The in vitro spectrum of a novel des-fluoro(6) quinolone, BMS-284756, was compared with those of five fluoroquinolones (trovafloxacin, moxifloxacin, levofloxacin, ofloxacin, and ciprofloxacin). BMS-284756 was among the most active and often was the most active quinolone against staphylococci (including methicillin-resistant strains), streptococci, pneumococci (including ciprofloxacin-nonsusceptible and penicillin-resistant strains), and Enterococcus faecalis. BMS-284756 inhibited Ϸ60 to Ϸ70% of the Enterococcus faecium (including vancomycin-resistant) strains and 90 to 100% of the Enterobacteriaceae strains and gastroenteric bacillary pathogens at the anticipated MIC susceptible breakpoint (<4 g/ml). Against the nonfermenters, BMS-284756 inhibited 90 to 100% of Pseudomonas fluorescens, Pseudomonas stutzeri, Stenotrophomonas maltophilia, Flavobacterium spp., and Acinetobacter spp. and 72% of Pseudomonas aeruginosa strains at 4 g/ml. Against anaerobic bacteria, BMS-284756 was among the most active, inhibiting essentially all strains tested. It had very low MICs against the fastidious and atypical microbial species, in particular against mycoplasmas or ureaplasmas, Borrelia burgdorferi, chlamydia, and gonococci. These results indicate that with its broad antibacterial spectrum, BMS-284756 should be evaluated clinically for the treatment of community and nosocomial infections.BMS-284756 is a novel des-fluoro(6) quinolone. This means that BMS-284756 differs from recently approved quinolones (i.e., the fluoroquinolones included in this study and gatifloxacin) in that BMS-284756 lacks a fluorine at the C-6 position. BMS-284756 (also known as T-3811ME) has antibacterial activity similar to those of fluorinated quinolones, but the des-F(6) derivatives are less acutely toxic in mice (K. Hayashi, Y. Todo, S. Hamamoto, K. Ojima, M. Yamada, T. Kito, M. Takahata, Y. Watanbe, and H. Narita, Abstr. 37th Intersci. Conf. Antimicrob. Agents Chemother., abstr. F-158, 1997).Quinolones can differ in their antibacterial spectra and potencies. Notable potency differences among quinolones occur in their activities versus gram-positive bacteria, pseudomonads, anaerobic bacteria, and mycobacteria. In the present study, the antibacterial spectrum of BMS-284756 is compared to those of five fluoroquinolones against 1,150 strains representing 66 bacterial species. While the antibacterial activity of BMS-284756 was reported previously by Takahata et al. (9), the present study included additional bacterial species and was performed using NCCLS-recommended susceptibility test methods, whenever they were available for specific bacterial groups. MATERIALS AND METHODSAntimicrobial agents. BMS-284756 was obtained from Toyama Chemical Co. Ltd., Toyama, Japan, and moxifloxacin (MFX) and ciprofloxacin (CIP) were obtained from Bayer Corporation, West Haven, Conn. Levofloxacin (LVX) and trovafloxacin (TVA) were extracted and purified from commercially available tablets and were determined to be Ն95% pure by high-performance liquid chromatography. Ofloxac...
Positive correlation between methicillin and oxacillin susceptibility test results and the detection of the mecA gene was observed for Staphylococcus aureus, S. epidermidis, and S. haemolyticus as well as among mecA ؉ strains of other species of coagulase-negative staphylococci (CNS). However, at least 50% of the mecA-negative strains of these other species of CNS were falsely classified as methicillin and oxacillin resistant.Methicillin and oxacillin resistance (MR) in staphylococci is due to the acquisition of the mecA gene, which encodes the low-affinity penicillin-binding protein PBP2a (3,4). Presence of the mecA gene defines the staphylococcus as MR, while absence of the gene from a staphylococcal strain indicates methicillin susceptibility (MS). mecA ϩ strains can differ in their level of expression of MR (4). Strains expressing low-level MR (i.e., heterogenously MR) can be difficult to identify by MIC testing; it is often difficult to identify mecA ϩ strains of coagulase-negative staphylococci (CNS) (11). Thus, correctly categorizing staphylococci as MR or MS based on MIC test results has been a challenge. Over the years, the National Committee for Clinical Laboratory Standards (NCCLS) has modified the MIC interpretative criteria for MR and MS so that the MS or MR phenotype correlates better with the mecA genotype (Table 1). While Staphylococcus aureus and CNS once shared the same MIC interpretative criteria for methicillin and oxacillin (8), the two groups now have different MIC interpretive criteria for determining MR and MS (9, 10). More recently, the oxacillin MIC breakpoints for CNS were lowered to allow for increased detection of mecA ϩ S. epidermidis strains, and oxacillin testing is no longer recommended for S. saprophyticus, since mecA-negative strains of this species often phenotypically appear to be resistant (10).In this study, we assessed the correlation between genotype and phenotypic (MS or MR) categorization of staphylococci. A total of 442 clinical isolates, including 155 S. aureus strains (120 mecA ϩ strains and 35 mecA-negative strains) and 287 CNS strains (104 mecA ϩ strains and 183 mecA-negative strains), were evaluated. S. aureus speciation was based on a positive coagulase test result, and CNS speciation was done using the API-Staph system (bioMérieux, Hazelwood, Mo.).The detection of the mecA gene was done according to the PCR assay described by Bignardi et al. (1). Precautions were taken to prevent the samples from being contaminated by each other or by the skin of laboratory personnel. These precautions included the use of prealiquoted reagents, gloves, disposable pipettes, and disposable tips with aerosol resistant filters; in addition, the preparation of the amplification reaction mixtures and the analysis of the amplified product were performed in separate areas. Included in every set of PCRs were positive (MR S. aureus strain A27283) and negative (S. aureus strain ATCC 29213) target DNA controls. The methicillin and oxacillin MICs were determined by the NCCLS-recommended agar...
The rates of development of resistance to ceftriaxone, ceftazidime, cefepime, and cefpirome in 10 strains of Enterobacter cloacae were determined by daily transfer for 7 days to fresh medium containing twofold serial dilutions of the antibiotics. Development of resistance to ceftriaxone was the most rapid; this was followed by ceftazidime, cefpirome, and cefepime. Resistant variants selected by ceftriaxone and ceftazidime were cross-resistant and produced very high levels of beta-lactamase. On the other hand, resistant variants selected by cefepime and cefpirome often had moderately high levels of beta-lactamase and diminished levels of the 39- to 40-kDa porin protein.
The recent emergence of methicillin-resistant Staphylococcus aureus (MRSA) with decreased susceptibility to vancomycin has intensified the search for alternative therapies for the treatment of infections caused by this organism. One approach has been to identify a -lactam with improved affinity for PBP 2a, the target enzyme responsible for methicillin resistance in staphylococci. BMS-247243 is such a candidate, with MICs that inhibit 90% of isolates tested (MIC 90 s) of 4, 2, and 8 g/ml for methicillin-resistant strains of S. aureus, S. epidermidis, and S. haemolyticus, respectively, as determined on plates with Mueller-Hinton agar and 2% NaCl. The BMS-247243 MICs for MRSA were minimally affected by the susceptibility testing conditions (inoculum size, prolonged incubation, addition of salt to the test medium) or by staphylococcal -lactamases. BMS-247243 MIC 90 s for methicillin-susceptible staphylococcal species ranged from <0.25 to 1 g/ml. The BMS-247243 MIC 90 for -lactamase-producing S. aureus strains was fourfold higher than that for -lactamase-nonproducing strains. BMS-247243 is hydrolyzed by staphylococccal -lactamases at 4.5 to 26.2% of the rates measured for cephaloridine. The affinity of BMS-247243 for PBP 2a was >100-fold better than that of methicillin or cefotaxime. BMS-247243 is bactericidal for MRSA, killing the bacteria twice as fast as vancomycin. These in vitro activities of BMS-247243 correlated with its in vivo efficacy against infections in animals, including the neutropenic murine thigh and rabbit endocarditis models involving MRSA strains. In conclusion, BMS-247243 has in vitro and in vivo activities against methicillin-resistant staphylococci and thus may prove to be useful in the treatment of infections caused by these multidrug-resistant organisms.
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