. Thomas’ Medical School
St. Thomas Hospital, London, SE1 7EH, U.K.,
Phone: +44 (0) 207 928 9292 Fax: +44 (0) 207 928 0730
Email: [email protected]
K. P. Shannon1, A. King1, G. L. French1 and the SENTRY Participants Group2
1Department of Infection, Guy’s, King’s and St. Thomas’ Medical School, St. Thomas’ Hospital, London,U.K., 2List of SENTRY Participant Group – Europe
All three quinolones had similar good activity against
Haemophilus influenzae, with all isolates susceptible and
98.6% of isolates being inhibited by 0.03 µg/ml of
BMS-284756. Similarly, they were all highly active against
Moraxella catarrhalis with all isolates susceptible and
99.3% inhibited by 0.03 µg/ml of BMS-284756.
FIG 8. In-vitro activity of other quinolones against 247 isolates of
Acinetobacter species
Percent
80
BMS-284756
60
40
20
Levofloxacin
Ciprofloxacin
REFERENCES
80
60
40
20
80
60
40
20
(<0.25 )
<0.03 0.125
1.
Fung-Tomc J, Minassian B, Kloek B, et al. (2000). Antibacterial spectrum of a novel des-Fluoro (6)
quinolone, BMS-284756. Antimicrobial Agents and Chemotherapy 44:3351–3356.
2.
Jones RN, Croco MAT, Kugler KC et al. (2000). Respiratory tract pathogens isolated from patients
hospitalized with suspected pneumonia: frequency of occurrence and antimicrobial susceptibility patterns
from the SENTRY Antimicrobial Surveillance Program (United States and Canada, 1997). Diagnostic
Microbiology and Infectious Disease 37:115-125.
3.
Jones RN, Pfaller MA, Stilwell M, & the SENTRY Antimicrobial Surveillance Program Participants Group
(2001). Activity and spectrum of BMS 284756, a new des-F (6) quinolone, tested against strains of
ciprofloxacin-resistant Gram-positive cocci. Diagnostic Microbiology and Infectious Disease 39:133-135.
4.
Takahata M, Mitsuyama J, Yamashiro Y, et al. (1999). In vitro and in vivo antimicrobial activities of T3811ME, a novel des-F(6)-quinolone. Antimicrobial Agents and Chemotherapy 43:1077–1084.
(>2)
0.5
MICs (µg/ml)
2
>4
A156-12