ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Feb. 993, p. 39-353 0066-0/93/0039-05$0.00/0 Copyright 993, American Society for Microbiology Vol. 37, No. In Vitro Antimicrobial Activity of, a Novel Azabicyclo-Naphthyridone BETH BRIGGS GOODING AND RONALD N. JONES* Anti-Infectives Research Center, Department of Pathology, University of Iowa College of Medicine, Iowa City, Iowa 5 Received 7 July 99/Accepted December 99 is a trifluoronaphthyridone with significant antibacterial activity that includes the family Enterobacteraceae (MICs for 90% of the strains tested [MIC90s], <0.05 to,ug/ml), MoraxeUla catarrhalis, Haemophilus influenzae, and gonococci (MICs, <0.05 p.g/ml). LegioneUla spp. were also susceptible, with MICs of 0.00 to,ug/ml. demonstrated activity greater than that of ciprofloxacin, ofloxacin, or enoxacin against Pseudomonas aeruginosa (MICg., p,g/ml), Xanthomonas maltophilia (MIC90,,ug/ml), Staphylococcus haemolyticus (MIC90,,ug/ml), Enterococcus faecalis (MIC90,,ug/ml), and pneumococci (MIC90,,ug/ml). Numerous ciprofloxacin-resistant isolates were susceptible to, a new compound showing potential value for further in vivo trials. is a novel investigational fluoroquinolone with a structure differing from those of norfloxacin, ciprofloxacin, and enoxacin (,,, ). It contains the C-7 ring moiety 7-(3-azabicyclo[3..0]hexyl) on a basic naphthyridone configuration. The bicyclo C-7 substitution has been previously evaluated and described in CP-7,667 (5). The -N substitution of is a difluorinated structure identical to that of tosufloxacin (3, 0) that produces enhanced activity against some ciprofloxacin-resistant organisms. In this study, we compared activity with those of four clinically available quinolones (ciprofloxacin, enoxacin, norfloxacin, and ofloxacin) by using standardized methods. Isolates from patients at University of Iowa hospitals and clinics in 99 and 99 were tested. Most of the strains were recent bloodstream isolates or from sterile (nonurinary) body fluids. The 00 Legionella pneumophila isolates were from both clinical and environmental sources (State of Iowa medical centers, 9 to 99). was provided by Pfizer Central Research (Groton, Conn.). The standard powders of ciprofloxacin, enoxacin, norfloxacin, ofloxacin, oxacillin, ampicillin, and erythromycin were obtained from their domestic manufacturers. Broth microdilution trays containing the fluoroquinolones diluted in cation-adjusted Mueller-Hinton broth were produced and quality controlled by Prepared Media Laboratories (Tualatin, Oreg.). The trays were stored at -60 C or below until used. National Committee for Clinical Laboratory Standards-recommended methods were used for dilution tests. For gonococci, fastidious species, and anaerobic bacteria, National Committee for Clinical Laboratory Standards modifications were utilized (6, 7). The antimicrobial agents for Legionella tests were diluted in buffered-starchyeast extract agar, and the isolates were inoculated at a concentration of 06 CFU per spot (9). The MIC results for nearly 00 clinical isolates are summarized in Table. had MICs for 90% of the strains tested (MIC90s) that were generally two- to eightfold greater than those of ciprofloxacin for the family Enterobac- * Corresponding author. 39 teriaceae (range, <0.05 to,ug/ml) but equal to or twofold less than those of ofloxacin. The activity of CP- 99,9 was comparable to or greater (MIC0s, c,ug/ml) than that of ciprofloxacin, ofloxacin, or enoxacin against Pseudomonas aeruginosa, Xanthomonas maltophilia, and methicillin-susceptible Staphylococcus aureus. The staphylococci least susceptible to were those having methicillin or oxacillin resistance. showed its greatest activity among the fluoroquinolones when tested against S. haemolyticus and other staphylococci (MIC90, or,ug/ml). enterococcal activity (MICg, or,ug/ml) was most comparable to that of ciprofloxacin but greater than that of ofloxacin or enoxacin. activity against the key respiratory tract pathogens Moraxella catarrhalis, Haemophilus influenzae, and pneumococci was very potent (all MICs, <,ug/ml; MIC0s, '0.05 to,ug/ml). This degree of potency was equal to or eightfold higher than that of ciprofloxacin. Neisseria species were extremely susceptible to (MIC90s, 0.00 to 0.00,g/ml), as were Bacillus cereus strains that produced a broad-spectrum beta-lactamase. Anaerobic bacteria such as Bacteroides fragilis (MIC50,,ug/ml) were the only species consistently resistant to. Legionella pneumophila was equally susceptible to, ciprofloxacin, and ofloxacin. This measured activity was eightfold greater than that of erythromycin (Table )., a new azabicyclo naphthyridone resembling CP-7,667 (5) and tosufloxacin, was evaluated in vitro against 70 recent bacterial isolates from a large university medical center. Generally, had a greater potency and spectrum of activity (susceptibility was defined as c,g/ml) (7) than ciprofloxacin or ofloxacin. Organisms for which the MICs were. p,g/ml were rare among current clinical strains (P. aeruginosa, B. fragilis, oxacillinresistant S. aureus, and S. haemolyticus). These preliminary in vitro results indicate that has a wide spectrum of activity and potential for use against some strains resistant to currently available fluoroquinolones. Further studies of pharmacokinetics, toxi-
350 NOTES ANTIMICROB. AGENTS CHEMOTHER. TABLE. In vitro activity of compared with those of other fluorinated antibiotics against gram-positive and gram-negative pathogens Organism Antimicrobial MIC (,g/ml) Citrobacter diversus (0) Citrobacterfreundii (0) Enterobacter aerogenes (0) C0.00 C 0.05 0.05 C0.05- C0.00- - C- - 50.05- <0.00-.-.-.0.05-.0.05-.0.00- -.- - Enterobacter agglomerans (0) '0.05.0.00.. 0.05.0.05-.0.00-0.05.-.- - Enterobacter cloacae (0) 0.05.0.05-.0.00-.-.- - Escherichia coli (0) '0.05.0.00. 0.05 <0.05-.0.00-.-.- - Kiebsiella oxytoca () 0.05.0.05-.0.00-.-.- 50.05- Kebsiella pneumoniae (0) 0.05.0.05-.0.00-.-.- 50.05- Morganella morganii (0).0.00 5 0.05. -.0.00- -.- - Proteus mirabilis (0) 0.05.. - 0.05- -. - Proteus vulgaris (0).. - 0.05- -. - Continued on following page
VOL. 37, 993 NOTES 35 TABLE -Continued Organism Antimicrobial MIC (,ug/ml) Providencia rettgeri (0) Providencia stuartii (0) Salmonella enteritidis (0) Serratia marcescens (0) Shigella spp. (0) Yersinia enterocolitica (0) Acinetobacter spp. (0) Pseudomonas aeruginosa (30) Xanthomonas maltophilia (0) Moraxella catarrhalis (0) Haemophilus influenzae (5) Neisseria gonorrhoeae (30) Neisseria spp. (0) Ampicillin 0.05 '0.05 0.05 '0.05 0.05 '0.05 6 '0.05 '0.05 0.00.0.00 0.00 0.00 0.00.0.05 0.05 6 >6 '0.05 '0.05 0.05 >3 0.00 0.00 0.00 0.00-0.05- - C- - - - -.- - - 0.05- - '- - - - - - -.0.05- '0.00-0.05 - <- - '0.05-0.05- - <- -.0.05- <0.00- <- <-6 0.05- - - ->6 - - - -> - ->6 - '0.05 <0.00-.0.05 <0.00-.->3.0.00-0.00.0.00-0.00.0.00-0.00.0.00-0.05 Continued on following page
35 NOTES ANTIMICROB. AGENTS CHEMOTHER. TABLE -Continued Organism Antimicrobial MIC (LLg/ml) Bacteroides fragilis (6) Legionella pneumophila (00) Erythromycin - - 0.00-0.05- -.0.05- Staphylococcus aureus, oxacillin susceptible (0) C0.05.0.05- - - - - Staphylococcus aureus, oxacillin resistant (0) C0.05 > >6.0.05- -> - -> 6 - Staphylococcus epidermidis (0) > >6 <0.05- -> - -> 6 - Staphylococcus haemolyticus (0) Oxacillin.0.05 >6 C0.05- -> - -> 6 - - Other coagulase-negative staphylococci (0)' C0.05- - - - - Enterococcus faecalis () - - - - - Enterococcus faecium (0) 6 > >6 - -> ->6 - Streptococci Group A (0) Group B (0) Groups C, F, G () Streptococcus pneumoniae (30).0.05- - - - <0.05-0.00-.0.05- - Bacillus cereus (0) '0.05.0.05.0.05- - - - - a Includes seven species.
VOL. 37, 993 NOTES 353 cology, and other in vitro characteristics appear to be indicated. We are grateful for the technical support of M. Barrett, M. Erwin, D. Johnson, S. Anderson, and L. Miller. This study was funded in part by a technical/research grant from Pfizer Inc. REFERENCES. Chin, N.-X., and H. C. Neu. 9., a quinolone carboxylic acid compound against aerobic and anaerobic bacteria. Antimicrob. Agents Chemother. 5:39-36.. Fuchs, P. C., A. L. Barry, R. N. Jones, and C. Thornsberry. 95. Evaluation of in vitro antibacterial activity of enoxacin: comparison with other orally absorbed antimicrobial agents, proposed disk diffusion test interpretive criteria, and quality control limits. Diagn. Microbiol. Infect. Dis. 3:3-. 3. Hooper, D. C., and J. S. Wolfson. 99. Fluoroquinolone antimicrobial agents. N. Engl. J. Med. 3:3-395.. Ito, A., K. Hirai, M. Inoue, H. Koga, S. Suzue, T. Irikura, and S. Mitsuhashi. 90. In vitro antibacterial activity of AM-75, a new nalidixic acid analog. Antimicrob. Agents Chemother. 7:03-0. 5. Jones, R. N., and M. E. Erwin. 99. In vitro activity of CP-7667 compared to four other fluoroquinolones. Diagn. Microbiol. Infect. Dis. 5:53-536. 6. National Committee for Clinical Laboratory Standards. 99. Tentative standard M-T. Methods for antimicrobial susceptibility testing of anaerobic bacteria. National Committee for Clinical Laboratory Standards, Villanova, Pa. 7. National Committee for Clinical Laboratory Standards. 990. Approved standard, M7-A. Standard methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. National Committee for Clinical Laboratory Standards, Villanova, Pa.. Sato, K., Y. Matsuura, M. Inoue, T. Une, Y. Osada, H. Ogawa, and S. Mitsuhashi. 9. In vitro and in vivo activity of DL-0, a new oxazine derivative. Antimicrob. Agents Chemother. :5-553. 9. Sawatari, K., N. Ito, M. Nagasawa, H. Nakasato, H. Koga, K. Watanabe, H. Tanaka, K. Fujita, Y. Shiegeno, K. Yanaguchi, K. Izumikawa, A. Saito, and K. Hara. 95. New susceptibility testing medium (BSYE agar) for Legionella and Legionella -like organisms. Chemotherapy 3:7-73. 0. Wolfson, J. S., and D. C. Hooper. 99. Fluoroquinolone antimicrobial agents. Clin. Microbiol. Rev. :37-.