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.

Ceftobiprole (previously known as BAL9141), an anti-methicillin-resistant Staphylococcus aureus cephalosporin, was very highly active against a panel of 299 drug-susceptible and -resistant pneumococci, with MIC 50 and MIC 90 values (g/ml) of 0.016 and 0.016 (penicillin susceptible), 0.06 and 0.5 (penicillin intermediate), and 0.5 and 1.0 (penicillin resistant). Ceftobiprole, imipenem, and ertapenem had lower MICs against all pneumococcal strains than amoxicillin, cefepime, ceftriaxone, cefotaxime, cefuroxime, or cefdinir. Macrolide and penicillin G MICs generally varied in parallel, whereas fluoroquinolone MICs did not correlate with penicillin or macrolide susceptibility or resistance. All strains were susceptible to linezolid, quinupristindalfopristin, daptomycin, vancomycin, and teicoplanin. Time-kill analyses showed that at 1؋ and 2؋ the MIC, ceftobiprole was bactericidal against 10/12 and 11/12 strains, respectively. Levofloxacin, moxifloxacin, vancomycin, and teicoplanin were each bactericidal against 10 to 12 strains at 2؋ the MIC. Azithromycin and clarithromycin were slowly bactericidal, and telithromycin was bactericidal against only 5/12 strains at 2؋ the MIC. Linezolid was mainly bacteriostatic, whereas quinupristin-dalfopristin and daptomycin showed marked killing at early time periods. Prolonged serial passage in the presence of subinhibitory concentrations of ceftobiprole failed to yield mutants with high MICs towards this cephalosporin, and single-passage selection showed very low frequencies of spontaneous mutants with breakthrough MICs towards ceftobiprole.The incidence of pneumococci resistant to penicillin G and other ␤-lactam antibiotics, as well as non-␤-lactam antibiotics, has increased worldwide at an alarming rate. Major foci of infection include South Africa, Spain, and central and eastern Europe (1,21,22,35,48). A survey published in the mid-1990s showed an increase in resistance by pneumococci to penicillin from Ͻ5% before 1989 (including Ͻ0.02% of isolates with MICs of Ն2 g/ml) to 6.6% in 1991 to 1992 (with 1.3% of isolates with MICs of Ն2 g/ml) (5). A more recent survey (23) reported that 50.4% of 1,476 clinically significant pneumococcal isolates were not susceptible to penicillin and that high rates of macrolide-resistant pneumococci occurred in strains with elevated penicillin MICs, for an overall pneumococcal macrolide resistance rate of approximately 33%. Rates of macrolide resistance are even higher in Spain, France, central and eastern Europe, Korea, and Japan (1, 23, 24, 35). Although pneumococcal fluoroquinolone resistance is still uncommon, relatively high rates have been reported in Canada, Hong Kong, Spain, and Croatia (19,29,39,45). Moreover, there is a high rate of isolation of penicillin-intermediate and -resistant pneumococci (approximately 30%) in middle ear fluids from patients with refractory otitis media, compared to rates from other isolation sites (3,15,16). The problem of drug-resistant pneumococci is compounded by the ability of resistant clones to spread rapi...

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...

For 260 pneumococcal and 266 staphylococcal strains, ranbezolid MICs ranged from <0.06 to 4 g/ml. The MICs for pneumococci were similar irrespective of the strains' ␤-lactam, macrolide, or quinolone susceptibilities, and ranbezolid MICs for coagulase-negative staphylococci were lower than those for Staphylococcus aureus. Ranbezolid was bacteriostatic against pneumococci. Ranbezolid MICs were similar to or lower than those of linezolid. Vancomycin and quinupristin-dalfopristin were also very active.The incidence of pneumococci being resistant to penicillin G and other ␤-lactams and non-␤-lactams has increased worldwide at an alarming rate, including in the United States (1, 5, 9). There is an urgent need for oral compounds for outpatient treatment of respiratory tract infections caused by resistant pneumococci (1,5,8). The emergence of methicillin-and quinolone-intermediate, and recently glycopeptide-intermediate, staphylococci, as well as the propensity of these organisms to cause serious systemic infections in immunocompromised hosts, also necessitates other therapeutic modalities (7,12,21).The MICs of linezolid, an oxazolidinone which has been available clinically for the past few years, for pneumococci and staphylococci range between 0.5 and 4 g/ml, irrespective of the organisms' resistance to other agents (2-4, 6, 10, 15, 18). Ranbezolid (RBX 7644; Ranbaxy Research Laboratories, New Delhi, India) is a new parenteral oxazolidinone with enhanced activity against gram-positive aerobes and gram-positive and gram-negative anaerobes.The present study compared (i) the antipneumococcal activity of ranbezolid with those of linezolid, vancomycin, teicoplanin, quinupristin-dalfopristin, amoxicillin-clavulanate, ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin, and erythromycin by using MIC and time-kill studies and (ii) the antistaphylococcal activity of ranbezolid with those of linezolid, vancomycin, teicoplanin, and quinupristin-dalfopristin by using an MIC study.The pneumococci tested comprised 89 penicillin-susceptible, 89 penicillin-intermediate, and 82 penicillin-resistant strains. Of these, 107 were erythromycin resistant. Twenty-six strains were quinolone resistant (levofloxacin MICs of Ն8 g/ml). For time-kill studies, 12 penicillin-susceptible, -intermediate, and -resistant strains (four of each), including six macrolide-resistant and two quinolone-resistant strains, were tested. Sixtyeight methicillin-resistant and 65 methicillin-susceptible Staphylococcus aureus strains and 69 methicillin-resistant and 64 methicillin-susceptible coagulase-negative staphylococci were examined.Ranbezolid susceptibility powder was obtained from Ranbaxy Research Laboratories. Other antimicrobials were obtained from their respective manufacturers. For testing with pneumococci, agar dilution was performed by using MuellerHinton agar (BBL Microbiology Systems, Cockeysville, Md.) supplemented with 5% sheep blood (11). Methicillin MIC plates for staphylococci were incubated for a full 24 h (11).For time-kill studies, tubes con...

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

GAR-936, a new glycylcycline, had lower MICs (<0.016 to 0.125 g/ml) for 201 penicillin-and tetracyclinesusceptible and -resistant pneumococcal strains than tetracycline (<0.06 to 128 g/ml), minocycline (<0.06 to 16.0 g/ml), or doxycycline (<0.06 to 32.0 g/ml). GAR-936 was also bactericidal against 11 of 12 strains tested at the MIC after 24 h, with significant kill rates at earlier time points.The incidence of pneumococcal resistance to penicillin G and other ß-lactam and non-ß-lactam compounds has increased worldwide at an alarming rate (1, 6, 7). In the United States, a recent survey of 1,476 strains showed that 49.6% were penicillin susceptible, 17.9% were of intermediate resistance (penicillin intermediate), and 32.5% were penicillin resistant. Macrolide MICs rose with those of penicillin G, with an overall macrolide resistance level of 33% (8).Resistance to conventional oral tetracyclines (including minocycline and doxycycline) occurs with increased frequency among penicillin-intermediate and -resistant pneumococci, and genes coding for macrolide and tetracycline resistance are carried on the same transposon (6, 7). GAR-936 is a new broad-spectrum parenteral glycylcycline. Preliminary studies have shown that this drug is active against penicillin-susceptible and -resistant pneumococci (13,15).This study compares the activity of GAR-936 against 201 penicillin-susceptible, -intermediate, or -resistant pneumococcal strains with those of three other tetracyclines, four ß-lactams, clarithromycin, and vancomycin. Additionally, the activities of these compounds against 12 penicillin-susceptible and -resistant strains of pneumococci were determined by the broth MIC and time-kill methods.For determination of MICs by agar dilution, 51 penicillinsusceptible, 72 penicillin-intermediate, and 78 penicillin-resistant strains of pneumococci were utilized. For time-kill studies, four penicillin-susceptible, four penicillin-intermediate, and four penicillin-resistant strains were tested; of these, five were tetracycline susceptible (MIC, Յ2.0 g/ml), 1 was tetracycline intermediate (MIC, 4.0 g/ml), and six were tetracycline resistant (MIC, Ն8.0 g/ml).The agar dilution method used in this study to determine MICs of various antimicrobial agents for 201 pneumococcal strains has been used routinely for many years by our group (6, 7); Mueller-Hinton agar (BBL Microbiology Systems, Cockeysville, Md.) supplemented with 5% sheep blood was employed. Microbroth MIC determinations for 12 strains were performed in accordance with the protocol recommended by the National Committee for Clinical Laboratory Standards (9). Standard quality control strains, including Streptococcus pneumoniae ATCC 49619 (9), were included in each run of agar and broth dilution MIC determinations. All MIC studies were performed in air. All strains, recently isolated from stocks stored at Ϫ70°C and subcultured twice, grew in air and did not require added CO 2 for growth. The susceptibility patterns of these strains are representative of those commonly encountered...

An agar dilution MIC method was used to test the activity of gatifloxacin, a new broad-spectrum fluoroquinolone, compared with ciprofloxacin, levofloxacin, sparfloxacin, trovafloxacin, amoxycillin, cefuroxime, ceftriaxone and clarithromycin against 71 penicillin-susceptible, 81 penicillin-intermediate and 55 penicillin-resistant pneumococci. Quinolone activity was unaffected by penicillin susceptibility, with MIC50/MIC90s (mg/L) of 0.25/0.5 for gatifloxacin; 1/2 for ciprofloxacin; 1/2 for levofloxacin; 0.25/0.5 for sparfloxacin; 0.125/0.25 for trovafloxacin. beta-Lactam and clarithromycin MICs rose with those of penicillin G; MIC50/MIC90 values (mg/L) for penicillin-susceptible, -intermediate and -resistant strains were: 0.03/0.06, 0.25/1, 2/4 for penicillin G; 0.03/0.03, 0.125/1, 2/4 for amoxycillin; 0.03/0.125, 0.5/4, 8/16 for cefuroxime; 0.03/0.03, 0.25/0.5, 2/4 for ceftriaxone; 0.03/0.06, 0.03/>64, 1/>64 for clarithromycin. Time-kill testing of four penicillin-susceptible, four -intermediate and four -resistant strains showed that levofloxacin at the MIC, gatifloxacin and sparfloxacin at 2 x MIC, and trovafloxacin and ciprofloxacin at 4 x MIC, were bactericidal (99.9% killing) for all strains after 12 h and 24 h. By contrast, amoxycillin, cefuroxime and ceftriaxone showed bactericidal activity after 24 h against all strains at 4, 8 and 4 x MIC, respectively. Against ten organisms with clarithromycin MICs of 0.03-4.0 mg/L, clarithromycin was bactericidal against seven strains at 8 x MIC after 24 h. Quinolones showed more rapid killing at lower concentrations and earlier time periods than did beta-lactams and clarithromycin.