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In vitro susceptibility study of BMS-284756 against legionella species
Diagnostic Microbiology and Infectious Disease 41 (2001) 79 – 82
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In vitro susceptibility study of BMS-284756 against legionella species Jacques Dubois*, Claude St-Pierre Novabyss Inc., Sherbrooke, Quebec, Canada Received May 2, 2001; accepted August 9, 2001
Abstract Legionella organisms are often associated with respiratory infections, and Legionella pneumonia results in significant mortality unless it is promptly and effectively treated. The present study was undertaken to compare the in vitro activity of BMS-284756 (T-3811ME), a novel des-F(6)-quinolone, against Legionella species versus the activity of other fluoroquinolones (levofloxacin, moxifloxacin, and ciprofloxacin) and of the macrolides erythromycin, clarithromycin, and azithromycin. The most potent agents tested against Legionella pneumophila serogroup 1, the largest group tested, were BMS-284756, moxifloxacin, and levofloxacin (MIC90 ⫽ 0.016 mg/L). The MIC90 range for BMS-284756 was 0.008 – 0.03 mg/L against the total panel of L pneumophila serogroups 1–9 and 12, with the lowest MIC90 observed for serogroup 7 and the highest for serogroup 2. BMS-284756 was one of the most potent agents tested against isolates of L micdadei, L longbeachae, and other Legionella species (MIC90 range: 0.008 – 0.06 mg/L). These results and the high intrinsic activity of BMS-284756 against other respiratory pathogens support its use as empiric monotherapy for a wide range of respiratory infections. © 2001 Elsevier Science Inc. All rights reserved.
1. Introduction BMS-284756 (T-3811ME) is a novel des-F(6)-quinolone that lacks the fluorine atom found at the 6-position in other fluoroquinolones, and it has potent activity against a wide range of Gram-positive pathogens, including methicillinresistant Staphylococcus aureus, Staphylococcus epidermidis, ciprofloxacin-resistant Streptococcus pneumoniae, and quinolone-resistant Gram-positive cocci with GyrA and ParC (GrlA) mutations (Fung-Tomc et al., 2000). BMS284756 is also active against clinically important Gramnegative aerobes and against atypical respiratory pathogens, including Chlamydia trachomatis, Mycoplasma pneumoniae, and Legionella species (Fung-Tomc et al., 2000). Legionella species are now recognized as important pathogens in both nosocomial pneumonia and CAP (Kirby et al., 1980; McNally et al., 2000). A wide range of Legionella species have been associated with the development of Legionella pneumonia, including L pneumophila, L bozemanii, and L anisa (McNally et al., 2000). Legionella pneumonia is a serious condition that results in significant mortality unless it is promptly and effectively treated. Falco´ et al. (Falco´ et al., 1991) reported that the overall mortality * Corresponding author. Tel.: ⫹1-819-562-7800; fax: ⫹1-819-5621551. E-mail address: [email protected]
associated with Legionella pneumonia was 10% but that this increased in patients who did not receive appropriate antimicrobial therapy. Fluoroquinolones are considered to be suitable agents for empiric therapy in patients with CAP (Bartlett, 2000), and results from resistance surveillance studies have indicated that many pathogens associated with respiratory infections remain susceptible to one or more drugs in this class (Jones & Pfaller, 2000). The present study was undertaken to compare the in vitro activity of BMS-284756 against Legionella species with that of other fluoroquinolones—levofloxacin, moxifloxacin, and ciprofloxacin—and with that of the macrolides erythromycin, clarithromycin, and azithromycin.
2. Methods The in vitro efficacies of BMS-284756 and comparator antimicrobials were evaluated using a methodology generally following that described previously by Dubois and St-Pierre (Dubois & St. Pierre, 2000). 2.1. Bacterial strains A panel of 238 Legionella strains were studied. The strains were isolated from patients with hospital- and community-acquired respiratory tract infections, as well as from
0732-8893/01/$ – see front matter © 2001 Elsevier Science Inc. All rights reserved. PII: S 0 7 3 2 - 8 8 9 3 ( 0 1 ) 0 0 2 8 5 - 1
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J. Dubois, C. St-Pierre / Diagnostic Microbiology and Infectious Disease 41 (2001) 79 – 82
environmental sources. The study included 204 strains of L pneumophila serogroups 1–9 and 12, of which 153 were clinical isolates and 51 were obtained from environmental sources. In addition, there were 34 strains of various other Legionella species: L dumoffii (n ⫽ 10), L micdadei (n ⫽ 10), L longbeachae (n ⫽ 7), and one strain each of L bozemanii, L feeleii, L jordanis, L gormanii, L oakridgensis, L sainthelensi, and L wadsworthii. Of these, 13 were isolated from clinical specimens and 21 from environmental sources. All strains were grown under aerobic conditions without addition of supplements/enhancements to agar dilution plates. Strains were identified by standard methods (Dubois & St-Pierre, 2000), described in the literature (Winn, 1999). 2.2. Antimicrobial agents Standard antimicrobial reference powders were obtained as follows: BMS-284756 from Bristol-Myers Squibb (Wallingford, CT, USA), levofloxacin from Janssen-Ortho (North York, Ontario, Canada), azithromycin from Pfizer (Montreal, Quebec, Canada), moxifloxacin and ciprofloxacin from Miles (Etobicoke, Ontario, Canada), erythromycin from Sigma Chemical (Mississauga, Ontario, Canada), and clarithromycin from Abbott Laboratories (Chicago, IL, USA).
mophila serogroup 1 (MIC90 ⫽ 0.06 mg/L), followed by azithromycin and erythromycin (MIC90 ⫽ 0.5 and 1.0 mg/L, respectively). Thus, all the quinolones tested showed higher potencies than any of the macrolides against this pathogen. The MIC90 range for BMS-284756 was 0.008 – 0.03 mg/L against the total panel of L pneumophila serogroups 1–9 and 12, with the lowest MIC90 observed for serogroup 7 and the highest for serogroup 2 (Table 1). The activity of BMS-284756 was significantly higher than that of erythromycin (0.25–1.0 mg/L) and slightly greater than that for azithromycin and clarithromycin (0.06 – 0.5 mg/L). With a MIC90 of approximately 0.016 mg/L for all serogroups of L pneumophila, BMS-284756 showed similar activity to moxifloxacin and levofloxacin and was slightly more active than ciprofloxacin (Table 1). BMS-284756 was one of the most potent agents tested against isolates of L micdadei, L longbeachae, and other Legionella species (MIC90 range: 0.008 – 0.06 mg/L) (Table 1). As a class, the quinolones displayed greater antimicrobial activity against these pathogens (MIC90 range: ⱕ0.004 – 0.06 mg/L) than did azithromycin (0.25– 0.5 mg/ L), clarithromycin (0.06 – 0.12 mg/L), and erythromycin (0.5–1.0 mg/L) (Table 1).
4. Discussion 2.3. Susceptibility testing Methods for testing antimicrobial susceptibility of bacteria followed approved standard M7-A4 of the National Committee for Clinical Laboratory Standards (NCCLS, 1997). In brief, the MIC, defined as the lowest concentration of an antimicrobial that completely inhibited visible growth of bacterial colonies, was determined by twofold agar dilution using buffered yeast-extract agar with a pH of 6.90 – 6.95 at 25°C. An inoculum of approximately 104 colonyforming units per spot was plated onto buffered yeastextract agar containing doubling dilutions of study antimicrobial agents (0.004 – 64 mg/L) and incubated at 35°C for 48 h in an aerobic atmosphere. Strains of L pneumophila ATCC 33152 and Pseudomonas aeruginosa ATCC 27853 were included as controls.
3. Results L pneumophila serogroup 1 was the largest group of isolates (n ⫽ 85) represented in this study (Table 1). The overall MIC90 range for quinolones tested against this pathogen was ⱕ0.004 – 0.03 mg/L. The most potent quinolones tested in this serogroup were BMS-284756, moxifloxacin, and levofloxacin (MIC90 range: ⱕ0.004 – 0.016 mg/L). These quinolones were more potent than ciprofloxacin (MIC90 ⫽ 0.03 mg/L). Of the macrolide antimicrobials, clarithromycin showed the highest potency against L pneu-
The results presented here indicate that BMS-284756 is highly active against a wide range of Legionella strains, with MIC90 values at least as low as, and often lower than, most of the other quinolones. Importantly, the MICs for comparator fluoroquinolones against Legionella reported here are generally consistent with those from previous studies (e.g., Hoogkamp-Korstanje, 1997). The activity of BMS-284756 against these organisms was also greater than the activities of the three macrolides evaluated in this study. The activity of BMS-284756 against serotype 1, the most frequently occurring L pneumophila, is particularly noteworthy because the MIC90 of erythromycin against this strain was relatively high (1.0 g/mL) and because this strain has often been associated with both CAP and nosocomial pneumonia (Kirby et al., 1980; Dubois & Joly, 1989, 1992). Other Legionella strains have also been identified as etiologic agents in specific outbreaks of Legionella pneumonia. A recent surveillance study identified L bozemanii as the most common causative pathogen in a cohort of patients with Legionella-associated CAP (McNally et al., 2000). Results of the current study showed that BMS-284756 was also highly active (MIC90 ⫽ 0.008 g/mL) against the single strain of this species tested. The present results extend information on the antimicrobial spectrum for BMS-284756. The results of one previous study showed that BMS-284756 was active against a wide range of Gram-positive pathogens, including methicillinresistant S aureus and ciprofloxacin-resistant S pneumoniae
J. Dubois, C. St-Pierre / Diagnostic Microbiology and Infectious Disease 41 (2001) 79 – 82
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Table 1 Activity of BMS-284756 and other quinolones and macrolides against Legionella Pneumophila serotypes and Legionella spp Organism L pneumophila serogroup 1 (n ⫽ 85) serogroup 2 (n ⫽ 17) serogroup 3 (n ⫽ 15) serogroup 4 (n ⫽ 26) serogroup 5 (n ⫽ 15) serogroup 6 (n ⫽ 40) serogroup 7 (n ⫽ 2) serogroups 8, 9, and 12 (n ⫽ 4) L dumoffii (n ⫽ 10) L micdadei (n ⫽ 10) L longbeachae (n ⫽ 7) Other Legionella spp (n ⫽ 7)
MIC
BMS-284756
Ciprofloxacin
Levofloxacin
Moxifloxacin
Azithromycin
Clarithromycin
Erythromycin
range MIC50 MIC90 range MIC50 MIC90 range MIC50 MIC90 range MIC50 MIC90 range MIC50 MIC90 range MIC50 MIC90 range MIC50 MIC90 range MIC50 MIC90 range MIC50 MIC90 range MIC50 MIC90 range MIC50 MIC90 range MIC50 MIC90
ⱕ0.004–0.06 0.016 0.016 0.008–0.03 0.008 0.03 ⱕ0.004–0.03 0.016 0.016 ⱕ0.004–0.03 0.008 0.016 0.008–0.016 0.008 0.016 ⱕ0.004–0.016 0.008 0.016 0.008 0.008 0.008 0.008–0.016 0.008 0.016 0.06 0.06 0.06 ⱕ0.004–0.008 ⱕ0.004 0.008 ⱕ0.004–0.016 ⱕ0.004 0.016 0.008 0.008 0.008
0.016–0.25 0.03 0.03 ⱕ0.004–0.03 0.016 0.016 ⱕ0.004–0.03 0.03 0.03 0.016–0.12 0.03 0.06 0.016–0.06 0.03 0.03 ⱕ0.004–0.03 0.03 0.03 0.03 0.03 0.03 0.016–0.03 0.03 0.03 0.016–0.03 0.016 0.03 0.016–0.03 0.016 0.03 ⱕ0.004–0.03 0.016 0.03 ⱕ0.004–0.03 0.016 0.03
ⱕ0.004–0.016 0.016 0.016 ⱕ0.004–0.016 0.008 0.008 0.008–0.016 0.008 0.016 ⱕ0.004–0.016 0.016 0.016 ⱕ0.004–0.016 0.008 0.016 0.008–0.016 0.008 0.016 0.008–0.016 0.008 0.016 0.008–0.016 0.008 0.016 0.016 0.016 0.016 0.008–0.016 0.016 0.016 0.008–0.016 0.016 0.016 0.008–0.016 0.016 0.016
ⱕ0.004–0.03 0.016 0.016 ⱕ0.004–0.016 0.008 0.008 ⱕ0.004–0.016 0.008 0.016 ⱕ0.004–0.016 0.016 0.016 ⱕ0.004–0.03 0.016 0.016 ⱕ0.004–0.016 0.008 0.016 ⱕ0.004–0.016 ⱕ0.004 0.016 0.016 0.016 0.016 0.008–0.03 0.03 0.03 0.008–0.03 0.016 0.03 0.008–0.03 0.016 0.03 0.008–0.03 0.008 0.03
0.008–1.0 0.06 0.5 0.008–0.12 0.06 0.12 0.016–0.25 0.12 0.25 0.008–0.25 0.12 0.12 0.008–0.5 0.03 0.25 0.016–0.25 0.06 0.12 0.06 0.06 0.06 0.008–0.06 0.06 0.06 0.12–0.25 0.12 0.25 0.016–0.25 0.25 0.25 0.016–0.25 0.12 0.25 0.016–0.5 0.12 0.5
ⱕ0.004–0.12 0.06 0.06 ⱕ0.004–0.06 0.03 0.06 0.016–0.06 0.03 0.06 ⱕ0.004–0.06 0.03 0.06 0.03–0.06 0.03 0.06 ⱕ0.004–0.06 0.016 0.06 0.016–0.06 0.016 0.06 0.016–0.06 0.016 0.06 0.03–0.06 0.03 0.06 0.03–0.12 0.06 0.06 0.008–0.06 0.06 0.06 ⱕ0.004–0.12 0.03 0.12
0.03–1.0 0.25 1.0 0.008–0.5 0.25 0.25 0.06–0.5 0.25 0.5 0.016–0.5 0.5 0.5 0.06–1.0 0.25 0.5 0.008–0.25 0.12 0.25 0.12–0.5 0.12 0.5 0.03–0.25 0.03 0.25 0.025–0.5 0.25 0.5 0.25–1.0 0.5 1.0 0.008–0.5 0.25 0.5 0.016–1.0 0.5 1.0
(Fung-Tomc et al., 2000). The study also found that BMS284756 is potently active against clinically important Gramnegative aerobes and anaerobes, including Bacteroides fragilis and Clostridium difficile (Fung-Tomc, 2000; Hoellman et al., 2001). Previous work has also documented the activity of BMS-284756 against all the atypical respiratory pathogens (Fung-Tomc, 2000; Takahata et al., 2001). The MIC90 of BMS-284756 against Mycoplasma pneumoniae was eightfold lower than that of moxifloxacin and 16- to 32-fold lower than that of levofloxacin and ciprofloxacin (Takahata et al., 2001). In summary, BMS-284756 is highly active against all strains of L pneumophila as well as other Legionella species, and this novel des-F(6)-quinolone is at least as active as, and often more potent than, other quinolones and macrolides. These results, along with the high intrinsic activity of BMS-284756 against other respiratory pathogens, support its use as monotherapy for a wide range of respiratory infections.
References Bartlett, J. G. (2000). Treatment of community-acquired pneumonia. Chemotherapy, 46 (Suppl 1), 24 –31. Dubois, J., & Joly, J. R. (1989). In vitro activity of lomefloxacin (SC 47111 or NY-198) against isolates of Legionella spp. Diagn Microbiol Infect Dis, 12 (3 suppl), 89S–91S. Dubois, J., & Joly, J. R. (1992). In-vitro activity of RP 59500, a new synergic antibacterial agent, against Legionella spp. J Antimicrob Chemother, 30 (Suppl A), 77– 81. Dubois, J., & St-Pierre, C. (2000). Comparative in vitro activity and post-antibiotic effect of gemifloxacin against Legionella spp. J Antimicrob Chemother, 45 (Suppl S1), 41– 46. Falco´ , V., Ferna´ ndez de Sevilla, T., Alegre, J., Ferrer, A., & Martı´nez Va´ zquez, J. M. (1991). Legionella pneumophila: a cause of severe community-acquired pneumonia. Chest, 100, 1007–1011. Fung-Tomc, J. C., Minassian, B., Kolek, B., Huczko, E., Aleksunes, L., Stickle, T., Washo, T., Gradelski, E., Valera, L., & Bonner, D. P. (2000). Antibacterial spectrum of a novel des-fluoro(6) quinolone, BMS-284756. Antimicrob Agents Chemother, 44, 3351– 3356.
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Hoellman, D. B., Kelly, L. M., Jacobs, M. R., & Appelbaum, P. C. (2001). Comparative antianaerobic activity of BMS 284756. Antimicrob Agents Chemother, 45, 589 –592. Hoogkamp-Korstanje, J. A. A. (1997). In-vitro activities of ciprofloxacin, levofloxacin, lomefloxacin, ofloxacin, pefloxacin, sparfloxacin and trovafloxacin against gram-positive and gram-negative pathogens from respiratory tract infections. J Antimicrob Chemother, 40, 427– 431. Jones, R. N., & Pfaller, M. A. (2000). In vitro activity of newer fluoroquinolones for respiratory tract infections and emerging patterns of antimicrobial resistance: data from the SENTRY Antimicrobial Surveillance Program. Clin Infect Dis, 31 (Suppl 2), S16 –S23. Kirby, B. D., Snyder, K. M., Meyer, R. D., & Finegold, S. M. (1980). Legionnaires’ disease: report of sixty-five nosocomially acquired cases and review of the literature. Medicine, 59, 188 –205.
McNally, C., Hackman, B., Fields, B. S., & Plouffe, J. F. (2000). Potential importance of Legionella species as etiologies in community acquired pneumonia (CAP). Diagn Microbiol Infect Dis, 38, 79 – 82. NCCLS (1997). Methods for Dilution Antimicrobial Tests for Bacteria That Grow Aerobically: Approved Standard M7–A4. Wayne, PA: National Committee for Clinical Laboratory Standards. Takahata, M., Shimakura, M., Hori, R., Kizawa, K., Todo, Y., Minami, S., Watanabe, Y., & Narita, H. (2001). In vitro and in vivo efficacies of T-3811ME (BMS-284756) against Mycoplasma pneumoniae. Antimicrob Agents Chemother, 45, 312–315. Winn, Jr. W. C. (1999). Legionella. In Murray et al, Manual of Clinical Microbiology, 7th ed. (pp. 572–585). Washington, DC: American Society for Microbiology.
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In vitro susceptibility study of BMS-284756 against legionella species Jacques Dubois*, Claude St-Pierre Novabyss Inc., Sherbrooke, Quebec, Canada Received May 2, 2001; accepted August 9, 2001
Abstract Legionella organisms are often associated with respiratory infections, and Legionella pneumonia results in significant mortality unless it is promptly and effectively treated. The present study was undertaken to compare the in vitro activity of BMS-284756 (T-3811ME), a novel des-F(6)-quinolone, against Legionella species versus the activity of other fluoroquinolones (levofloxacin, moxifloxacin, and ciprofloxacin) and of the macrolides erythromycin, clarithromycin, and azithromycin. The most potent agents tested against Legionella pneumophila serogroup 1, the largest group tested, were BMS-284756, moxifloxacin, and levofloxacin (MIC90 ⫽ 0.016 mg/L). The MIC90 range for BMS-284756 was 0.008 – 0.03 mg/L against the total panel of L pneumophila serogroups 1–9 and 12, with the lowest MIC90 observed for serogroup 7 and the highest for serogroup 2. BMS-284756 was one of the most potent agents tested against isolates of L micdadei, L longbeachae, and other Legionella species (MIC90 range: 0.008 – 0.06 mg/L). These results and the high intrinsic activity of BMS-284756 against other respiratory pathogens support its use as empiric monotherapy for a wide range of respiratory infections. © 2001 Elsevier Science Inc. All rights reserved.
1. Introduction BMS-284756 (T-3811ME) is a novel des-F(6)-quinolone that lacks the fluorine atom found at the 6-position in other fluoroquinolones, and it has potent activity against a wide range of Gram-positive pathogens, including methicillinresistant Staphylococcus aureus, Staphylococcus epidermidis, ciprofloxacin-resistant Streptococcus pneumoniae, and quinolone-resistant Gram-positive cocci with GyrA and ParC (GrlA) mutations (Fung-Tomc et al., 2000). BMS284756 is also active against clinically important Gramnegative aerobes and against atypical respiratory pathogens, including Chlamydia trachomatis, Mycoplasma pneumoniae, and Legionella species (Fung-Tomc et al., 2000). Legionella species are now recognized as important pathogens in both nosocomial pneumonia and CAP (Kirby et al., 1980; McNally et al., 2000). A wide range of Legionella species have been associated with the development of Legionella pneumonia, including L pneumophila, L bozemanii, and L anisa (McNally et al., 2000). Legionella pneumonia is a serious condition that results in significant mortality unless it is promptly and effectively treated. Falco´ et al. (Falco´ et al., 1991) reported that the overall mortality * Corresponding author. Tel.: ⫹1-819-562-7800; fax: ⫹1-819-5621551. E-mail address: [email protected]
associated with Legionella pneumonia was 10% but that this increased in patients who did not receive appropriate antimicrobial therapy. Fluoroquinolones are considered to be suitable agents for empiric therapy in patients with CAP (Bartlett, 2000), and results from resistance surveillance studies have indicated that many pathogens associated with respiratory infections remain susceptible to one or more drugs in this class (Jones & Pfaller, 2000). The present study was undertaken to compare the in vitro activity of BMS-284756 against Legionella species with that of other fluoroquinolones—levofloxacin, moxifloxacin, and ciprofloxacin—and with that of the macrolides erythromycin, clarithromycin, and azithromycin.
2. Methods The in vitro efficacies of BMS-284756 and comparator antimicrobials were evaluated using a methodology generally following that described previously by Dubois and St-Pierre (Dubois & St. Pierre, 2000). 2.1. Bacterial strains A panel of 238 Legionella strains were studied. The strains were isolated from patients with hospital- and community-acquired respiratory tract infections, as well as from
0732-8893/01/$ – see front matter © 2001 Elsevier Science Inc. All rights reserved. PII: S 0 7 3 2 - 8 8 9 3 ( 0 1 ) 0 0 2 8 5 - 1
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J. Dubois, C. St-Pierre / Diagnostic Microbiology and Infectious Disease 41 (2001) 79 – 82
environmental sources. The study included 204 strains of L pneumophila serogroups 1–9 and 12, of which 153 were clinical isolates and 51 were obtained from environmental sources. In addition, there were 34 strains of various other Legionella species: L dumoffii (n ⫽ 10), L micdadei (n ⫽ 10), L longbeachae (n ⫽ 7), and one strain each of L bozemanii, L feeleii, L jordanis, L gormanii, L oakridgensis, L sainthelensi, and L wadsworthii. Of these, 13 were isolated from clinical specimens and 21 from environmental sources. All strains were grown under aerobic conditions without addition of supplements/enhancements to agar dilution plates. Strains were identified by standard methods (Dubois & St-Pierre, 2000), described in the literature (Winn, 1999). 2.2. Antimicrobial agents Standard antimicrobial reference powders were obtained as follows: BMS-284756 from Bristol-Myers Squibb (Wallingford, CT, USA), levofloxacin from Janssen-Ortho (North York, Ontario, Canada), azithromycin from Pfizer (Montreal, Quebec, Canada), moxifloxacin and ciprofloxacin from Miles (Etobicoke, Ontario, Canada), erythromycin from Sigma Chemical (Mississauga, Ontario, Canada), and clarithromycin from Abbott Laboratories (Chicago, IL, USA).
mophila serogroup 1 (MIC90 ⫽ 0.06 mg/L), followed by azithromycin and erythromycin (MIC90 ⫽ 0.5 and 1.0 mg/L, respectively). Thus, all the quinolones tested showed higher potencies than any of the macrolides against this pathogen. The MIC90 range for BMS-284756 was 0.008 – 0.03 mg/L against the total panel of L pneumophila serogroups 1–9 and 12, with the lowest MIC90 observed for serogroup 7 and the highest for serogroup 2 (Table 1). The activity of BMS-284756 was significantly higher than that of erythromycin (0.25–1.0 mg/L) and slightly greater than that for azithromycin and clarithromycin (0.06 – 0.5 mg/L). With a MIC90 of approximately 0.016 mg/L for all serogroups of L pneumophila, BMS-284756 showed similar activity to moxifloxacin and levofloxacin and was slightly more active than ciprofloxacin (Table 1). BMS-284756 was one of the most potent agents tested against isolates of L micdadei, L longbeachae, and other Legionella species (MIC90 range: 0.008 – 0.06 mg/L) (Table 1). As a class, the quinolones displayed greater antimicrobial activity against these pathogens (MIC90 range: ⱕ0.004 – 0.06 mg/L) than did azithromycin (0.25– 0.5 mg/ L), clarithromycin (0.06 – 0.12 mg/L), and erythromycin (0.5–1.0 mg/L) (Table 1).
4. Discussion 2.3. Susceptibility testing Methods for testing antimicrobial susceptibility of bacteria followed approved standard M7-A4 of the National Committee for Clinical Laboratory Standards (NCCLS, 1997). In brief, the MIC, defined as the lowest concentration of an antimicrobial that completely inhibited visible growth of bacterial colonies, was determined by twofold agar dilution using buffered yeast-extract agar with a pH of 6.90 – 6.95 at 25°C. An inoculum of approximately 104 colonyforming units per spot was plated onto buffered yeastextract agar containing doubling dilutions of study antimicrobial agents (0.004 – 64 mg/L) and incubated at 35°C for 48 h in an aerobic atmosphere. Strains of L pneumophila ATCC 33152 and Pseudomonas aeruginosa ATCC 27853 were included as controls.
3. Results L pneumophila serogroup 1 was the largest group of isolates (n ⫽ 85) represented in this study (Table 1). The overall MIC90 range for quinolones tested against this pathogen was ⱕ0.004 – 0.03 mg/L. The most potent quinolones tested in this serogroup were BMS-284756, moxifloxacin, and levofloxacin (MIC90 range: ⱕ0.004 – 0.016 mg/L). These quinolones were more potent than ciprofloxacin (MIC90 ⫽ 0.03 mg/L). Of the macrolide antimicrobials, clarithromycin showed the highest potency against L pneu-
The results presented here indicate that BMS-284756 is highly active against a wide range of Legionella strains, with MIC90 values at least as low as, and often lower than, most of the other quinolones. Importantly, the MICs for comparator fluoroquinolones against Legionella reported here are generally consistent with those from previous studies (e.g., Hoogkamp-Korstanje, 1997). The activity of BMS-284756 against these organisms was also greater than the activities of the three macrolides evaluated in this study. The activity of BMS-284756 against serotype 1, the most frequently occurring L pneumophila, is particularly noteworthy because the MIC90 of erythromycin against this strain was relatively high (1.0 g/mL) and because this strain has often been associated with both CAP and nosocomial pneumonia (Kirby et al., 1980; Dubois & Joly, 1989, 1992). Other Legionella strains have also been identified as etiologic agents in specific outbreaks of Legionella pneumonia. A recent surveillance study identified L bozemanii as the most common causative pathogen in a cohort of patients with Legionella-associated CAP (McNally et al., 2000). Results of the current study showed that BMS-284756 was also highly active (MIC90 ⫽ 0.008 g/mL) against the single strain of this species tested. The present results extend information on the antimicrobial spectrum for BMS-284756. The results of one previous study showed that BMS-284756 was active against a wide range of Gram-positive pathogens, including methicillinresistant S aureus and ciprofloxacin-resistant S pneumoniae
J. Dubois, C. St-Pierre / Diagnostic Microbiology and Infectious Disease 41 (2001) 79 – 82
81
Table 1 Activity of BMS-284756 and other quinolones and macrolides against Legionella Pneumophila serotypes and Legionella spp Organism L pneumophila serogroup 1 (n ⫽ 85) serogroup 2 (n ⫽ 17) serogroup 3 (n ⫽ 15) serogroup 4 (n ⫽ 26) serogroup 5 (n ⫽ 15) serogroup 6 (n ⫽ 40) serogroup 7 (n ⫽ 2) serogroups 8, 9, and 12 (n ⫽ 4) L dumoffii (n ⫽ 10) L micdadei (n ⫽ 10) L longbeachae (n ⫽ 7) Other Legionella spp (n ⫽ 7)
MIC
BMS-284756
Ciprofloxacin
Levofloxacin
Moxifloxacin
Azithromycin
Clarithromycin
Erythromycin
range MIC50 MIC90 range MIC50 MIC90 range MIC50 MIC90 range MIC50 MIC90 range MIC50 MIC90 range MIC50 MIC90 range MIC50 MIC90 range MIC50 MIC90 range MIC50 MIC90 range MIC50 MIC90 range MIC50 MIC90 range MIC50 MIC90
ⱕ0.004–0.06 0.016 0.016 0.008–0.03 0.008 0.03 ⱕ0.004–0.03 0.016 0.016 ⱕ0.004–0.03 0.008 0.016 0.008–0.016 0.008 0.016 ⱕ0.004–0.016 0.008 0.016 0.008 0.008 0.008 0.008–0.016 0.008 0.016 0.06 0.06 0.06 ⱕ0.004–0.008 ⱕ0.004 0.008 ⱕ0.004–0.016 ⱕ0.004 0.016 0.008 0.008 0.008
0.016–0.25 0.03 0.03 ⱕ0.004–0.03 0.016 0.016 ⱕ0.004–0.03 0.03 0.03 0.016–0.12 0.03 0.06 0.016–0.06 0.03 0.03 ⱕ0.004–0.03 0.03 0.03 0.03 0.03 0.03 0.016–0.03 0.03 0.03 0.016–0.03 0.016 0.03 0.016–0.03 0.016 0.03 ⱕ0.004–0.03 0.016 0.03 ⱕ0.004–0.03 0.016 0.03
ⱕ0.004–0.016 0.016 0.016 ⱕ0.004–0.016 0.008 0.008 0.008–0.016 0.008 0.016 ⱕ0.004–0.016 0.016 0.016 ⱕ0.004–0.016 0.008 0.016 0.008–0.016 0.008 0.016 0.008–0.016 0.008 0.016 0.008–0.016 0.008 0.016 0.016 0.016 0.016 0.008–0.016 0.016 0.016 0.008–0.016 0.016 0.016 0.008–0.016 0.016 0.016
ⱕ0.004–0.03 0.016 0.016 ⱕ0.004–0.016 0.008 0.008 ⱕ0.004–0.016 0.008 0.016 ⱕ0.004–0.016 0.016 0.016 ⱕ0.004–0.03 0.016 0.016 ⱕ0.004–0.016 0.008 0.016 ⱕ0.004–0.016 ⱕ0.004 0.016 0.016 0.016 0.016 0.008–0.03 0.03 0.03 0.008–0.03 0.016 0.03 0.008–0.03 0.016 0.03 0.008–0.03 0.008 0.03
0.008–1.0 0.06 0.5 0.008–0.12 0.06 0.12 0.016–0.25 0.12 0.25 0.008–0.25 0.12 0.12 0.008–0.5 0.03 0.25 0.016–0.25 0.06 0.12 0.06 0.06 0.06 0.008–0.06 0.06 0.06 0.12–0.25 0.12 0.25 0.016–0.25 0.25 0.25 0.016–0.25 0.12 0.25 0.016–0.5 0.12 0.5
ⱕ0.004–0.12 0.06 0.06 ⱕ0.004–0.06 0.03 0.06 0.016–0.06 0.03 0.06 ⱕ0.004–0.06 0.03 0.06 0.03–0.06 0.03 0.06 ⱕ0.004–0.06 0.016 0.06 0.016–0.06 0.016 0.06 0.016–0.06 0.016 0.06 0.03–0.06 0.03 0.06 0.03–0.12 0.06 0.06 0.008–0.06 0.06 0.06 ⱕ0.004–0.12 0.03 0.12
0.03–1.0 0.25 1.0 0.008–0.5 0.25 0.25 0.06–0.5 0.25 0.5 0.016–0.5 0.5 0.5 0.06–1.0 0.25 0.5 0.008–0.25 0.12 0.25 0.12–0.5 0.12 0.5 0.03–0.25 0.03 0.25 0.025–0.5 0.25 0.5 0.25–1.0 0.5 1.0 0.008–0.5 0.25 0.5 0.016–1.0 0.5 1.0
(Fung-Tomc et al., 2000). The study also found that BMS284756 is potently active against clinically important Gramnegative aerobes and anaerobes, including Bacteroides fragilis and Clostridium difficile (Fung-Tomc, 2000; Hoellman et al., 2001). Previous work has also documented the activity of BMS-284756 against all the atypical respiratory pathogens (Fung-Tomc, 2000; Takahata et al., 2001). The MIC90 of BMS-284756 against Mycoplasma pneumoniae was eightfold lower than that of moxifloxacin and 16- to 32-fold lower than that of levofloxacin and ciprofloxacin (Takahata et al., 2001). In summary, BMS-284756 is highly active against all strains of L pneumophila as well as other Legionella species, and this novel des-F(6)-quinolone is at least as active as, and often more potent than, other quinolones and macrolides. These results, along with the high intrinsic activity of BMS-284756 against other respiratory pathogens, support its use as monotherapy for a wide range of respiratory infections.
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