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Antimicrobial Agents and Chemotherapy, January 2002, p. 234-238, Vol. 46, No. 1
0066-4804/01/$04.00+0     DOI: 10.1128/AAC.46.1.234-238.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Antimicrobial Activities of BMS-284756 Compared with Those of Fluoroquinolones and ß-Lactams against Gram-Positive Clinical Isolates

Matteo Bassetti,^1* Louise M. Dembry,^1,2 Patricia A. Farrel,² Deborah A. Callan,² and Vincent T. Andriole¹

Yale University School of Medicine,¹ Yale-New Haven Hospital New Haven, Connecticut²

Received 27 April 2001/ Returned for modification 30 July 2001/ Accepted 5 October 2001

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The in vitro antibacterial activity of BMS-284756 was compared to those of ciprofloxacin, gatifloxacin, moxifloxacin, ceftriaxone, imipenem, piperacillin-tazobactam, and amoxicillin-clavulanic acid against 492 gram-positive clinical isolates. BMS-284756 was the most-active agent against Streptococcus pneumoniae, Streptococcus viridans, beta-hemolytic streptococci, methicillin-sensitive and -resistant Staphylococcus aureus, methicillin-sensitive and -resistant coagulase-negative staphylococci, and enterococci.

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The fluoroquinolones have considerable antimicrobial activity against most gram-negative bacilli and cocci (15). However, ciprofloxacin and other early fluoroquinolones provide limited activity against most gram-positive organisms (1). The synthesis of newer fluoroquinolones has focused on overcoming the limitations of the early fluoroquinolones by expanding their spectrum of activity with regard to gram-positive organisms (2, 5, 8, 9, 13). Serious infections due to Streptococcus pneumoniae, viridans group streptococci, and enterococci have become major treatment problems because of their resistance to several, if not most, currently available antimicrobial agents (8, 9, 14).

BMS-284756 is a novel des-fluoro(6) quinolone that differs from the fluoroquinolones in that it lacks a fluorine molecule at the C-6 position. BMS-284756 has a broad spectrum of antimicrobial activity, including activity against gram-positive bacteria (6, 10). A potential advantage of the des-fluoro(6) quinolone derivatives are that they show less acute toxicity in mice than the fluorinated quinolone compounds and may therefore have the potential of an improved toxicity profile in humans as well (K. Hayashi, Y. Todo, S. Hamamaoto, K. Ojima, M. Yamada, T. Kito, M. Takahata, Y. Watanabe, and H. Narita, Abstr. 37th Intersci. Conf. Antimicrob. Agents Chemother., abstr. F-158, 1997).

In the present study, the in vitro activity of BMS-284756 was tested and compared to those of ciprofloxacin, gatifloxacin, moxifloxacin, ceftriaxone, imipenem, piperacillin-tazobactam, and amoxicillin-clavulanic acid against 492 gram-positive clinical isolates from Yale-New Haven Hospital. A total of 145 streptococcal isolates (65 Streptococcus pneumoniae, 38 Streptococcus viridans, 17 Streptococcus pyogenes, 15 Streptococcus agalactiae, and 10 group G streptococci), 297 staphylococcal isolates (175 Staphylococcus aureus and 122 coagulase-negative staphylococci, including 45 Staphylococcus epidermidis), and 50 enterococcal isolates (25 Enterococcus faecalis and 25 Enterococcus faecium) were tested. S. aureus ATCC 29213, E. faecalis ATCC 29212, and S. pneumoniae ATCC 49619 were used as control strains.

BMS-284756 E-test was obtained from Bristol-Myers Squibb, Princeton, N.J. The E-test strips for the other antibiotics were obtained from AB Biodisk North America Inc., Piscataway, N.J. All organisms were tested using the E-test methodology for susceptibility testing (4, 11). Specifically, 2 ml of tryptic soy broth was inoculated with organisms to a density of a 0.5 McFarland standard from a freshly grown subculture (grown overnight) and applied to a 150-mm-diameter Mueller-Hinton agar plate for testing of staphylococci and enterococci and to Mueller-Hinton agar supplemented with 5% sheep blood for testing of streptococci. E-test strips were applied following the manufacturer’s recommendations. Staphylococci and enterococci were incubated at 37°C in an ambient air incubator, and streptococci were incubated in a 5% CO₂ incubator at 37°C. The plates were examined after 16 to 20 h of incubation. The lowest concentration of drug inhibiting visible growth was used as the MIC. All tests were performed, and susceptibility data were evaluated using the criteria of the National Committee for Clinical Laboratory Standards (12). An MIC of 0.5 µg/ml was used to determine the susceptibility of S. pneumoniae to amoxicillin-clavulanic acid (]February 1996 package insert supplement for E-test amoxicillin-clavulanic acid; AB Biodisk). Susceptibility breakpoints for BMS-284756 have yet to be determined.

The susceptibility testing results are summarized in Table 1. BMS-284756 demonstrated excellent activity against all streptococcal species tested (MIC at which 90% of the isolates tested are inhibited [MIC₉₀] 0.25 µg/ml). Ciprofloxacin (MIC₉₀, 4 µg/ml) was the least-active agent against penicillin-susceptible S. pneumoniae, while BMS-284756 (MIC₉₀, 0.12 µg/ml) was the most-active agent. BMS-284756 was also the most-active agent against penicillin-nonsusceptible S. pneumoniae (MIC₉₀, 0.12 µg/ml), followed by moxifloxacin (MIC₉₀, 0.25 µg/ml). Other studies have shown that BMS-284756 and newer fluoroquinolones maintain activity against penicillin-intermediate and -resistant strains of S. pneumoniae (6, 13, 16). The most-active agents against S. viridans were BMS-284756, moxifloxacin, and imipenem, with MIC₉₀s of 0.12, 0.25, and 0.25 µg/ml, respectively. BMS-284756, imipenem, amoxicillin-clavulanic acid, ceftriaxone, and piperacillin-tazobactam were the most-active agents against the beta-hemolytic streptococci.

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TABLE 1. Antimicrobial activity of BMS-284756 compared to those of other antibiotics tested by reference methods (12) (E-test; AB Biodisk) against streptococci, staphylococci, and enterococcia

A total of 297 staphylococcal strains were tested. BMS-284756 was the most-active agent against methicillin-susceptible S. aureus and coagulase-negative staphylococci, with MIC₉₀s of 0.06 and 0.12 µg/ml, respectively. All the agents tested, with the exception of ceftriaxone, demonstrated excellent activity against methicillin-susceptible S. aureus, regardless of penicillin susceptibility. Ciprofloxacin had good activity against methicillin-sensitive S. aureus (MIC₉₀, 0.5 µg/ml), but the MIC₉₀ for BMS-284756 was threefold lower (MIC₉₀, 0.06 µg/ml). BMS-284756 was the most-active agent against methicillin-resistant, ciprofloxacin-sensitive S. aureus, with an MIC₉₀ of 0.12 µg/ml. BMS-284756 was the most-active agent against methicillin- and ciprofloxacin-resistant S. aureus, with an MIC₉₀ of 4 µg/ml.

Imipenem (MIC₉₀, 0.25 µg/ml), moxifloxacin (MIC₉₀, 1 µg/ml), BMS-284756 (MIC₉₀, 2 µg/ml), and piperacillin-tazobactam (MIC₉₀, 2 µg/ml) had good activity against methicillin-sensitive S. epidermidis. BMS-284756 had the lowest MIC₉₀ (4 µg/ml) against methicillin-resistant S. epidermidis. Of the methicillin-sensitive and -resistant coagulase-negative staphylococci tested, BMS-284756 was the most-active agent (MIC₉₀s of 0.12 and 4 µg/ml, respectively). Overall, BMS-284756 was the most-active agent against methicillin-resistant staphylococci. Previous experience with ciprofloxacin and levofloxacin has shown that quinolone resistance among staphylococci can develop, particularly among methicillin-resistant organisms, with widespread use of these agents (3, 7). Whether this will also occur with the newer fluoroquinolones or BMS-284756 is unknown and will require further clinical studies.

A total of 50 enterococcal isolates were tested. BMS-284756 and amoxicillin-clavulanic acid were the most-active agents against E. faecalis. Ciprofloxacin demonstrated the least activity against E. faecalis and E. faecium. Although the MIC₉₀ for BMS-284756 against E. faecium was 32 µg/ml, it was nevertheless the most-active agent against this organism. Ten enterococcal strains, 6 E. faecium and 4 E. faecalis strains, were vancomycin resistant, and the MIC₅₀ and MIC₉₀ for BMS-284756 were 4 and 16 µg/ml, respectively. Overall, BMS-284756 showed in vitro effectiveness against E. faecalis; however, it was less active against E. faecium, as are most antibiotics.

This study illustrates the superior activity of BMS-284756 against gram-positive organisms compared to those of other fluoroquinolones and beta-lactam antimicrobial agents. The enhanced gram-positive bacterial activity of BMS-284756 and the advantages of the quinolone class of antibiotics, which include excellent oral bioavailability, convenient dosing schedules, and favorable adverse event profiles, should make this new agent a good alternative for treatment of many types of infections, including those caused by organisms resistant to currently available antimicrobial agents.

 
This study was supported in part by a grant from Bristol-Myers Squibb, Wallingford, Conn.

 
* Corresponding author. Mailing address: Clinica Malattie Infettive, Universitá di Genova, Ospedale San Martino, Largo R. Benzi, 10, 16132 Genova, Italy. Phone: 39 010 5552668. Fax: 39 010 3537680. E-mail: mattba{at}tin.it.

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Antimicrobial Agents and Chemotherapy, January 2002, p. 234-238, Vol. 46, No. 1
0066-4804/01/$04.00+0     DOI: 10.1128/AAC.46.1.234-238.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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