Journal of Antimicrobial Chemotherapy (2002) 49, 851-855
© 2002 The British Society for Antimicrobial Chemotherapy
BMS284756 (formerly T-3811, a des-fluoroquinolone) potency and spectrum tested against over 10 000 bacterial bloodstream infection isolates from the SENTRY antimicrobial surveillance programme (2000)
University of Iowa College of Medicine, Iowa City; the JONES Group/JMI Laboratories, North Liberty, IA; and Tuft’s University School of Medicine, Boston, MA, USA
Received 27 July 2001; returned 7 January 2002; revised 6 February 2002; accepted 13 February 2002.
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Abstract |
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BMS284756 is a novel des-F (6)-quinolone, which has a wide range of activity against many species of Gram-positive and -negative organisms. The potency of BMS284756 was compared with that of other quinolones, including ciprofloxacin, gatifloxacin and levofloxacin, and was tested against >10 000 bloodstream isolates from the year 2000 SENTRY antimicrobial surveillance programme. Twelve pathogens accounted for nearly all of the referred isolates and included Staphylococcus aureus, coagulase-negative staphylococci, Escherichia coli, Klebsiella pneumoniae, Enterobacter spp., Serratia spp., Pseudomonas aeruginosa, Acinetobacter spp., Enterococcus spp., Streptococcus pneumoniae and ß-haemolytic or viridans group streptococci. Of the four quinolones tested, BMS284756 was the most active overall against Staphylococcus spp. (MIC50
0.03 mg/L) and Streptococcus spp. (MIC50 0.06 mg/L). In contrast, BMS284756 was less potent than the other quinolones against the enteric Gram-negative bacilli (MIC50 0.03–1 mg/L). With a proposed breakpoint of 4 mg/L, BMS284756 may be a therapeutic alternative pending the results of clinical trials. |
Introduction |
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As a class, quinolone compounds have a wide therapeutic spectrum of activity against Gram-positive and -negative organisms; however, differences in potency among the marketed fluoroquinolones can occur.1,2 Although the newer fluoroquinolones generally have increased activity against Gram-positive and fastidious pathogens, they are no more active than ciprofloxacin and levofloxacin against many enteric and non-enteric Gram-negative species.3 In previous studies, BMS284756 (formerly T-3811), a novel des-F (6)-quinolone, has shown good in vitro activity against methicillin-resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae, b-haemolytic Streptococcus spp. and Enterococcus faecalis.4 BMS284756 was determined to have greater oral bioavailability compared with ciprofloxacin,1 and was less toxic (both acute and chronic) than levofloxacin in animal models.5,6
The purpose of this study was to determine the in vitro activity of BMS284756 against bacterial bloodstream infection (BSI) isolates from the SENTRY antimicrobial surveillance programme. The potency and spectrum of BMS284756 were compared with that of other quinolones, including ciprofloxacin, gatifloxacin and levofloxacin.
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Materials and methods |
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Bacterial isolates
A total of >10 000 bacterial BSI isolates were obtained from participant laboratories in North America (31 sites), Latin America (10 sites) and Europe (17 sites) from January to December 2000, as part of the SENTRY programme. The top 12 occurring pathogens accounted for 10 654 isolate epi-sodes during this time period and were as follows: S. aureus (3094 isolates), Escherichia coli (1866), coagulase-negative staphylococci (CoNS; 1461), Enterococcus spp. (1045) Klebsiella spp. (884), Pseudomonas aeruginosa (556), S. pneumoniae (482), Enterobacter spp. (437), b-haemolytic streptococci (303), Acinetobacter spp. (210), viridans group streptococci (164) and Serratia spp. (152). This rank order was very similar to the rank order in previous SENTRY programme years since 1997, with Serratia spp. replacing Proteus mirabilis in the top 12 pathogens for the 2000 SENTRY pro-gramme in the United States (US) and Canada.7 Likewise, the rank order of pathogens from Latin America was similar to previous years.8
Study design and susceptibility methods
The study protocol dictated that each medical centre collect the first 20 consecutive clinically significant BSI isolates (one per patient episode) per month and forward them to the reference laboratory (University of Iowa and JMI Laboratories, IA, USA) for susceptibility testing. Isolates were identified using the Vitek System (bioMérieux Inc., Hazelwood, MO, USA) supplemented with conventional tests as needed. Stock cultures of all isolates were kept at –80°C. All isolates were susceptibility tested, utilizing NCCLS reference broth microdilution methods, against a panel of antimicrobial agents, including BMS284756, ciprofloxacin, levofloxacin and gatifloxacin.9,10 A colony suspension equal to a 0.5 McFarland standard was made for all organisms and a volume of 50 µL (100 µL for S. pneumoniae) of this suspension was pipetted into 10 mL of cation-adjusted Mueller–Hinton broth or Mueller–Hinton broth supplemented with lysed horse blood for the Streptococcus spp. Using an autoinoculator, 100 µL of the inoculum suspension were dispensed into the wells of a dry form panel (TREK Diagnostics, Westlake, OH, USA). Colony counts were carried out regularly to ensure a starting inoculum of c. 3–5 x 105 cfu/mL. The panels were incubated in an ambient air environment at 35°C for 16–20 h for all Gram-negative organisms and 20–24 h for all Gram-positive and fastidious organisms. Trays were then read manually and an endpoint of no organism growth was established as the MIC per NCCLS standards.9,10 Quality control was carried out using the following strains recommended by NCCLS: S. aureus ATCC 29213, E. faecalis ATCC 29212, S. pneumoniae ATCC 49619, Haemophilus influenzae ATCC 49766 and 49247, E. coli ATCC 25922 and 35218, and P. aeruginosa ATCC 27853.
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Results |
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BMS284756 demonstrated good activity against the Gram-positive cocci (Table 1). Among the four quinolones tested, BMS284756 was the most active compound overall tested against oxacillin-susceptible and -resistant S. aureus (MIC50,
0.03 and 2 mg/L) and CoNS (MIC50, 2 and 1 mg/L), viridans group and ß-haemolytic streptococci (MIC50 0.06 mg/L) and S. pneumoniae (MIC50 0.06 mg/L). None of the tested fluoroquinolones was very active against enterococci, with MIC50s of 0.5–>4 mg/L and percentage susceptibility ranging from 40% (ciprofloxacin) to 76% (BMS284756). BMS284756 was the most active against vancomycin-resistant isolates with 46% inhibited at 4 mg/L.
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Using the proposed susceptibility breakpoint of
4 mg/L,5 92–>99% of the staphylococcal isolates, regardless of oxacillin susceptibility, were considered susceptible to BMS284756. The remaining quinolones had decreased activity against staphylococci (combined oxacillin-susceptible and -resistant populations) ranging in percentage susceptibility from 68% (ciprofloxacin) to 79% (gatifloxacin) for S. aureus, and 51% (ciprofloxacin) to 90% (gatifloxacin) for CoNS. In general, ciprofloxacin, levofloxacin and gatifloxacin were less active against oxacillin-resistant strains of Staphylococcus spp. than oxacillin-susceptible strains (Table 1). Although the fluoroquinolones tested were very active against the viridans group streptococci (98–100% susceptible) and ß-haemolytic streptococci (99–100%), BMS284756 was at least four-fold more potent than the other quinolones (MIC90 0.12 versus 0.5–1 mg/L). Against S. pneumoniae, BMS284756 (MIC90 0.06 mg/L) was eight-fold more potent than gatifloxacin (MIC90 0.5 mg/L), 16-fold more potent than levofloxacin (MIC90 1 mg/L) and 32-fold more potent than ciprofloxacin (MIC90 2 mg/L). However, as seen with the other Streptococcus spp., levofloxacin (>99% of pneumococcal isolates susceptible), gatifloxacin (>99% susceptible) and BMS284756 (100% susceptible) were all very active against S. pneumoniae at their respective NCCLS breakpoint concentrations.9–11
BMS284756 was generally two- to four-fold less potent than the other quinolones against Enterobacteriaceae, with MIC90s ranging from 0.5 mg/L (E. coli) to >4 mg/L (Serratia spp.), compared with 0.25–2 mg/L of the other three agents (Table 2). At the proposed or recommended NCCLS breakpoints, BMS284756 was comparable to the other agents against E. coli (92% susceptible versus 91–92%), Enterobacter spp. (91% versus 90–92%) and Klebsiella spp. (95% versus 93–95%), but was less active against Serratia spp. (88% versus 92–97%).
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As a group, the four quinolones were only marginally active against P. aeruginosa (MIC90
4 mg/L; 71–74% sus-ceptible) and Acinetobacter spp. (MIC90 2 mg/L; 45–55% susceptible). BMS284756 was the least active agent against BSI isolates of P. aeruginosa (MIC50 2 mg/L; 71% susceptible) but was the most active drug against Acinetobacter spp. (MIC50 4 mg/L; 55% susceptible). |
Discussion |
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Of the four quinolones tested, BMS284756 was the most potent and demonstrated the broadest spectrum of activity towards Gram-positive BSI isolates, confirming earlier results.1,2,4–6 In contrast, BMS284756 was less potent against the Gram-negative enteric bacilli and P. aeruginosa BSI isolates. None of the quinolones tested showed significant activity against Enterococcus or Acinetobacter spp. How-ever, given the potential breakpoint of
4 mg/L, excellent bioavailibility and other favourable pharmacokinetic parameters, BMS284756 may be a possible therapeutic alternative for infections due to a wide variety of pathogens, pending clinical trial results.5
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Footnotes |
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* Correspondence address. The Jones Group, 345 Beaver Kreek Centre, Suite A, North Liberty, IA 52317, USA. Tel: +1-319-665-3370; Fax: +1-319-665-3371; E-mail: ronald-jones{at}jmilabs.com
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References |
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1 . Takahata, M., Mitsuyama, J., Yamashiro, Y., Yonezawa, M., Araki, H., Yamada, H. et al. (1997). T-3811, a novel des-F(6)-quinolone: in vitro and in vivo antimicrobial activities. In Program and Abstracts of the Thirty-seventh Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Canada, 1997. Abstract F159, p. 173. American Society for Microbiology, Washington, DC.
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Felmingham, D., Robbins, M. J., Ingley, K., Mathias, I., Bhogal, H. & Leakey, A. (1997). In-vitro activity of trovafloxacin, a new fluoroquinolone, against recent clinical isolates. Journal of Antimicrobial Chemotherapy 39, Suppl. B, 43–9.
4 . Hayashi, K., Todo, Y., Hamamoto, S., Ojima, K., Yamada, M., Kito, T. et al. (1997). T-3811, a novel des-f (6)-quinolone: synthesis and in vitro activity of 7-(isoindolin-5-yl) derivatives. In Program and Abstracts of the Thirty-seventh Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Canada, 1997. Abstract F158, p. 173. American Society for Microbiology, Washington, DC.
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Fung-Tomc, J. C., Minassian, B., Kolek, B., Huczko, E., Aleksunes, L., Stickle, T. et al. (2000). Antibacterial spectrum of a novel des-fluoro (6) quinolone, BMS-284756. Antimicrobial Agents and Chemotherapy 44, 3351–6.
6 . Nagai, A., Takahata, M., Miyazaki, M., Kawamura, Y., Kodama, T., Todo, Y. et al. (1997). T-3811, a novel des-F(6)-quinolone: toxicological evaluation. In Program and Abstracts of the Thirty-seventh Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Canada, 1997. Abstract F162, p. 173. American Society for Microbiology, Washington, DC.
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8 . Sader, H. S., Pfaller, M. A., Jones, R. N., Doern, G. V., Gales, A. C., Winokur, P. L. et al. (1999). Bacterial pathogens isolated from patients with blood stream infections in Latin America, 1997: frequencies of occurrence and antimicrobial susceptibility patterns from the SENTRY Antimicrobial Surveillance Program. The Brazilian Journal of Infectious Diseases 3, 97–110.
9 . National Committee for Clinical Laboratory Standards. (2000). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically—Fifth Edition: Approved Standard M7-A5. NCCLS, Wayne, PA.
10 . National Committee for Clinical Laboratory Standards. (2001). MIC Testing: Supplemental Tables M100-S10 (M7). NCCLS, Wayne, PA.
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