In vitro activities of RWJ-54428 (MC-02,479) against multiresistant gram-positive bacteria

RWJ-54428 (MC-02,479) is a new cephalosporin with a high level of activity against gram-positive bacteria. In a broth microdilution susceptibility test against methicillin-resistant Staphylococcus aureus (MRSA), RWJ-54428 was as active as vancomycin, with an MIC at which 90% of isolates are inhibited (MIC(90)) of 2 microg/ml. For coagulase-negative staphylococci, RWJ-54428 was 32 times more active than imipenem, with an MIC(90) of 2 microg/ml. RWJ-54428 was active against S. aureus, Staphylococcus epidermidis, and Staphylococcus haemolyticus isolates with reduced susceptibility to glycopeptides (RWJ-54428 MIC range, < or = 0.0625 to 1 microg/ml). RWJ-54428 was eight times more potent than methicillin and cefotaxime against methicillin-susceptible S. aureus (MIC(90), 0.5 microg/ml). For ampicillin-susceptible Enterococcus faecalis (including vancomycin-resistant and high-level aminoglycoside-resistant strains), RWJ-54428 had an MIC(90) of 0.125 microg/ml. RWJ-54428 was also active against Enterococcus faecium, including vancomycin-, gentamicin-, and ciprofloxacin-resistant strains. The potency against enterococci correlated with ampicillin susceptibility; RWJ-54428 MICs ranged between < or = 0.0625 and 1 microg/ml for ampicillin-susceptible strains and 0.125 and 8 microg/ml for ampicillin-resistant strains. RWJ-54428 was more active than penicillin G and cefotaxime against penicillin-resistant, -intermediate, and -susceptible strains of Streptococcus pneumoniae (MIC(90)s, 0.25, 0.125, and < or = 0.0625 microg/ml, respectively). RWJ-54428 was only marginally active against most gram-negative bacteria; however, significant activity was observed against Haemophilus influenzae and Moraxella catarrhalis (MIC(90)s, 0.25 and 0.5 microg/ml, respectively). This survey of the susceptibilities of more than 1,000 multidrug-resistant gram-positive isolates to RWJ-54428 indicates that this new cephalosporin has the potential to be useful in the treatment of infections due to gram-positive bacteria, including strains resistant to currently available antimicrobials.     

RWJ-54428 (MC-02,479), a new cephalosporin with high affinity for penicillin-binding proteins,including PBP 2a,and stability to staphylococcal beta-lactamases

RWJ-54428 (MC-02,479) is a new cephalosporin active against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). The potency of this new cephalosporin against MRSA is related to a high affinity for penicillin-binding protein 2a (PBP 2a), as assessed in a competition assay using biotinylated ampicillin as the reporter molecule. RWJ-54428 had high activity against MRSA strains COL and 67-0 (MIC of 1 micro g/ml) and also showed affinity for PBP 2a, with a 50% inhibitory concentration (IC(50)) of 0.7 micro g/ml. RWJ-54428 also displayed excellent affinity for PBP 5 from Enterococcus hirae R40, with an IC(50) of 0.8 micro g/ml and a MIC of 0.5 micro g/ml. The affinity of RWJ-54428 for PBPs of beta-lactam-susceptible S. aureus (MSSA), enterococci (E. hirae), and Streptococcus pneumoniae showed that the good affinity of RWJ-54428 for MRSA PBP 2a and E. hirae PBP 5 does not compromise its binding to susceptible PBPs. RWJ-54428 showed stability to hydrolysis by purified type A beta-lactamase isolated from S. aureus PC1. In addition, RWJ-54428 displayed low MICs against strains of S. aureus bearing the four classes of staphylococcal beta-lactamases, including beta-lactamase hyperproducers. The frequency of isolation of resistant mutants to RWJ-54428 from MRSA strains was very low. In summary, RWJ-54428 has high affinity to multiple PBPs and is stable to beta-lactamase, properties that may explain our inability to find resistance by standard methods. These data are consistent with its excellent activity against beta-lactam-resistant gram-positive bacteria.     

In vitro and in vivo activities of a novel cephalosporin, BMS-247243, against methicillin-resistant and -susceptible staphylococci

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 beta-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 microg/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 beta-lactamases. BMS-247243 MIC(90)s for methicillin-susceptible staphylococcal species ranged from < or = 0.25 to 1 microg/ml. The BMS-247243 MIC(90) for beta-lactamase-producing S. aureus strains was fourfold higher than that for beta-lactamase-nonproducing strains. BMS-247243 is hydrolyzed by staphylococcal beta-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.     

Antistaphylococcal activity of WCK 771, a tricyclic fluoroquinolone, in animal infection models

WCK 771, the arginine salt of S-(-)-nadifloxacin, was evaluated in animal models of staphylococcal infection and in vitro. For 302 methicillin-susceptible strains the MIC at which 50% of isolates are inhibited (MIC50) and the MIC90 of WCK 771 were 0.03 and 0.03 microg/ml, respectively, and for 198 methicillin-resistant strains the MIC50 and the MIC90 were 0.5 and 1.0 microg/ml, respectively. All methicillin-susceptible staphylococci were quinolone susceptible, and almost all methicillin-resistant staphylococci were quinolone resistant. WCK 771 was more potent than moxifloxacin, trovafloxacin, levofloxacin, and ciprofloxacin and had potency comparable to that of clinafloxacin. Only WCK 771 and clinafloxacin demonstrated strong potencies against vancomycin-intermediate Staphylococcus aureus strains (MICs = 1 microg/ml). WCK 771 is not a substrate of the NorA pump, as evident from the lack of an effect of reserpine on the MICs and similar protective doses against infections caused by efflux-positive and -negative staphylococci. WCK 771 was effective by both the oral and the subcutaneous routes in mice infected intraperitoneally with quinolone-susceptible methicillin-susceptible S. aureus (MSSA) strains. For infections caused by quinolone-resistant methicillin-resistant S. aureus (MRSA) strains, the activity of WCK 771 administered subcutaneously was superior to those of trovafloxacin and sparfloxacin, with a 50% effective dose range of 27.8 to 46.8 mg/kg of body weight. The activity of WCK 771 was superior to those of moxifloxacin, vancomycin, and linezolid in a mouse cellulitis model of infection caused by one MSSA and two MRSA strains, with effective doses of 2.5 and 5 mg/kg for the MSSA strain and 10-fold higher effective doses for MRSA strains. WCK 771, like vancomycin and linezolid, eradicated MRSA from mouse liver, spleen, kidney, and lung when it was administered subcutaneously at a dose of 50 mg/kg for four doses. These studies have demonstrated the effectiveness of WCK 771, administered orally and parenterally, for the treatment of diverse staphylococcal infections in mice, including those caused by quinolone-resistant strains.     

In vitro activities of novel trans-3,5-disubstituted pyrrolidinylthio-1beta-methylcarbapenems with potent activities against methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa

The in vitro activities of the novel 1beta-methylcarbapenems J-111, 225, J-114,870, and J-114,871, which have a structurally unique side chain that consists of a trans-3,5-disubstituted 5-arylpyrrolidin-3-ylthio moiety at the C-2 position, were compared with those of reference antibiotics. Among isolates of both methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant coagulase-negative staphylococci (MRCoNS), 90% were inhibited by J-111,347 (prototype), J-111,225, J-114,870, and J-114,871 at concentrations of 2, 4, 4, and 4 microgram/ml (MICs at which 90% of isolates are inhibited [MIC(90)s]), respectively, indicating that these agents were 32- to 64-fold more potent than imipenem, which has an MIC(90) of 128 microgram/ml. Although these drugs were less active in vitro than vancomycin, which had MIC(90)s of 1 and 2 microgram/ml for MRSA and MRCoNS, respectively, the new carbapenems displayed better killing kinetics than vancomycin. The potent anti-MRSA activity was ascribed to the excellent affinities of the new carbapenems for penicillin-binding protein 2a of MRSA. Since the new carbapenems also exhibited good activity against gram-positive and -negative bacteria including clinically important pathogens such as penicillin-resistant Streptococcus pneumoniae, Haemophilus influenzae, members of the family Enterobacteriaceae, Pseudomonas aeruginosa, and Clostridium difficile, as well as MRSA, the novel carbapenems are worthy of further evaluation.     

In vitro evaluation of BO-3482, a novel dithiocarbamate carbapenem with activity against methicillin-resistant staphylococci.

BO-3482, a dithiocarbamate carbapenem, inhibited clinical isolates of methicillin-resistant staphylococci (MRS) at 6.25 microg/ml (MIC at which 90% of isolates tested are inhibited [MIC90]), while the MIC90 of imipenem was > 100 microg/ml. BO-3482 was generally less active than imipenem against methicillin-susceptible Staphylococcus aureus, streptococci, enterococci, and gram-negative bacteria, although BO-3482 showed better activity (MIC90) than imipenem against Enterococcus faecium, Haemophilus influenzae, Proteus mirabilis, and Clostridium difficile. The affinities (50% inhibitory concentrations) of BO-3482 for penicillin-binding protein (PBP) PBP 2' of MRS and PBP 5 of E. faecium (both PBPs have low affinities for ordinary beta-lactam antibiotics) were 3.8 and 20 microg/ml, respectively, reflecting the greater activity of BO-3482 against MRS than against E. faecium.     

Activity of ceftobiprole against community-associated methicillin-resistant Staphylococcus aureus isolates recently recovered from US military trainees

Ceftobiprole MICs at which 50% and 90% of isolates were inhibited (MIC50 and MIC90), determined by the Clinical and Laboratory Standards Institute broth microdilution method, were both 1 microg/mL (range, 0.5-1 microg/mL) against 143 community-associated methicillin-resistant Staphylococcus aureus isolates and 0.5 microg/mL (range, 0.25-0.5 microg/mL) with 29 methicillin-susceptible isolates recovered from military trainees during 2 prospective investigations.     

In vitro activities of dalbavancin and 12 other agents against 329 aerobic and anaerobic gram-positive isolates recovered from diabetic foot infections

Tests of dalbavancin's in vitro activity against 209 aerobic and 120 anaerobic isolates from pretreatment diabetic foot infections showed an MIC(90) of < or =0.125 microg/ml against methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA), and 120 anaerobes (Clostridium perfringens, other clostridia, Peptoniphilus asaccharolyticus, Finegoldia magna, and Anaerococcus prevotii), compared to respective MIC(90)s for MSSA and MRSA of 0.5 and 1 microg/ml for vancomycin, 4 and 4 microg/ml for linezolid, 0.5 and 0.5 microg/ml for daptomycin, and 0.25 and >8 microg/ml for clindamycin.     

Antistaphylococcal activity of ceftobiprole, a new broad-spectrum cephalosporin

Ceftobiprole (formerly BAL9141), the active component of the prodrug BAL5788 (ceftobiprole medocaril), is a novel cephalosporin with expanded activity against gram-positive bacteria. Among 152 Staphylococcus aureus isolates, including 5 vancomycin-intermediate and 2 vancomycin-resistant strains, MIC(50) and MIC(90) values for ceftobiprole were each 0.5 microg/ml against methicillin-susceptible strains and 2 mug/ml against methicillin-resistant strains. Against 151 coagulase-negative staphylococci (including 4 vancomycin-intermediate strains), MIC(50) and MIC(90) values were, respectively, 0.125 microg/ml and 1 microg/ml against methicillin-susceptible and 1 microg/ml and 2 microg/ml against methicillin-resistant strains. Teicoplanin was less active than vancomycin against coagulase-negative strains. Linezolid, quinupristin-dalfopristin, and daptomycin were active against all strains, whereas increased MICs for amoxicillin-clavulanate, cefazolin, minocycline, gentamicin, trimethoprim-sulfamethoxazole, levofloxacin, rifampin, mupirocin, fusidic acid, and fosfomycin were sometimes observed. At 2x MIC, ceftobiprole was bactericidal against 11 of 12 test strains by 24 h. Prolonged serial passage in the presence of subinhibitory concentrations of ceftobiprole failed to select for clones with MICs >4 times those of the parents; the maximum MIC achieved for ceftobiprole after 50 passages (in 1 of 10 strains) was 8 mug/ml. Single-passage selections showed very low frequencies of resistance to ceftobiprole irrespective of genotype or phenotype; the maximal ceftobiprole MIC of recovered clones was 8 mug/ml.     

In vitro activity of a new cephalosporin,RWJ-54428, against streptococci,enterococci and staphylococci,including glycopeptide-intermediate Staphylococcus aureus

The need for new antimicrobial agents with activity against Gram-positive organisms has become increasingly important because of emerging resistance. We compared the activity of a new b-lactam antimicrobial agent, RWJ-54428 (MC-02 479), with representatives of other classes of antimicrobial agents against 76 Staphylococcus aureus (including four glycopeptide- intermediate strains), 50 coagulase-negative staphylococci, 20 Enterococcus faecalis, 20 Enterococcus faecium, 10 Enterococcus gallinarum/Enterococcus casseliflavus, 54 Streptococcus pneumoniae and 22 viridans streptococcal isolates. The MIC(90) of RWJ-54,428 was < or = 2 mg/L for all groups of bacteria tested except E. faecium. The activity against four strains of glycopeptide-intermediate S. aureus was similar to that for other methicillin-resistant S. aureus isolates (range 0.5-2.0 mg/L).     

In vitro activity of telavancin against gram-positive clinical isolates recently obtained in Europe

The in vitro activity of telavancin was tested against 620 gram-positive isolates. For staphylococci, MICs at which 50 and 90% of isolates were inhibited (MIC(50) and MIC(90)) were both 0.25 microg/ml, irrespective of methicillin resistance. MIC(50) and MIC(90) were 0.25 and 0.5 microg/ml for vancomycin-susceptible enterococci and 1 and 2 microg/ml for vancomycin-resistant enterococci, respectively. Streptococcus pneumoniae, group A and B beta-hemolytic streptococci, and viridans streptococci were inhibited by < or =0.12 microg/ml.     

Comparative In vitro activities of daptomycin and vancomycin against resistant gram-positive pathogens

The in vitro activity of daptomycin against 224 current gram-positive clinical isolates including vancomycin-resistant Enterococcus faecium (VREF), methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus spp. (MRSS), and penicillin-resistant Streptococcus pneumoniae (PRSP) was evaluated. The MICs at which 90% of isolates are inhibited for daptomycin and vancomycin, respectively, were as follows: MRSA, 1 and 2 microg/ml; MRSS, 1 and 4 microg/ml; PRSP, 1 and 0.5 microg/ml; and VREF, 2 and >64 microg/ml. Daptomycin was bactericidal against 82% of 17 VREF isolates. The antibacterial activity of daptomycin was strongly dependent on the calcium concentration of the medium. Daptomycin was active against all gram-positive cocci tested.     

In vitro activity of S-3578, a new broad-spectrum cephalosporin active against methicillin-resistant staphylococci

The in vitro antibacterial activity of S-3578, a new parenteral cephalosporin, against clinical isolates was evaluated. The MICs of the drug at which 90% of the isolates were inhibited were 4 micro g/ml for methicillin-resistant Staphylococcus aureus (MRSA) and 2 micro g/ml for methicillin-resistant Staphylococcus epidermidis, which were fourfold higher than and equal to those of vancomycin, respectively. The anti-MRSA activity of S-3578 was considered to be due to its high affinity for penicillin-binding protein 2a (50% inhibitory concentration, 4.5 micro g/ml). In time-kill studies with 10 strains each of MRSA and methicillin-susceptible S. aureus, S-3578 caused more than a 4-log(10) decrease of viable cells on the average at twice the MIC after 24 h of exposure, indicating that it had potent bactericidal activity. Furthermore, in population analysis of MRSA strains with heterogeneous or homogeneous resistance to imipenem, no colonies emerged from about 10(9) cells on agar plates containing twice the MIC of S-3578, suggesting the low frequency of emergence of S-3578-resistant strains from MRSA. S-3578 was also highly active against penicillin-resistant Streptococcus pneumoniae (PRSP), with a MIC(90) of 1 micro g/ml, which was comparable to that of ceftriaxone. S-3578 also had antibacterial activity against a variety of gram-negative bacteria including Pseudomonas aeruginosa, though its activity was not superior to that of cefepime. In conclusion, S-3578 exhibited a broad antibacterial spectrum and, particularly, had excellent activity against gram-positive bacteria including methicillin-resistant staphylococci and PRSP. Thus, S-3578 was considered to be worthy of further evaluation.     

Pharmacodynamics of RWJ-54428 against Staphylococcus aureus, Streptococcus pneumoniae, and Enterococcus faecalis in a neutropenic mouse thigh infection model

RWJ-54428 (also known as MC-02,479) is a new cephalosporin with promising activity against gram-positive bacteria. The pharmacodynamics (PDs) of RWJ-54428 against Staphylococcus aureus, Streptococcus pneumoniae, and Enterococcus faecalis were studied in a neutropenic mouse thigh infection model. The RWJ-54428 MICs ranged from 0.25 to 1 mg/liter. Mice with ca. 10(6) CFU/thigh at the initiation of therapy were treated intraperitoneally with RWJ-54428 at doses that ranged from 3 to 1,200 mg/kg of body weight/day (in 2, 3, 4, 6, or 12 divided doses) for 24 h. The maximal reductions in bacterial counts in thigh tissues at 24 h for the methicillin-resistant S. aureus, penicillin-resistant S. pneumoniae, and E. faecalis strains were -2.8, -3.8, and -1.7 log10 CFU/thigh, respectively. The percentage of a 24-h dosing interval that the unbound serum RWJ-54428 concentrations exceeded the MIC (fT>MIC) was the pharmacokinetic (PK)-PD parameter that best described the efficacy of RWJ-54428. The fT>MICs for a bacteriostatic effect (no net change in the numbers of CFU/thigh over 24 h) ranged from 14 to 20% for staphylococci and streptococci; for maximal reductions in the numbers of CFU/thigh, the fT>MICs ranged from 22 to 36% for these strains. For E. faecalis, the ranges of fT>MICs for static and maximal effects were 30 to 46% and 55 to 60%, respectively. These data show that treatment with RWJ-54428 results in marked antibacterial effects in vivo, with the PK-PD parameters for efficacy being comparable to those for the efficacy of penicillins and carbapenems active against staphylococci and pneumococci.     

In vitro activity of quinupristin/dalfopristin against clinical isolates of common gram-positive bacteria in Taiwan

The MICs of quinupristin/dalfopristin against common Gram-positive bacteria isolated from various clinical specimens at a university hospital in Taiwan were determined by the agar dilution method. The tested bacteria included methicillin-resistant Staphylococcus aureus (MRSA), methicillin-susceptible S. aureus (MSSA), methicillin-resistant Staphylococcus epidermidis (MRSE), methicillin-susceptible S. epidermidis (MSSE), Streptococcus pyogenes, Streptococcus pneumoniae, and Enterococcus faecalis. With the exception of E. faecalis all bacteria were susceptible to quinupristin/dalfopristin. The MIC50 and MIC90 were, respectively, 0.25 microgram/mL and 0.5 microgram/mL for both MRSA and MSSA; 0.25 microgram/mL and 0.5 microgram/mL for MRSE; 0.25 microgram/mL and 0.25 microgram/mL for MSSE; 0.125 microgram/mL and 0.125 microgram/mL for S. pyogenes; and < or = 0.03 microgram/mL and 0.25 microgram/mL for S. pneumoniae. Eighty-two percent of the tested E. faecalis isolates were intermediately resistant or resistant to quinupristin/dalfopristin, with an MIC50 of 2 micrograms/mL and an MIC90 of 4 micrograms/mL. Quinupristin/dalfopristin seems to be a promising antimicrobial agent against common Gram-positive bacteria other than E. faecalis in Taiwan.     

In vitro antibacterial activities of DQ-113, a potent quinolone, against clinical isolates

The antibacterial activity of DQ-113, formerly D61-1113, was compared with those of antibacterial agents currently available. MICs at which 90% of the isolates tested are inhibited (MIC90s) of DQ-113 against clinical isolates of methicillin-susceptible and -resistant Staphylococcus aureus and methicillin-susceptible and -resistant coagulase-negative staphylococci were 0.03, 0.008, 0.03, and 0.06 microg/ml, respectively. Moreover, DQ-113 showed the most potent activity against ofloxacin-resistant and methicillin-resistant S. aureus, with a MIC90 of 0.25microg/ml. DQ-113 inhibited the growth of all strains of Streptococcus pneumoniae, including penicillin-resistant strains, and Streptococcus pyogenes at 0.06 microg/ml, and DQ-113 was more active than the other quinolones tested against Enterococcus faecalis and Enterococcus faecium with MIC90s of 0.25 and 2 microg/ml, respectively. Against vancomycin-resistant enterococci, DQ-113 showed the highest activity among the reference compounds, with a MIC range from 0.25 to 2 microg/ml. DQ-113 also showed a potent activity against Haemophilus influenzae, including ampicillin-resistant strains (MIC90, 0.015 microg/ml), and Moraxella catarrhalis (MIC90, 0.03 microg/ml). The activity of DQ-113 was roughly comparable to that of levofloxacin against all species of ENTEROBACTERIACEAE: The MICs of DQ-113 against ofloxacin-susceptible Pseudomonas aeruginosa ranged from 0.25 to 2 microg/ml, which were four times higher than those of ciprofloxacin. From these results, DQ-113 showed the most potent activity against gram-positive pathogens among antibacterial agents tested.     

Antistaphylococcal activity of CG400549, a new experimental FabI inhibitor, compared with that of other agents

Among 203 strains of Staphylococcus aureus, the MICs of CG400549 were 0.06 to 1.0 microg/ml, with MIC(50) and MIC(90) values of 0.25 microg/ml each. All strains were susceptible to linezolid and quinupristin-dalfopristin (MICs, 0.25 to 2.0 microg/ml). The daptomycin MICs were 0.25 to 2.0 microg/ml for methicillin-susceptible and 0.25 to 4.0 microg/ml against methicillin-resistant strains (including vancomycin-intermediate strains). Single-passage selection testing showed low resistance frequencies with CG400549, but multistep analysis showed that CG400549 yielded resistant mutants after 14 to 17 days in all strains tested.     

Comparative in vitro activities of AC98-6446, a novel semisynthetic glycopeptide derivative of the natural product mannopeptimycin alpha, and other antimicrobial agents against gram-positive clinical isolates

AC98-6446 is a novel semisynthetic cyclic glycopeptide antibiotic related to the natural product mannopeptimycin alpha (AC98-1). In the present study the activity of AC98-6446 was evaluated against a variety of recent clinical gram-positive pathogens including multiply resistant strains. AC98-6446 demonstrated similar potent activities against methicillin-susceptible and methicillin-resistant staphylococci and glycopeptide-intermediate staphylococcal isolates (MICs at which 90% of isolates are inhibited [MIC(90)s], 0.03 to 0.06 microg/ml). AC98-6446 also demonstrated good activities against both vancomycin-resistant and -susceptible strains of enterococci (MIC(90)s, 0.12 and 0.25 microg/ml, respectively) as well as against streptococcal strains (MIC(90)s, 3 log(10) CFU/ml) of staphylococcal and streptococcal isolates and a marked decrease in the viable counts of most enterococcal strains (from 0.2 to 2.5 log(10) CFU/ml). Unlike vancomycin, which demonstrates time-dependent killing, AC98-6446 demonstrated concentration-dependent killing. The potent activity, novel structure, and bactericidal activity demonstrated by AC98-6446 make it an attractive candidate for further development.     

In vitro activities of DA-7157 and DA-7218 against Mycobacterium tuberculosis and Nocardia brasiliensis

The in vitro activities of DA-7157, a novel oxazolidinone, against clinical isolates of Nocardia brasiliensis and Mycobacterium tuberculosis were determined. Equal MIC(50)s and MIC(90)s (0.25 and 0.5 microg/ml, respectively) were found for susceptible and multidrug-resistant isolates of M. tuberculosis. The N. brasiliensis isolates showed an MIC(90) of 1 microg/ml and an MIC(50) of 1 microg/ml. The DA-7157 prodrug, DA-7218, exhibited similar MICs for M. tuberculosis but fivefold-higher MICs for N. brasiliensis.     

Quinolone resistance in Staphylococci: activities of new nonfluorinated quinolones against molecular targets in whole cells and clinical isolates

The activity of three new, 8-methoxy-nonfluorinated quinolones (NFQs) against multiple-drug-resistant staphylococci was investigated. First, using Staphylococcus aureus strains containing point mutations in the serine 84-80 hot spots of the target genes (gyrA and grlA), cell growth inhibition potencies of the NFQs as a result of DNA gyrase and topoisomerase IV inhibition were estimated and compared with those of known fluoroquinolones. The NFQs and clinafloxacin showed higher affinities toward both the targets than ciprofloxacin, trovafloxacin and gatifloxacin. Furthermore, the ratio of the calculated affinity parameter for DNA gyrase to that for topoisomerase IV was lower in the case of the NFQs, clinafloxacin, and gatifloxacin than in the case of ciprofloxacin and trovafloxacin. These results suggest that the former group of quinolones is better able to exploit both the targets. Next, using clinical isolates of methicillin-resistant S. aureus (MRSA; n = 34) and coagulase-negative staphylococci (CoNS; n = 24), the NFQs and clinafloxacin were shown to be more potent (MIC at which 90% of the isolates are inhibited [MIC90] = 2 microg/ml for MRSA and 0.5 microg/ml for CoNS) than ciprofloxacin, trovafloxacin, and gatifloxacin (MIC90 = 16 to >64 microg/ml for MRSA and 4 to >32 microg/ml for CoNS). Bactericidal kinetics experiments, using two MRSA isolates, showed that exposure to the NFQs at four times the MIC reduced the bacterial counts (measured in CFU per milliliter) by > or =3 log units in 2 to 4 h. Overall, the NFQs and clinafloxacin were less susceptible than the other quinolones to existing mechanisms of quinolone resistance in staphylococci.