Resistance in these 28 strains was associated with mutations in parC, gyrA, parE, and/or gyrB or efflux, with some strains having multiple resistance mechanisms. For 12 penicillin-susceptible and -resistant pneumococcal strains (2 quinolone resistant), time-kill results showed that levofloxacin at the MIC, gemifloxacin and sparfloxacin at two times the MIC, and ciprofloxacin, grepafloxacin, and trovafloxacin at four times the MIC were bactericidal for all strains after 24 h. Gemifloxacin was uniformly bactericidal after 24 h at <0.5 g/ml. Various degrees of 90 and 99% killing by all quinolones were detected after 3 h. Gemifloxacin and trovafloxacin were both bactericidal at two times the MIC for the two quinolone-resistant pneumococci. Amoxicillin at two times the MIC and cefuroxime at four times the MIC were uniformly bactericidal after 24 h, with some degree of killing at earlier time points. Macrolides gave slower killing against the seven susceptible strains tested, with 99.9% killing of all strains at two to four times the MIC after 24 h. PAEs for five quinolonesusceptible strains were similar (0.3 to 3.0 h) for all quinolones, and significant quinolone PAEs were found for the quinolone-resistant strain.The incidence of pneumococci resistant to penicillin G and other ␤-lactam and non-␤-lactam compounds has increased worldwide at an alarming rate, including in the United States. Major foci of infections presently include South Africa, Spain, Central and Eastern Europe, and parts of Asia (1, 9, 10, 13, 14). In the United States a recent survey has shown an increase in resistance to penicillin from Ͻ5% before 1989 (including Ͻ0.02% of isolates for which MICs were Ն2.0 g/ml) to 6.6% in 1991 to 1992 (with 1.3% of isolates for which MICs were Ն2.0 g/ml) (3). In another, more recent survey, 23.6% (360) of 1,527 clinically significant pneumococcal isolates were not susceptible to penicillin (8). It is also important to note the high rates of isolation of penicillin-intermediate and -resistant pneumococci (approximately 30%) in middle ear fluids from patients with refractory otitis media, compared to other isolation sites (2). The problem of drug-resistant pneumococci is compounded by the ability of resistant clones to spread from country to country and from continent to continent (16,17).There is an urgent need for oral compounds for outpatient treatment of otitis media and respiratory tract infections caused by penicillin-intermediate and -resistant pneumococci (9,10,13,14). Available quinolones such as ciprofloxacin and ofloxacin yield moderate in vitro activity against pneumococci, with MICs clustering around the breakpoints (22,25,26). Gemifloxacin (SB 265805; LB 20304a) is a new broad-spectrum fluoronaphthyridone carboxylic acid with a novel pyrrolidone substituent (5,12,19). Previous preliminary studies (5,12,19) have shown that this compound is very active against pneumococci. This study further examined the antipneumococcal activity of gemifloxacin compared to those of ciprofloxacin, levofloxacin, sparfloxa...

The macrolide and levofloxacin susceptibilities of 992 isolates of Streptococcus pneumoniae from clinical specimens collected in 1999 and 2000 were determined in 10 centers in Central and Eastern European countries. The prevalences of penicillin G-intermediate (MICs, 0.125 to 1 g/ml) and penicillin-resistant (MICs, <2 g/ml) Streptococcus pneumoniae isolates were 14.3 and 16.6%, respectively. The MICs at which 50% of isolates are inhibited (MIC 50 s) and the MIC 90 s of telithromycin were 0.016 and 0.06 g/ml, respectively; those of erythromycin were 0.06 and >64 g/ml, respectively; those of azithromycin were 0.125 and >64 g/ml, respectively; those of clarithromycin were 0.03 and >64 g/ml, respectively; and those of clindamycin were 0.06 and >64 g/ml, respectively. Erythromycin resistance was found in 180 S. pneumoniae isolates (18.1%); the highest prevalence of erythromycin-resistant S. pneumoniae was observed in Hungary (35.5%). Among erythromycin-resistant S. pneumoniae isolates, strains harboring erm ( (2 strains [1.1%]). Similar pulsed-field gel electrophoresis patterns suggested that some strains containing L4 mutations from the Slovak Republic, Bulgaria, and Latvia were clonally related. Of nine strains highly resistant to levofloxacin (MICs, >8 g/ml) six were isolated from Zagreb, Croatia. Telithromycin at <0.5 g/ml was active against 99.8% of S. pneumoniae isolates tested and may be useful for the treatment of respiratory tract infections caused by macrolide-resistant S. pneumoniae isolates.

Among 1,011 recently isolated Streptococcus pyogenes isolates from 10 Central and Eastern European centers, the MICs at which 50% of isolates are inhibited (MIC 50 s) and the MIC 90 s were as follows: for telithromycin, 0.03 and 0.06 g/ml, respectively; for erythromycin, azithromycin, and clarithromycin, 0.06 to 0.125 and 1 to 8 g/ml, respectively; and for clindamycin, 0.125 and 0.125 g/ml, respectively. Erythromycin resistance occurred in 12.3% of strains. Erm(A) [subclass erm(TR)] was most commonly encountered (60.5%), followed by mef(A) (23.4%) and erm(B) (14.5%). At <0.5 g/ml, telithromycin was active against 98.5% of the strains tested.Streptococcus pyogenes strains continue to be penicillin susceptible, but erythromycin resistance has increasingly been reported. A recent Canadian study (10) has documented that 2.1% of S. pyogenes strains collected in 1997 were macrolide resistant. Significant rates of erythromycin resistance have been reported in many countries including Finland, Sweden, Spain, France, and Italy (1,3,6,8,11,12,16,18,20,21,24). In the United States, it has been assumed that the rate of erythromycin resistance is low (14, 15). However, a recent study has reported erythromycin resistance rates of 32% among isolates from specimens from patients with invasive disease and 9% among isolates from cultures of throat swab specimens isolated between 1994 and 1995 in the San Francisco, California, area (25).For S. pyogenes isolates from most areas tested, macrolide resistance is mediated by the mef(A) gene (23), making the isolates resistant to 14-and 15-membered-ring macrolides but susceptible to 16-membered-ring macrolides and clindamycin. Erm(A) [subclass erm(TR)] has also been described (21); strains containing erm(A) are usually inducibly resistant to 14-and 15-membered-ring macrolides but are susceptible to 16-membered-ring macrolides and lincosamides. The erm(B) gene has also been described, with strains that contain this gene being resistant to macrolides and lincosamide (6,10,11,16).Telithromycin is a ketolide (9, 13, 19) with low MICs for erythromycin-susceptible and -resistant S. pyogenes strains except those carrying erm(B). To understand macrolide susceptibility in areas where high rates of drug-resistant pneumococcci have been described, Central and Eastern Europe (2), we tested the activities of telithromycin, erythromycin, azithromycin, clarithromycin, and clindamycin against 1,011 isolates of S. pyogenes. Levofloxacin was tested as the representative fluoroquinolone.Strains were consecutively obtained from clinical isolates recovered during 1999 and 2000 and were screened by the bacitracin disk method. Organisms were frozen at all collection sites except Warsaw (where swabs in Amies transport medium were used) and were transported on dry ice to Hershey Medical Center, where they were stored frozen in double-strength skim milk (Difco Laboratories, Detroit, Mich.) at Ϫ70°C until use. The identities of the organisms were confirmed by colonial morphology, bacitracin testing, beta-hemolys...

Anaerobes are becoming increasingly resistant to ␤-lactams due to ␤-lactamase production and other mechanisms. Although ␤-lactamase production, and concomitant resistance to ␤-lactams, is the norm among the Bacteroides fragilis group, other anaerobic gram-negative bacilli in the genera Prevotella, Porphyromonas, and Fusobacterium have increasingly become ␤-lactamase positive. ␤-Lactamase production also has been described for clostridia. Metronidazole resistance in organisms other than non-spore-forming gram-positive bacilli has been described, as has clindamycin resistance in anaerobic gramnegative bacilli (1-5).Quinolones such as ciprofloxacin, ofloxacin, fleroxacin, pefloxacin, enoxacin, and lomefloxacin are inactive or marginally active against anaerobes. Newer quinolones with increased antianaerobic activity include (i) those with slightly increased activity against aerobic gram-positive and some nonfermentative gram-negative bacteria (sparfloxacin, grepafloxacin, and levofloxacin) and (ii) those with significantly improved antianaerobic activity (with clinafloxacin and sitafloxacin being the most active, followed by trovafloxacin, moxifloxacin, and gatifloxacin) (6-11, 13, 16).BMS 284756 (T-3811) (15) is a novel des-F(6)-quinolone with a broad spectrum of activity. The present study tested the antianaerobic activity of BMS 284756 compared to those of ciprofloxacin, levofloxacin, moxifloxacin, trovafloxacin, amoxicillin-clavulanate, piperacillin-tazobactam, imipenem, clindamycin, and metronidazole against 357 anaerobes.All anaerobes were clinical strains, isolated during the past four years, identified by standard procedures (14) and kept frozen in 200 g of dehydrated skim milk (Difco Laboratories, Detroit, Mich.) per liter at Ϫ70°C until use. No history regarding prior in vivo exposure to quinolones or other antibiotics tested is available, and no advanced quinolone-resistant strains or very recent clinical strains (isolated within a few months prior to the study) were included. Prior to testing, strains were subcultured twice onto enriched sheep blood agar plates (14). BMS 284756 susceptibility powder was obtained from BristolMyers Squibb Laboratories, Wallingford, Conn., and other drugs were obtained from their manufacturers. ␤-Lactamase testing was by the nitrocefin disk method (Cefinase; BBL Microbiology Systems, Cockeysville, Md.). Agar dilution susceptibility testing was according to the latest method recommended by the National Committee for Clinical Laboratory Standards (NCCLS) (12), using brucella agar with 5% sterile defibrinated sheep blood for non-B. fragilis group strains. Clavulanate was added to amoxicillin at a fixed ratio of 1:2, and tazobactam was added to piperacillin at a fixed concentration of 4.0 g/ml. All quality control gram-negative and -positive strains recommended by NCCLS were included with each run; in every case, results (where available) were in the control range.Among the anaerobic gram-negative bacilli tested, 76 of 80 B. fragilis group strains (95%) 54 of 89 Prevotella and...

The activity of gemifloxacin against Haemophilus influenzae and Moraxella catarrhalis was compared to those of 11 other agents. All quinolones were very active (MICs,

The in vitro activity of DX-619, a new des-F(6)-quinolone, was tested against staphylococci and compared to those of other antimicrobials. DX-619 had the lowest MIC ranges/MIC 50 s/MIC 90 s (g/ml) against 131 Staphylococcus aureus strains (<0.002 to 2.0/0.06/0.5) and 128 coagulase-negative staphylococci (0.004 to 0.25/0.016/ 0.125). Among strains tested, 76 S. aureus strains and 51 coagulase-negative staphylococci were resistant to ciprofloxacin. DX-619 had the lowest MIC 50 /MIC 90 values against 127 quinolone-resistant staphylococci (0.125/0.5), followed by sitafloxacin (0.5/4), moxifloxacin (2/8), gatifloxacin (4/16), levofloxacin (16/>32), and ciprofloxacin (>32/>32). Raised quinolone MICs were associated with mutations in GyrA (S84L) and single or double mutations in GrlA (S80F or Y; E84K, G, or V) in all S. aureus strains tested. A recent vancomycinresistant S. aureus (VRSA) strain (Hershey) was resistant to available quinolones and was inhibited by DX-619 at 0.25 g/ml and sitafloxacin at 1.0 g/ml. Vancomycin (except VRSA), linezolid, ranbezolid, tigecycline, and quinupristin-dalfopristin were active against all strains, and teicoplanin was active against S. aureus but less active against coagulase-negative staphylococci. DX-619 produced resistant mutants with MICs of 1 to >32 g/ml after <50 days of selection compared to 16 to >32 g/ml for ciprofloxacin, sitafloxacin, moxifloxacin, and gatifloxacin. DX-619 and sitafloxacin were also more active than other tested drugs against selected mutants and had the lowest mutation frequencies in single-step resistance selection. DX-619 and sitafloxacin were bactericidal against six quinolone-resistant (including the VRSA) and seven quinolone-susceptible strains tested, whereas gatifloxacin, moxifloxacin, levofloxacin, and ciprofloxacin were bactericidal against 11, 10, 7, and 5 strains at 4؋ MIC after 24 h, respectively. DX-619 was also bactericidal against one other VRSA strain, five vancomycin-intermediate S. aureus strains, and four vancomycin-intermediate coagulase-negative staphylococci. Linezolid, ranbezolid, and tigecycline were bacteriostatic and quinupristin-dalfopristin, teicoplanin, and vancomycin were bactericidal against two, eight, and nine strains, and daptomycin and oritavancin were rapidly bactericidal against all strains, including the VRSA. DX-619 has potent in vitro activity against staphylococci, including methicillin-, ciprofloxacin-, and vancomycin-resistant strains.The emergence of methicillin-and quinolone-resistant, and recently glycopeptide-intermediate, staphylococci, as well as the propensity of these organisms to cause serious systemic infections in immunocompromised hosts, necessitates other therapeutic modalities (2,9,10,19,24,29). During 2002, two clinical strains of vancomycin-resistant Staphylococcus aureus (VRSA) carrying vanA, one from Detroit, Mich., and one from our hospital, have been isolated (3, 28). Several months ago, a third VRSA was isolated in New York city (14).Most methicillin-resistant staphylococci are also resistant...

MIC methodology was used to test the antibacterial activity of XRP 2868, a new oral combination of two semisynthetic streptogramins, RPR 132552A and RPR 202868, compared to activities of other antibacterial agents against pneumococci, Haemophilus influenzae, and Haemophilus parainfluenzae. For 261 pneumococci, XRP 2868 and pristinamycin MICs were similar, irrespective of penicillin G and erythromycin A susceptibilities (MIC at which 50% of isolates were inhibited [MIC 50 ], 0.25 g/ml; MIC 90 , 0.5 g/ml), while quinupristin/ dalfopristin had MICs which were 1 to 2 dilutions higher. Single components of both XRP 2868 and quinupristin/dalfopristin had higher MICs. Erythromycin A, azithromycin, clarithromycin, and clindamycin MICs were higher for penicillin G-intermediate and -resistant than -susceptible pneumococci. Against 150 H. influenzae strains, all compounds tested had unimodal MIC distributions. XRP 2868 had an overall MIC 50 of 0.25 g/ml and an MIC 90 of 1.0 g/ml, with no differences between ␤-lactamase-positive, ␤-lactamase-negative, and ␤-lactamase-negative ampicillin-resistant strains. Of note was the similarly low activity of one of its components, RPR 132552A. Pristinamycin and quinupristin/dalfopristin had MICs of 0.125 to 8.0 g/ml; quinupristin alone had MICs of 8.0 to >64.0 g/ml, and dalfopristin had MICs of 1.0 to >64.0 g/ml. Erythromycin A, azithromycin, and clarithromycin had modal MICs of 4.0, 1.0, and 8.0 g/ml, respectively. MICs of all compounds against H. parainfluenzae were 1 to 2 dilutions higher than against H. influenzae. XRP 2868 showed potent activity against pneumococci and Haemophilus strains irrespective of their susceptibility to other agents.

Telithromycin had low MICs against all strains, irrespective of macrolide, azalide or clindamycin resistance. Ribosomal methylation was the most prevalent resistance mechanism among all resistant strains, except in Sofia, where the prevalence of the efflux mechanism was higher.