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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