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Antimicrobial Agents and Chemotherapy, April 2000, p. 1102-1107, Vol. 44, No. 4
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

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


    ABSTRACT
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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.


    TEXT
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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 Wilkins-Chalgren 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 µg/ml. The MIC50s ranged from <= 0.008 to 1 µg/ml, and the MIC90s ranged from 0.015 to 2 µg/ml. The MIC90 for Providencia spp. was the highest (2 µg/ml), followed by those for Enterobacter aerogenes and Escherichia coli (1 µg/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 µg/ml and were similar to those of ciprofloxacin. However, sitafloxacin was four times more active than ciprofloxacin against Citrobacter freundii, Klebsiella pneumoniae, Morganella 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).

                              
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  		TABLE 1.   Susceptibilities of 8,796 clinical isolates to the seven fluoroquinolones tested

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 cross-resistance between ciprofloxacin and sitafloxacin was observed in Pseudomonas aeruginosa, with only 5% of the 165 ciprofloxacin-resistant isolates being susceptible to sitafloxacin at <= 1 µg/ml.

Sitafloxacin showed good activity against staphylococci, with some species variability. The MIC90s for oxacillin-resistant strains ranged from 0.25 to 1 µg/ml and were considerably higher than those for oxacillin-susceptible strains (MIC90, 0.03 to 0.12 µg/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 >= 4 µg/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 µg/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 µg/ml; MIC90, 4 µg/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 µg/ml. No difference was observed between penicillin-susceptible and penicillin-resistant isolates, 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 <= 0.008 µg/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 µg/ml.

Of the 406 strains of anaerobic bacteria tested, 96.3% were inhibited by sitafloxacin at a concentration of 1 µg/ml. The MIC50s and MIC90s ranged from 0.03 to 0.12 µg/ml and from 0.06 to 0.25 µg/ml, respectively, with the exception of the Bacteroides species tested (MIC50, 0.12 µg/ml; MIC90, 1 µg/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, gram-negative, 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.


    ACKNOWLEDGMENTS

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 Gür, Serhat Unal, Louise Marcus, Marque Venter, and Judy Walsh.

This work was funded by DAIICHI Pharmaceutical Co. Limited.


    FOOTNOTES

* Corresponding author. Mailing address: Eijkman-Winkler Institute, University Hospital Utrecht, G04.614, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. Phone: 31-30-2507625. Fax: 31-30-2541770. E-mail: d.milatovic{at}lab.azu.nl.


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Antimicrobial Agents and Chemotherapy, April 2000, p. 1102-1107, Vol. 44, No. 4
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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