ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Feb. 993, p. 366-370 Vol. 37, No. 0066-0/93/00366-05$0.00/0 Copyright 993, American Society for Microbiology In Vitro Activity of CP-99,9, a New Fluoroquinolone, against Clinical Isolates of Gram-Positive Bacteria G. M. ELIOPOULOS, * K. KLIMM, C. T. ELIOPOULOS,' M. J. FERRARO,'3 AND R. C. MOELLERING, JR.' Department of Medicine, New England Deaconess Hospital, and Harvard Medical School, Boston, Massachusetts 05, and Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 03 Received 3 August 99/Accepted December 99 The in vitro activity of the fluoroquinolone CP-99,9 against gram-positive bacteria was compared with those of five other antimicrobial agents. Against ciprofloxacin-susceptible staphylococci and against streptococci, MICs were <0. and.,ig/ml, respectively. CP-99,9 was also more active than ciprofloxacin against ciprofloxacin-resistant staphylococci, most enterococci, Leuconostoc spp., and lactobacilli. CP-99,9 is a new fluoroquinolone antimicrobial agent with the chemical designation 7-(3-azabicyclo[3..0]hexyl) naphthyridone (3). As the currently available antimicrobial agents of this class demonstrate relatively modest activities against many gram-positive bacteria (), in the present study we evaluated the in vitro activity of CP-99,9 against 370 gram-positive bacteria representing a broad range of antimicrobial resistance patterns. (This work was presented in part at the 3nd Interscience Conference on Antimicrobial Agents and Chemotherapy, Anaheim, Calif., to October, 99.) Bacterial strains used in this study were recently obtained (990 to 99) clinical isolates collected at the Massachusetts General Hospital, with the exception of some strains collected from other sources because of specific or unusual resistance traits.,b-lactamase-producing enterococci were recovered earlier in Boston, Mass. (9), or in Houston, Tex. (), as described previously. Isolates of Enterococcus avium and Enterococcus raffinosus were referred to our laboratories from various sources (6). -resistant strains of enterococci were obtained from Boston; the Centers for Disease Control; the National Institutes of Health; Long Island, N.Y.; Providence, R.I.; and Madrid, Spain. Listeria monocytogenes, Leuconostoc spp., Lactobacillus spp., Pediococcus spp., and corynebacteria had been collected over several years. We also examined the activity of CP-99,9 against 30 isolates of Staphylococcus aureus collected in Boston approximately one decade earlier () to determine whether levels of resistance to fluoroquinolones had changed over time. CP-99,9 was provided by Pfizer, Inc., Groton, Conn. Other powders for antimicrobial susceptibility testing were generous gifts of their manufacturers: ciprofloxacin, Miles, Inc., West Haven, Conn.; sparfloxacin, Warner-Lambert Co., Ann Arbor, Mich.; imipenem, Merck Sharp & Dohme, West Point, Pa.; and vancomycin, Eli Lilly & Co., Indianapolis, Ind. (Abbott Laboratories, North Chicago, Ill.) became available to us after the study began, so not all species were examined for susceptibility to this agent, which has since been withdrawn from the market. Antimicrobial agents were incorporated into Mueller-Hinton II agar (Becton Dickinson Microbiology Systems, Cockeysville, * Corresponding author. 366 Md.) which was supplemented with 5% sheep blood for testing corynebacteria, streptococci, lactobacilli, Leuconostoc spp., and Pediococcus spp. Inocula of approximately 0 CFU per spot were applied to the surface of the plates with a multiprong inoculator, and plates were read after approximately h of incubation, except for the plates with corynebacteria, which were incubated h to ensure adequate growth. With the exclusion of corynebacteria, strains tested on blood-supplemented media were incubated in 5% CO. Differences in incubation conditions did not influence the activity of any drug against the control strain S. aureus ATCC 93. Results are shown in Table. Against ciprofloxacinsusceptible strains of staphylococci, MICs for 90% of isolates tested (MIC90s) of CP-99,9 were '0.,ug/ml, and the new agent was more active than ciprofloxacin and temafloxacin against these strains. Among the ciprofloxacinsusceptible strains of S. aureus, isolates that were methicillin susceptible or resistant demonstrated comparable susceptibilities to CP-99,9. The new drug was the most active quinolone against ciprofloxacin-resistant isolates, but relatively high concentrations were required for inhibition (MIC0s, to 6,ug/ml). CP-99,9 was four- to eightfold more active than temafloxacin or ciprofloxacin against streptococci (groups A, B, and G and viridans group streptococci) and pneumococci. Activity of sparfloxacin against these strains fell between that of CP-99,9 and those of ciprofloxacin and temafloxacin. CP-99,9 was fourfold more active than ciprofloxacin against ciprofloxacin-susceptible Enterococcus faecalis (MIC90s, to,g/ml) and against both vancomycin-susceptible and -resistant Enterococcus faecium (MIC90s,,ug/ml). The new quinolone was the most active drug tested against Leuconostoc spp. and Pediococcus spp. and was the most potent quinolone against Corynebacterium jeikeium. Inhibitory concentrations of CP-99,9 against the latter varied over a wide range, however, and were relatively high. Only vancomycin proved to be uniformly active against these strains. There was no difference in the activity against recent isolates of ciprofloxacin-susceptible S. aureus and that against strains collected more than 0 years ago for either CP-99,9 or ciprofloxacin. Against most species we have tested, CP-99,9 was more active than ciprofloxacin and temafloxacin. While the new quinolone was generally more active than sparfloxacin, MIC90s of these two drugs against the more-common patho- Downloaded from http://aac.asm.org/ on October, 0 by guest
VOL. 37, 993 NOTES 367 TABLE. Comparative in vitro activity of CP-99,9 Organism (no.) Antimicrobial MIC (plg/ml)a Staphylococcus aureus Methicillin susceptible, ciprofloxacin susceptible (0) Methicillin resistant, ciprofloxacin susceptible (0) Methicillin resistant, ciprofloxacin resistant (0) Methicillin susceptible, ciprofloxacin resistant (5) Staphylococcus saprophyticus (0) CP-99,9 CP-99,9 CP-99,9 CP-99,9 CP-99,9 - - -0. - - - -0. - -> 0.- -> -3-6 - -> - 3-> - -0. - -0. 0. 6 6 0. 0. 0. 0. 6 > 3 6 6 0. 0. Downloaded from http://aac.asm.org/ Coagulase-negative staphylococci susceptible (0) resistant (0) Streptococcus pneumoniae () CP-99,9 CP-99,9 CP-99,9-0. 0.- 0.- - 0.05-> -6 -> -6 - - 0.- - - - 0.00-0. 3 6 0.00 0. 6 6 > 3 0. on October, 0 by guest Streptococcus spp. Group A (0) CP-99,9 0.- - - 0.00-0. 0.05 0.05 Continued on following page
36 NOTES Group B (0) Group C (7) Group G (0) Organism (no.) Viridans group streptococci Penicillin susceptible () Penicillin resistant () Enterococcus faecalis (0) Enterococcus faecalis High-level gentacimin resistant (0) 3-Lactamase positive (0) TABLE -Continued ANTIMICROB. AGENTS CHEMOTHER. Antimicrobial MIC ( g/ml)a CP-99,9 CP-99,9 CP-99,9 CP-99,9 CP-99,9 CP-99,9 CP-99,9 CP-99,9 - - - - - - 0.- - 0.05-0.00-0. - - - - - <0.00- - - - - - 0.00-0.- - - - - 0.- - - - - - - 0.-6-6 -3-3 - - 0.- - - 0.05 0. 6 3 3 3 Downloaded from http://aac.asm.org/ on October, 0 by guest Enterococcus faecium (0) CP-99,9 - -6.0- - -6 -> 6 > Continued on following page
VOL. 37, 993 NOTES 369 TABLE -Continued. Organism (no.) Antimicrobial MIC (,Lg/ml)a Enterococcus raffinosus (0) CP-99,9 - - - - - - 3 Enterococcus avium (0) Corynebactenum group JK (0) Leuconostoc spp. (0) Lactobacillus spp. (0) Pediococcus spp. () Listeria monocytogenes (0) a 50% and 90%, MIC50 and MIC90, respectively. CP-99,9 CP-99,9 CP-99,9 CP-99,9 CP-99,9 CP-99,9 - - - - 0.- 0.-6 - -3 0.-6 -> - -6 - - > - - - - - > - - -3-6 -6 > - - - - 0.- 3 > > > 0. 0. 3 6 3 > > > Downloaded from http://aac.asm.org/ on October, 0 by guest gens usually differed by no more than one dilution. Activity of the new drug was slightly lower than that which we have previously reported for WIN 5773, another fluoroquinolone, against ciprofloxacin-susceptible strains of staphylococci (MIC90 of WIN 5773,,ug/ml) and group A streptococci (MIC. of WIN 5773, 0.,ug/ml) (). WIN 5773 was considerably more active (MIC90,ug/ml) against Streptococcus pneumoniae (). Although comparisons of studies using different collections of organisms must be interpreted circumspectly, CP-99,9 demonstrated activities against S. aureus and coagulase-negative staphylococci comparable to those of PD 7,39, a fluoroquinolone noted to have particularly good activity against gram-positive bacteria (MIC90s of PD 7,39 of and,ug/ml, respectively, have been reported [5]). PD 7,39 appears, however, to have greater activity than CP-99,9 against beta-hemolytic streptococci (MIC90,,ug/ml) and enterococci (MIC90s, to,ug/ml) (5, 7).
370 NOTES On the basis of the results of this study and published data pertaining to activity of other antimicrobial agents (), CP- 99,9 demonstrated higher activity than currently available fluoroquinolones against most isolates of gram-positive bacteria. However, whether activity against ciprofloxacin-resistant staphylococci and enterococci would be sufficient to permit use against such organisms must await pharmacokinetic evaluation of the new compound. This work was supported by a grant from Pfizer Inc. REFERENCES. Eliopoulos, G. M., and C. T. Eliopoulos. 99. Quinolone antimicrobial agents: activity in vitro. In J. Wolfson and D. C. Hooper (ed.), Quinolone antimicrobial agents, nd ed. American Society for Microbiology, Washington, D.C. (in press).. Eliopoulos, G. M., A. Gardella, and R. C. Moellering, Jr. 9. In vitro activity of Sch9 in comparison with other oral antibiotics. J. Antimicrob. Chemother. 9(Suppl. C):3-5. 3. Eliopoulos, G. M., K. Klimm, C. T. Eliopoulos, M. J. Ferraro, and R. C. Moellering, Jr. 99. In vitro activity of CP-99,9, a new fluoroquinolone, against clinical isolates of gram-positive bacteria. Program Abstr. 3nd Intersci. Conf. Antimicrob. Agents Chemother., Anaheim, Calif.. Eliopoulos, G. M., K. Klimm, L. B. Rice, M. J. Ferraro, and R. C. Moellering, Jr. 990. Comparative in vitro activity of WIN 5773, ANTIMICROB. AGENTS CHEMOTHER. a new fluoroquinolone antimicrobial agent. Antimicrob. Agents Chemother. 3:5-59. 5. Fuchs, P. C., A. L. Barry, M. A. Pfaller, S. D. Allen, and E. H. Gerlach. 99. Multicenter evaluation of the in vitro activities of three new quinolones, sparfloxacin, CI-960, and PD 3,6, compared with the activity of ciprofloxacin against 5,5 clinical bacterial isolates. Antimicrob. Agents Chemother. 35:76-766. 6. Grayson, M. L., G. M. Eliopoulos, C. B. Wennersten, K. L. Ruoff, K. Klimm, F. L. Sapico, A. S. Bayer, and R. C. Moellering, Jr. 99. Comparison of Enterococcus raffinosus with Enterococcus avium on the basis of penicillin susceptibility, penicillin-binding protein analysis, and high-level aminoglycoside resistance. Antimicrob. Agents Chemother. 35:0-. 7. Miranda, A. G., A. R. Wanger, K. V. Singh, and B. E. Murray. 99. Comparative in vitro activity of PD 739, a new fluoroquinolone agent, against susceptible and resistant clinical isolates of gram-positive cocci. Antimicrob. Agents Chemother. 36:35-3.. Murray, B. E., and B. Mederski-Samoraj. 93. Transferable,B-lactamase. A new mechanism for in vitro penicillin resistance in Streptococcus faecalis. J. Clin. Invest. 7:6-7. 9. Rhinehart, E., N. E. Smith, C. Wennersten, E. Gorss, J. Freeman, G. M. Eliopoulos, R. C. Moellering, Jr., and D. A. Goldmann. 990. Rapid dissemination of P-lactamase-producing, aminoglycoside-resistant Enterococcus faecalis among patients and staff on an infant-toddler surgical ward. N. Engl. J. Med. 33:-. Downloaded from http://aac.asm.org/ on October, 0 by guest