ABSTRACT

1. In-vitro Activity of BMS-284756 (T-3811ME), a des-F(6)-Quinolone, Against Organisms Collected in the SENTRY (2000) European Susceptibility Study TABLE 1: List of the participating centers in Euro SENTRY 2000 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 Country France Greece Israel Spain Spain Spain Turkey Turkey Italy Italy Italy Belgium SwitzerlandGermany Germany Sweden Poland UK Poster #713 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 • 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: gary.french@kcl.ac.uk ABSTRACT Background: BMS-284756, is a des-F(6)-quinolone that has shown good activity against a wide variety of bacteria. Methods: Thein-vitroactivities 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. RESULTS Staphylococci BMS-284756was 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 was also more active than levofloxacin or ciprofloxacin against coagulase-negative staphylococci (Figure 2). Enterobacteriaceae 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) Pseudomonas aeruginosa 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 • CONCLUSIONS • 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. • BMS-284756 is less active against enterococci (and E. faecium [modalMIC >4µg/ml is even less susceptible than E. faecalis [modal MIC0.25 µg/ml]). Nevertheless, it is more effective than ciprofloxacin and levofloxacin against these organisms. • 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). • BMS-284756 is less active than ciprofloxacin or levofloxacin against P. aeruginosa, andnone of these three quinolones has reliable activity against Acinetobacter spp (modal MICs >2 µg/ml). • BMS-284756 is a promising new quinolone which deserves further clinical investigation. Streptococci and enterococci 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. The quinolones were less effective against the enterococci, especially E. faecium, but BMS-284756 had the highest activity (Figure 5). INTRODUCTION 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. 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.   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. REFERENCES METHODS AND MATERIALS 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 Chemotherapy44:3351–3356. 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 Disease37:115-125. 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 Disease39:133-135. 4. Takahata M, Mitsuyama J, Yamashiro Y, et al. (1999). In vitro and in vivo antimicrobial activities of T-3811ME, a novel des-F(6)-quinolone. Antimicrobial Agents and Chemotherapy43:1077–1084. 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) 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. A156-12