Activity of the novel des-fluoro(6) quinolone BMS-284756 against methicillin-susceptible and -resistant staphylococci.

Sir, BMS-284756 is a novel des-fluoro(6) quinolone and is more active in vitro than marketed quinolones against staphylococci, Streptococcus pneumoniae and other ciprofloxacinresistant Gram-positive cocci. The rapid development of resistance to ciprofloxacin among methicillin (oxacillin)resistant Staphylococcus aureus (MRSA) strains has led to doubts about quinolone use against this organism. The fact that clinical resistance developed quickly with ciprofloxacin is not surprising (ciprofloxacin susceptibility breakpoint 1 mg/L), given its relatively borderline activity against staphylococci (MIC50 0.5 mg/L for MRSA). 1 BMS-284756 is 10-fold more active than ciprofloxacin against staphylococci (MIC50 0.03 mg/L) 1 and has threefold greater drug exposure (3 AUC of ciprofloxacin using standard doses), indicating that BMS-284756 may be of potential use for treatment of MRSA infection. In this study, we compared the activity of BMS-284756 with those of levofloxacin and ciprofloxacin against 144 mecA and 124 mecA staphylococcal strains. All strains were clinical isolates collected within the past 5 years. GISA (glycopeptide-intermediate susceptible S. aureus) strains were kindly provided by T. Walsh (Bristol, UK), and the BORSA (borderline oxacillin-resistant S. aureus) isolates were obtained from J. Swenson (CDC, Atlanta, GA, USA) and L. Jette (Labortoire de Sante Publique de Quebec, Canada). S. aureus was identified by a positive tube coagulase test. Coagulase-negative staphylococcal strains were speciated using the API-Staph system (bioMérieux, Hazelwood, MO, USA). BMS-284756 was obtained from Toyama Chemical Co. Ltd, Toyama, Japan; ciprofloxacin from Bayer Corporation, West Haven, CT, USA; levofloxacin was extracted and purified from commercially available tablets and determined to be 95% pure by high-performance liquid chromatography; and oxacillin was purchased from Sigma Chemical Co., St Louis, MO, USA. Genotypic determination of methicillin resistance was done by detection of the mecA gene, following the PCR procedure of Bignardi et al. MICs were determined by an agar dilution method, using Mueller–Hinton agar (MHA), and, for oxacillin, MHA 2% NaCl. Bacterial inoculum size was c. 5 10 cfu/spot, and plates were incubated at 35°C for 24 h. The MIC endpoint was read as the lowest drug concentration that prevented visible growth. BMS-284756 was the most active quinolone against staphylococci. Based on MIC90 or modal MIC values (Table), BMS-284756 was more active than ciprofloxacin and levofloxacin, by four to eight times against mecA staphylococcal strains, with an even greater differential (32–128 times) against BORSA strains. Most notable was the enhanced potency of BMS-284756 against methicillin-resistant staphylococci. Compared with levofloxacin and ciprofloxacin, BMS-284756 was 16 times more active against MRSA. BMS-284756 was four-fold more active than levofloxacin, 32-fold more active than ciprofloxacin against mecA Staphylococcus epidermidis, and two-fold more active than levofloxacin and over eight times more active than ciprofloxacin against mecA Staphylococcus haemolyticus isolates. Similarly, BMS-284756 was four to eight times more potent than the comparator quinolones against other mecA species of coagulasenegative staphylococci, and eight-fold or more active than comparators against mecA GISA strains. Based on its AUC following a 400 mg oral dose, the tentative BMS-284756 susceptibility breakpoint for MRSA strains is 2 mg/L. Ninety per cent of MRSA, 56% of GISA, 97% of oxacillin-resistant S. epidermidis, 89% of mecA S. haemolyticus and 100% of all mecA strains belonging to other coagulase-negative Staphylococcus spp. had BMS-284756 MICs of 2 mg/L. These results indicate that BMS-284756 is more active than comparator quinolones against methicillin-resistant staphylococci. Given that these strains are often multidrug resistant, and that the few agents with activity against MRSA (such as vancomycin, linezolid and quinupristin/ dalfopristin) are bacteriostatic or poorly bactericidal, BMS-284756 may provide a therapeutic alternative for infections caused by these pathogens. Correspondence Journal of Antimicrobial Chemotherapy (2001) 48, 735–748