In Vitro Activities of Sitaffoxacin (DU-6859a) - Antimicrobial Agents and ...

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Apr. 2000, p. 1102–1107 0066-4804/00/$04.00⫹0 Copyright © 2000, American Society for Microbiology. All Rights Reserved.

Vol. 44, No. 4

In Vitro Activities of Sitafloxacin (DU-6859a) and Six Other Fluoroquinolones against 8,796 Clinical Bacterial Isolates DANA MILATOVIC,* FRANZ-JOSEF SCHMITZ, SYLVAIN BRISSE, JAN VERHOEF,

AND

AD C. FLUIT

Eijkman-Winkler Institute for Microbiology, Infectious Diseases & Inflammation, University Hospital Utrecht, Utrecht, The Netherlands Received 17 August 1999/Returned for modification 9 November 1999/Accepted 10 January 2000

The in vitro activities of sitafloxacin, ciprofloxacin, trovafloxacin, levofloxacin, clinafloxacin, gatifloxacin, and moxifloxacin against 5,046 gram-negative bacteria, 3,344 gram-positive cocci, and 406 anaerobes were determined. Sitafloxacin was the most active agent against gram-positive cocci and anaerobes. Against Enterobacteriaceae and nonfermenters, its activity was either equivalent to or better than that of clinafloxacin. morganii, and Serratia marcescens and at least eight times more active against E. aerogenes, Enterobacter cloacae, E. coli, and Proteus mirabilis. In general, the activity of sitafloxacin against ciprofloxacin-susceptible strains was equal to or slightly better than that of ciprofloxacin, whereas for ciprofloxacin-resistant strains the MIC50 and MIC90 of sitafloxacin were at least 3 dilution steps lower than those of ciprofloxacin. Among the seven fluoroquinolones tested, sitafloxacin and clinafloxacin were the most active substances; corresponding results have been reported by others (1, 2, 4). Gram-negative nonfermenters are generally less susceptible to quinolones (4, 20). Sitafloxacin was at least eight times more active than ciprofloxacin against Acinetobacter spp., Burkholderia cepacia, and Stenotrophomonas maltophilia. However, assuming the same breakpoints for ciprofloxacin and sitafloxacin as those proposed by Jones et al. (6), almost complete crossresistance between ciprofloxacin and sitafloxacin was observed in Pseudomonas aeruginosa, with only 5% of the 165 ciprofloxacin-resistant isolates being susceptible to sitafloxacin at ⱕ1 ␮g/ml. Sitafloxacin showed good activity against staphylococci, with some species variability. The MIC90s for oxacillin-resistant strains ranged from 0.25 to 1 ␮g/ml and were considerably higher than those for oxacillin-susceptible strains (MIC90, 0.03 to 0.12 ␮g/ml), as shown for other quinolones (1, 3). Sitafloxacin was the most active agent against oxacillin-resistant strains, being two times more active than clinafloxacin and at least eight times more active than the other quinolones. Of the 457 methicillin-resistant Staphylococcus aureus strains tested, 95.4% were resistant to ciprofloxacin, whereas only 0.4% were resistant to clinafloxacin and 0.2% were resistant to sitafloxacin (MIC ⱖ4 ␮g/ml). In common with other quinolones, the activity of sitafloxacin against enterococci was generally lower than that against other gram-positive cocci (3, 4). For Enterococcus faecalis, the MIC50 and MIC90 were 0.12 and 2 ␮g/ml, respectively. Sitafloxacin and clinafloxacin were at least four times more active than the other fluoroquinolones. The MICs of sitafloxacin for Enterococcus faecium were higher (MIC50, 0.5 ␮g/ml; MIC90, 4 ␮g/ ml). For vancomycin-susceptible and -resistant enterococci, the MICs of all quinolones tested were comparable. Jones et al. and Korten et al. described similar in vitro activities of sitafloxacin against multiresistant enterococcal isolates (7, 11). Sitafloxacin was very active against Streptococcus pneumoniae and the other Streptococcus spp. tested, with MIC90s ranging from 0.03 to 0.12 ␮g/ml. No difference was observed between penicillin-susceptible and penicillin-resistant isolates,

Sitafloxacin (DU-6859a) is a new fluoroquinolone active against gram-positive and gram-negative bacteria, including anaerobes (3, 7, 13). In the present study, the in vitro activities of sitafloxacin against a large number of contemporary and clinically relevant bacterial isolates were determined and compared with those of ciprofloxacin, clinafloxacin, gatifloxacin, levofloxacin, moxifloxacin, and trovafloxacin. A total of 8,796 bacterial strains were tested which had been isolated between April 1997 and February 1999 from patients in 24 university hospitals in 14 European countries, 1 in Israel, and 3 in South Africa. Only one isolate per patient was permitted. Strains were reidentified in our laboratory using a combination of standard methods and either the VITEK or the API system (BioMerieux, s’Hertogenbosch, The Netherlands). MICs were determined by a microdilution method described by the National Committee for Clinical Laboratory Standards (15), using cation-adjusted Mueller-Hinton broth. For testing Streptococcus spp. and Neisseria spp., 5% lysed horse blood was added. Haemophilus spp. were tested using Haemophilus test medium. The inoculum was adjusted to 5 ⫻ 105 CFU/ml. Plates were read after 20 to 24 h of incubation at 35°C in ambient air. Anaerobic bacteria were tested with WilkinsChalgren broth and a final inoculum of 106 CFU/ml. Plates were read after 48 h of incubation at 35°C in an anaerobic environment (16). The results of susceptibility testing are presented as the MICs at which 50 and 90% of the isolates tested are inhibited (MIC50 and MIC90) and the ranges of MICs (Table 1). Sitafloxacin was very active against enterobacterial species, inhibiting 96.9% of the 3,129 strains at a concentration of 1 ␮g/ml. The MIC50s ranged from ⱕ0.008 to 1 ␮g/ml, and the MIC90s ranged from 0.015 to 2 ␮g/ml. The MIC90 for Providencia spp. was the highest (2 ␮g/ml), followed by those for Enterobacter aerogenes and Escherichia coli (1 ␮g/ml for each). These three species also exhibited the highest rates of ciprofloxacin resistance (51.6, 38.5, and 14.6%, respectively). The MIC90s of sitafloxacin for Citrobacter koseri, Klebsiella oxytoca, Pantoea agglomerans, Proteus vulgaris, salmonellae, Serratia liquefaciens, Shigella spp., and Yersinia enterocolitica ranged from 0.015 to 0.12 ␮g/ml and were similar to those of ciprofloxacin. However, sitafloxacin was four times more active than ciprofloxacin against Citrobacter freundii, Klebsiella pneumoniae, Morganella * Corresponding author. Mailing address: Eijkman-Winkler Institute, University Hospital Utrecht, G04.614, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. Phone: 31-30-2507625. Fax: 31-302541770. E-mail: [email protected]. 1102

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TABLE 1. Susceptibilities of 8,796 clinical isolates to the seven fluoroquinolones tested Organism(s) (no. of strains) and antimicrobial agent

MIC (␮g/ml) Range

50%

90%

Escherichia coli (411) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin Moxifloxacin

ⱕ0.008–4 ⱕ0.008–⬎16 ⱕ0.008–⬎16 ⱕ0.008–⬎16 ⱕ0.008–8 ⱕ0.008–⬎16 0.015–⬎16

ⱕ0.008 0.015 0.015 0.03 ⱕ0.008 0.03 0.06

Klebsiella pneumoniae (445) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin Moxifloxacin

ⱕ0.008–8 ⱕ0.008–⬎16 ⱕ0.008–⬎16 0.015–⬎16 ⱕ0.008–16 0.015–⬎16 0.03–⬎16

0.015 0.03 0.06 0.06 0.015 0.06 0.12

0.12 0.5 0.5 0.5 0.12 1 1

Klebsiella oxytoca (241) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin Moxifloxacin

ⱕ0.008–8 ⱕ0.008–16 0.015–16 0.015–8 ⱕ0.008–2 0.015–16 0.03–16

0.015 0.015 0.03 0.06 0.015 0.06 0.12

0.03 0.06 0.12 0.12 0.03 0.12 0.25

Proteus mirabilis (319) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin Moxifloxacin

ⱕ0.008–⬎16 0.015–⬎16 0.03–⬎16 0.03–⬎16 ⱕ0.008–16 0.06–⬎16 0.12–⬎16

0.03 0.03 0.25 0.06 0.03 0.25 0.5

Proteus vulgaris (39) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin Moxifloxacin

ⱕ0.008–1 0.015–8 0.03–8 0.015–8 ⱕ0.008–1 0.06–16 0.06–⬎16

0.03 0.03 0.25 0.03 0.03 0.25 0.5

0.12 0.06 1 0.12 0.06 0.5 1

Serratia marcescens (211) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin Moxifloxacin

ⱕ0.008–4 0.015–⬎16 0.03–⬎16 0.03–⬎16 ⱕ0.008–8 0.015–⬎16 0.03–⬎16

0.06 0.12 0.5 0.12 0.06 0.25 0.5

0.5 2 4 2 0.25 2 4

Serratia liquefaciens (14) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin Moxifloxacin

ⱕ0.008–0.12 ⱕ0.008–0.5 ⱕ0.008–0.12 0.015–1 ⱕ0.008–0.12 0.015–1 0.015–2

ⱕ0.008 0.03 0.06 0.03 ⱕ0.008 0.06 0.06

0.03 0.03 0.06 0.06 0.03 0.12 0.12

Citrobacter freundii (109) Sitafloxacin Ciprofloxacin

ⱕ0.008–4 ⱕ0.008–⬎16

0.03 0.015

1 16 ⬎16 8 1 8 16

0.5 4 16 4 0.5 4 16

0.5 2

Organism(s) (no. of strains) and antimicrobial agent

MIC (␮g/ml) Range

50%

90%

Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin Moxifloxacin

ⱕ0.008–⬎16 0.03–⬎16 ⱕ0.008–4 0.015–⬎16 0.03–⬎16

0.06 0.06 0.03 0.06 0.12

4 2 0.25 4 4

Citrobacter koseri (72) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin Moxifloxacin

ⱕ0.008–0.5 ⱕ0.008–8 ⱕ0.008–4 0.015–4 ⱕ0.008–0.5 0.015–2 ⱕ0.008–2

ⱕ0.008 0.015 0.015 0.03 ⱕ0.008 0.03 0.06

0.03 0.03 0.06 0.12 0.03 0.06 0.12

Enterobacter aerogenes (192) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin Moxifloxacin

ⱕ0.008–8 ⱕ0.008–⬎16 ⱕ0.008–⬎16 0.03–⬎16 ⱕ0.008–8 0.015–⬎16 0.03–⬎16

0.03 0.06 0.06 0.12 0.03 0.12 0.12

Enterobacter cloacae (378) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin Moxifloxacin

ⱕ0.008–8 ⱕ0.008–⬎16 ⱕ0.008–⬎16 0.015–⬎16 ⱕ0.008–8 ⱕ0.008–⬎16 0.015–⬎16

0.015 0.03 0.06 0.06 0.015 0.06 0.12

Pantoea agglomerans (12) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin Moxifloxacin

ⱕ0.008–0.03 ⱕ0.008–0.03 ⱕ0.008–0.06 0.015–0.06 ⱕ0.008–0.06 ⱕ0.008–0.12 0.015–0.12

ⱕ0.008 0.015 0.03 0.03 ⱕ0.008 0.03 0.06

Morganella morganii (138) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin Moxifloxacin

ⱕ0.008–16 ⱕ0.008–⬎16 0.015–⬎16 0.015–⬎16 ⱕ0.008–⬎16 0.03–⬎16 0.03–⬎16

0.015 0.015 0.25 0.06 0.015 0.06 0.12

Providencia spp.a (31) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin Moxifloxacin

ⱕ0.008–2 0.015–⬎16 0.06–⬎16 0.06–⬎16 ⱕ0.008–4 0.12–⬎16 0.25–⬎16

0.5 4 4 4 0.5 4 8

Salmonellaeb (326) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin

ⱕ0.008–2 ⱕ0.008–⬎16 ⱕ0.008–16 ⱕ0.008–8 ⱕ0.008–2

ⱕ0.008 0.015 0.03 0.06 ⱕ0.008

1 ⬎16 ⬎16 16 2 16 ⬎16 0.25 2 2 2 0.25 1 2 0.015 0.03 0.06 0.06 0.015 0.06 0.12 0.25 1 4 1 0.25 2 4 2 16 8 16 1 8 16 0.015 0.03 0.06 0.06 0.015

Continued on following page

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NOTES TABLE 1—Continued


Gatifloxacin Moxifloxacin

MIC (␮g/ml) Range

ⱕ0.008–8 0.015–16

50%

90%

0.03 0.06

0.06 0.12

0.015–8 0.12–⬎16 ⱕ0.008–⬎16 0.12–⬎16 0.015–4 0.06–16 0.03–16

0.25 16 1 4 0.5 4 2

Staphylococcus epidermidis Methicillin sensitive (214) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin Moxifloxacin

ⱕ0.008–0.5 0.03–⬎16 0.015–8 0.12–16 0.015–2 0.06–4 0.03–4

0.015 0.25 0.03 0.12 0.03 0.12 0.06

Methicillin resistant (436) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin Moxifloxacin

ⱕ0.008–1 0.06–⬎16 ⱕ0.008–16 0.03–⬎16 ⱕ0.008–2 0.015–16 ⱕ0.008–16

0.12 4 1 4 0.25 1 1

Staphylococcus haemolyticus Methicillin sensitive (15) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin Moxifloxacin

ⱕ0.008–0.12 0.06–16 0.015–2 0.06–4 0.015–0.25 0.06–2 0.03–1

0.015 0.25 0.015 0.12 0.03 0.12 0.06


0.015–2 0.12–⬎16 0.015–⬎16 0.12–⬎16 0.015–2 0.06–16 0.06–8

0.25 4 1 2 0.5 2 1

Other CoNSe Methicillin sensitive (111) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin Moxifloxacin

ⱕ0.008–1 0.06–⬎16 ⱕ0.008–16 0.06–⬎16 0.015–2 0.06–8 0.03–8

0.015 0.25 0.03 0.12 0.03 0.12 0.12

0.03 0.5 0.03 0.25 0.03 0.12


ⱕ0.008–4 0.06–⬎16 0.015–16 0.06–⬎16 0.015–4 0.03–⬎16 0.03–⬎16

0.03 0.5 0.06 0.5 0.06 0.25 0.12

0.015 0.03 0.03 0.03 ⱕ0.008 0.03 0.06

Yersinia enterocolitica (88) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin Moxifloxacin

ⱕ0.008–0.12 ⱕ0.008–2 ⱕ0.008–2 ⱕ0.008–1 ⱕ0.008–0.12 ⱕ0.008–0.5 ⱕ0.008–1

ⱕ0.008 0.015 0.015 0.03 ⱕ0.008 0.015 0.03

0.015 0.03 0.06 0.06 0.015 0.06 0.06

Acinetobacter spp.d (428) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin Moxifloxacin

ⱕ0.008–8 0.015–⬎16 ⱕ0.008–⬎16 0.015–⬎16 ⱕ0.008–16 ⱕ0.008–⬎16 ⱕ0.008–⬎16

Burkholderia cepacia (47) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin Moxifloxacin

0.015–8 0.25–⬎16 0.06–⬎16 0.25–⬎16 0.015–16 0.12–⬎16 0.12–⬎16

0.25 2 1 2 0.5 2 2

4 ⬎16 ⬎16 ⬎16 8 ⬎16 ⬎16

0.03–16 0.03–⬎16 0.06–⬎16 0.12–⬎16 0.03–16 0.06–⬎16 0.12–⬎16

0.12 0.25 0.5 0.5 0.12 1 2

4 ⬎16 ⬎16 ⬎16 4 ⬎16 ⬎16

Stenotrophomonas maltophilia (106) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin Moxifloxacin Staphylococcus aureus Methicillin sensitive (434) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin

ⱕ0.008–1 0.12–16 ⱕ0.008–4 0.06–8 ⱕ0.008–2 0.03–8 ⱕ0.008–4

ⱕ0.008–4 0.06–⬎16 ⱕ0.008–4 0.06–⬎16 ⱕ0.008–2 0.03–16

0.12 2 0.25 0.5 0.12 0.5 0.25

0.015 0.25 0.015 0.12 0.03 0.06

50%


ⱕ0.008 0.015 0.015 0.03 ⱕ0.008 0.03 0.03

Pseudomonas aeruginosa (615) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin Moxifloxacin

Range

0.06

ⱕ0.008–0.5 ⱕ0.008–0.12 ⱕ0.008–0.25 0.015–0.06 ⱕ0.008–0.03 ⱕ0.008–0.25 ⱕ0.008–0.12

2 ⬎16 16 16 4 8 16

Moxifloxacin

MIC (␮g/ml)

0.015–4

Shigella spp.c (103) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin Moxifloxacin

1 16 1 4 1 4 4

Organisms(s) (no. of strains) and antimicrobial agent

0.25 16 2 8 0.5 4 2

90%

0.06 0.5 ⬎16 8 16 1 4 4

0.12 16 1 4 0.25 2 1 0.25 ⬎16 4 8 0.5 2 2

0.12 8 1 2 0.12 1 1 1 ⬎16 16 ⬎16 2 8 8

0.12 0.5 0.25 0.5 0.12 0.25 0.5 0.25 ⬎16 4 8 0.5 4 2


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TABLE 1—Continued Organism(s) (no. of strains) and antimicrobial agent

MIC (␮g/ml) Range

50%

90%

Enterococcus faecalis Vancomycin sensitive (230) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin Moxifloxacin

0.015–4 0.25–⬎16 0.03–⬎16 0.25–⬎16 0.03–4 0.06–⬎16 0.06–⬎16

0.12 2 1 ⬎16 0.25 8 1 16 0.12 2 0.5 16 0.25 8

Vancomycin resistant (27) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin Moxifloxacin

0.03–2 0.25–⬎16 0.06–16 0.5–⬎16 0.06–4 0.12–⬎16 0.06–16

0.12 2 1 ⬎16 0.25 16 1 ⬎16 0.12 2 0.5 16 0.25 16

Enterococcus faecium Vancomycin sensitive (137) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin Moxifloxacin

0.015–⬎16 0.12–⬎16 0.03–⬎16 0.25–⬎16 0.03–⬎16 0.06–⬎16 0.06–⬎16

0.5 4 2 4 0.5 2 2

4 ⬎16 16 ⬎16 8 ⬎16 16

Vancomycin resistant (38) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin Moxifloxacin

0.03–16 0.25–⬎16 0.06–⬎16 0.25–⬎16 0.03–⬎16 0.12–⬎16 0.12–⬎16

0.25 2 1 2 0.25 1 1

8 ⬎16 16 ⬎16 16 ⬎16 ⬎16

ⱕ0.008–0.5 0.03–⬎16 ⱕ0.008–8 0.12–⬎16 ⱕ0.008–1 ⱕ0.008–8 ⱕ0.008–4

0.03 1 0.12 1 0.06 0.25 0.12

0.06 2 0.25 1 0.12 0.5 0.25

Penicillin intermediate (93) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin Moxifloxacin

0.015–0.5 0.5–⬎16 0.03–4 0.5–8 0.015–1 0.12–4 0.06–2

0.03 1 0.12 1 0.06 0.25 0.12

0.06 2 0.25 1 0.12 0.5 0.25

Penicillin resistant (129) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin Moxifloxacin

0.015–0.5 0.25–⬎16 0.06–8 0.5–16 0.015–0.5 0.12–8 0.03–4

0.03 1 0.12 1 0.06 0.25 0.12

0.06 2 0.25 1 0.12 0.5 0.25

ⱕ0.008–0.12

0.06

0.03

Streptococcus pneumoniae Penicillin sensitive (205) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin Moxifloxacin

Beta-hemolytic streptococcif (454) Sitafloxacin


Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin Moxifloxacin

MIC (␮g/ml) Range

50%

90%

0.12–4 ⱕ0.008–0.5 0.12–4 ⱕ0.008–0.5 0.06–1 ⱕ0.008–1

0.5 0.12 0.5 0.06 0.25 0.12

1 0.25 1 0.12 0.5 0.25

Viridans group streptococcig (97) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin Moxifloxacin

ⱕ0.008–0.25 0.12–16 0.03–0.5 0.12–4 0.015–0.5 0.06–2 0.015–0.5

0.03 1 0.12 1 0.06 0.25 0.12

0.12 4 0.25 1 0.12 0.5 0.25

Streptococcus milleri (40) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin Moxifloxacin

ⱕ0.008–0.06 0.25–1 0.03–0.25 0.25–1 0.015–0.12 0.06–0.5 ⱕ0.008–0.25

0.03 0.5 0.12 0.5 0.06 0.25 0.12

0.03 1 0.12 0.5 0.06 0.25 0.25

Haemophilus influenzae (224) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin Moxifloxacin

ⱕ0.008–0.03 ⱕ0.008–0.03 ⱕ0.008–0.25 ⱕ0.008–0.06 ⱕ0.008–0.03 ⱕ0.008–0.25 ⱕ0.008–0.25

ⱕ0.008ⱕ0.008 ⱕ0.008 0.015 ⱕ0.008ⱕ0.008 0.015 0.015 ⱕ0.008ⱕ0.008 ⱕ0.008 0.015 0.015 0.03

Moraxella catarrhalis (213) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin Moxifloxacin

ⱕ0.008–0.03 0.015–1 ⱕ0.008–0.06 0.03–0.5 ⱕ0.008–0.06 0.015–0.25 ⱕ0.008–0.12

ⱕ0.008ⱕ0.008 0.03 0.03 0.015 0.015 0.03 0.06 ⱕ0.008 0.015 0.03 0.03 0.06 0.06

Neisseria meningitidis (99) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin Moxifloxacin

ⱕ0.008–0.015 ⱕ0.008–ⱕ0.008 ⱕ0.008–0.015 ⱕ0.008–ⱕ0.008 ⱕ0.008–0.015 ⱕ0.008–0.015 ⱕ0.008–0.015

ⱕ0.008ⱕ0.008 ⱕ0.008ⱕ0.008 ⱕ0.008ⱕ0.008 ⱕ0.008ⱕ0.008 ⱕ0.008ⱕ0.008 ⱕ0.008ⱕ0.008 ⱕ0.008ⱕ0.008

Neisseria gonorrhoeae (185) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin Moxifloxacin

ⱕ0.008–0.12 ⱕ0.008–8 ⱕ0.008–4 ⱕ0.008–4 ⱕ0.008–0.25 ⱕ0.008–2 ⱕ0.008–4

ⱕ0.008ⱕ0.008 ⱕ0.008ⱕ0.008 ⱕ0.008ⱕ0.008 ⱕ0.008ⱕ0.008 ⱕ0.008ⱕ0.008 ⱕ0.008ⱕ0.008 ⱕ0.008 0.015

Bacteroides fragilis group (157) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin

0.03–⬎16 2–⬎16 0.06–16 0.5–⬎16

0.12 1 8 ⬎16 0.5 2 2 ⬎16


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ANTIMICROB. AGENTS CHEMOTHER. TABLE 1—Continued


Clinafloxacin Gatifloxacin Moxifloxacin Bacteroides spp. (39) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin Moxifloxacin Clostridium difficile (143) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin Moxifloxacin Clostridium perfringens (20) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin Moxifloxacin

MIC (␮g/ml) Range

50%

90%

0.06–⬎16 0.25–⬎16 0.12–⬎16

0.25 1 1

2 8 8

ⱕ0.008–4 0.12–⬎16 0.06–⬎16 0.12–⬎16 0.015–16 0.06–⬎16 0.06–⬎16

0.12 16 1 4 0.25 1 1

1 ⬎16 8 16 1 8 8

0.03–1 2–16 0.12–8 1–16 0.12–1 0.5–8 0.25–8

0.12 8 1 4 0.25 1 1

0.12 16 1 4 0.25 2 2

0.015–0.06 0.25–1 0.06–0.5 0.25–1 0.06–0.12 0.25–1 0.25–1

0.06 1 0.25 0.5 0.12 0.5 0.5

0.06 1 0.25 1 0.12 1 1

Peptostreptococcus spp. (35) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin Moxifloxacin

ⱕ0.008–0.5 0.12–16 0.015–2 0.12–16 ⱕ0.008–0.5 0.06–8 0.03–2

0.03 1 0.25 1 0.12 0.5 0.25

0.12 4 1 4 0.5 2 1

Prevotella spp. (12) Sitafloxacin Ciprofloxacin Trovafloxacin Levofloxacin Clinafloxacin Gatifloxacin Moxifloxacin

ⱕ0.008–0.25 1–⬎16 0.12–1 0.5–4 0.03–0.5 0.25–4 0.25–8

0.06 4 0.5 1 0.12 0.5 0.5

0.25 ⬎16 1 4 0.5 2 2

a

Includes 22 P. stuartii, 1 P. alcalifaciens, and 8 P. rettgeri strains. Includes 103 S. typhi enterica serovar and 223 other S. enterica strains. Includes 22 S. boydii, 15 S. dysenteriae, 48 S. flexneri, and 9 S. sonnei strains and 9 strains not identified to the species level. d Includes 397 A. calcoaceticus-baumannii group, 1 A. junii, and 30 A. lwoffii strains. e Includes 50 S. auricularis, 56 S. hominis, 31 S. capitis, 14 S. warneri, 9 S. cohnii, 11 S. saprophyticus, 7 S. simulans, 3 S. sciuri, 3 S. xylosus, 1 S. lugdunensis, 1 S. schleiferi, 1 S. chromogenes, and 2 S. equorum strains and 24 coagulase-negative staphylococcal strains (CoNS) not identified to the species level. f Includes 181 group A, 210 group B, 18 group C, and 45 group G strains. g Includes 54 S. mitis, 12 S. salivarius, and 31 S. sanguis strains. b c

confirming previous results (21). Sitafloxacin was the most active agent, followed by clinafloxacin, trovafloxacin, moxifloxacin, gatifloxacin, levofloxacin, and ciprofloxacin. Sitafloxacin was highly active against Haemophilus influenzae, Moraxella catarrhalis, Neisseria meningitidis, and Neisseria

gonorrhoeae, the MIC90 being ⱕ0.008 ␮g/ml for all species, including beta-lactamase-positive strains. The sitafloxacin MICs for five gonococcal strains resistant to ciprofloxacin ranged from 0.03 to 0.12 ␮g/ml. Of the 406 strains of anaerobic bacteria tested, 96.3% were inhibited by sitafloxacin at a concentration of 1 ␮g/ml. The MIC50s and MIC90s ranged from 0.03 to 0.12 ␮g/ml and from 0.06 to 0.25 ␮g/ml, respectively, with the exception of the Bacteroides species tested (MIC50, 0.12 ␮g/ml; MIC90, 1 ␮g/ ml). Similarly, other studies have demonstrated good activity of sitafloxacin against various anaerobic species (5, 17, 22). The results of our in vitro investigation confirm the broad spectrum of activity of sitafloxacin against gram-positive, gramnegative, and anaerobic bacteria which has been previously determined using smaller collections of isolates from Japan and the United States (3, 8, 12, 13). Due to its favorable pharmacokinetic profile (14), excellent in vitro potency, and in particular its enhanced activity against gram-positive organisms and anaerobes, sitafloxacin clearly has potential as a useful agent for the treatment of a variety of infections. Preliminary clinical results (9, 10, 19) indicate that sitafloxacin might be efficient in treating infections of the respiratory and genitourinary tract, as well as in treating intra-abdominal and skin and soft tissue infections. We thank Marita Hautvast, Margriet Jansze, Mirjam Klootwijk, Karlijn Kusters, Alice van der Meij-Florijn, and Stefan de Vaal for their expert technical assistance. We thank the following colleagues for referring isolates from their institutes: Helmut Mittermayer, Marc Struelens, Jacques Acar, Vincent Jarlier, Jerome Etienne, Rene Courcol, Franz Daschner, Ulrich Hadding, Nikos Legakis, Gian-Carlo Schito, Carlo Mancini, Piotr Heczko, Waleria Hyrniewicz, Dario Costa, Evilio Perea, Fernando Baquero, Rogelio Martin Alvarez, Jacques Bille, Gary French, Nathan Keller, Volkan Korten, Deniz Gu ¨r, Serhat Unal, Louise Marcus, Marque Venter, and Judy Walsh. This work was funded by DAIICHI Pharmaceutical Co. Limited. REFERENCES 1. Bauernfeind, A. 1997. Comparison of the antibacterial activities of the quinolones Bay 12-8039, gatifloxacin (AM 1155), trovafloxacin, clinafloxacin, levofloxacin and ciprofloxacin. J. Antimicrob. Chemother. 40:639–651. 2. Cohen, M. A., M. D. Huband, J. W. Gage, S. L. Yoder, G. E. Roland, and S. J. Gracheck. 1997. In-vitro activity of clinafloxacin, trovafloxacin, and ciprofloxacin. J. Antimicrob. Chemother. 40:205–211. 3. Cormican, M. G., S. A. Marshall, and R. N. Jones. 1995. Cross-resistance analysis for DU-6859a, a new fluoroquinolone, compared to six structurally similar compounds (ciprofloxacin, clinafloxacin, fleroxacin, levofloxacin, ofloxacin, and sparfloxacin). Diagn. Microbiol. Infect. Dis. 21:51–54. 4. Fuchs, P. C., A. L. Barry, and S. D. Brown. 1998. In vitro activities of clinafloxacin against contemporary clinical bacterial isolates from 10 North American centers. Antimicrob. Agents Chemother. 42:1274–1277. 5. Hecht, D. W., and H. M. Wexler. 1996. In vitro susceptibility of anaerobes to quinolones in the United States. Clin. Infect. Dis. 23(Suppl. 1):S2–S8. 6. Jones, R. N., M. S. Barrett, and D. J. Biedenbach. 1994. Interpretive criteria for susceptibility tests with DU-6859a and FK-037 tested against Haemophilus influenzae and Neisseria gonorrhoeae. Diagn. Microbiol. Infect. Dis. 19:93–99. 7. Jones, R. N., D. M. Johnson, D. J. Biedenbach, and S. A. Marshall. 1995. Activity of two novel fluoroquinolones (DU-6859a and DV-7751a) tested against glycopeptide-resistant enterococcal isolates. Diagn. Microbiol. Infect. Dis. 23:123–127. 8. Kato, N., H. Kato, K. Tanaka-Bando, K. Watanabe, and K. Ueno. 1996. Comparison of in vitro activities of DU-6859a and other fluoroquinolones against Japanese isolates of anaerobic bacteria. Clin. Infect. Dis. 23(Suppl. 1):S31–S35. 9. Kawada, Y. 1999. Sitafloxacin (DU-6859a) in the treatment of genitourinary tract infections. J. Antimicrob. Chemother. 44(Suppl. A):142. 10. Kobayashi, H. 1999. The clinical efficacy of sitafloxacin (DU-6859a) in respiratory tract infection. J. Antimicrob. Chemother. 44(Suppl. A):130. 11. Korten, V., I. Erdem, and B. E. Murray. 1996. Bactericidal activity of the fluoroquinolone DU-6859a alone and in combination with other antimicrobial agents against multiresistant enterococci. Diagn. Microbiol. Infect. Dis. 26:79–85. 12. Marshall, S. A., and R. N. Jones. 1993. In vitro activity of DU-6859a, a new

VOL. 44, 2000 fluorocyclopropyl quinolone. Antimicrob. Agents Chemother. 37:2747–2753. 13. Nakane, T., S. Iyobe, K. Sato, and S. Mitsuhashi. 1995. In vitro antibacterial activity of DU-6859a, a new fluoroquinolone. Antimicrob. Agents Chemother. 39:2822–2826. 14. Nakashima, M., T. Uematsu, K. Kosuge, K. Umemura, H. Hakusui, and M. Tanaka. 1995. Pharmacokinetics and tolerance of DU-6859a, a new fluoroquinolone, after single and multiple oral doses in healthy volunteers. Antimicrob. Agents Chemother. 39:170–174. 15. National Committee for Clinical Laboratory Standards. 1997. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. Approved standard M7-A4. National Committee for Clinical Laboratory Standards, Wayne, Pa. 16. National Committee for Clinical Laboratory Standards. 1997. Methods for antimicrobial susceptibility testing of anaerobic bacteria. Approved standard M11-A4. National Committee for Clinical Laboratory Standards, Wayne, Pa. 17. Nord, C. E. 1996. In vitro activity of quinolones and other antimicrobial agents against anaerobic bacteria. Clin. Infect. Dis. 23(Suppl. 1):S15–S18.

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18. Summanen, P., E. J. Baron, D. Citron, C. Strong, H. M. Wexler, and S. M. Finegold. 1993. Wadsworth anaerobic bacteriology manual, 5th ed. Star Publishing Company, Belmont, Calif. 19. Takifuji, K., H. Tanimura, Y. Nagai, and S. Iwakura. 1999. Clinical effects of sitafloxacin (DU-6859a) on surgical infection and pharmacokinetic evaluation. J. Antimicrob. Chemother. 44:146. 20. Visalli, M. A., S. Bajaksouzian, M. R. Jacobs, and P. C. Appelbaum. 1997. Comparative activity of trovafloxacin, alone and in combination with other agents, against gram-negative nonfermentative rods. Antimicrob. Agents Chemother. 41:1475–1481. 21. Visalli, M. A., M. R. Jacobs, and P. C. Appelbaum. 1996. MIC and time-kill study of activities of DU-6859a, ciprofloxacin, levofloxacin, sparfloxacin, cefotaxime, imipenem, and vancomycin against nine penicillin-susceptible and -resistant pneumococci. Antimicrob. Agents Chemother. 40:362–366. 22. Wexler, H. M., E. Molitoris, D. Reeves, and S. M. Finegold. 1994. In vitro activity of DU-6859a against anaerobic bacteria. Antimicrob. Agents Chemother. 38:2504–2509.