In Vitro Activity of Cephalosporin RWJ-54428 (MC-02479) against Multidrug-Resistant Gram-Positive Cocci

RWJ-54428 (MC-02479) is a novel cephalosporin that binds to penicillin-binding protein (PBP) PBP 2' (PBP 2a) of methicillin-resistant staphylococci. Its in vitro activity was assessed against 472 gram-positive cocci, largely selected as epidemiologically unrelated isolates with multidrug resistance. The MIC at which 50% of isolates are inhibited (MIC(50)) and MIC(90) of RWJ-54428 for methicillin-resistant Staphylococcus aureus (MRSA) were 1 and 2 microg/ml, respectively, whereas they were 0.5 and 0.5 microg/ml, respectively, for methicillin-susceptible S. aureus. The MIC(50) and MIC(90) were 1 and 4 microg/ml, respectively, for methicillin-resistant coagulase-negative staphylococci (MRCoNS), whereas they were 0.25 and 1 microg/ml, respectively, for methicillin-susceptible isolates. The highest MICs for MRSA and MRCoNS isolates were 2 and 4 microg/ml, respectively. The MIC(50) and MIC(90) of RWJ-54428 for Enterococcus faecalis were 0.5 and 1 microg/ml, respectively, but they were 4 and 8 microg/ml, respectively, for Enterococcus faecium. For penicillin-susceptible, -intermediate, and -resistant pneumococci, the MIC(90)s of RWJ-54428 were 0.03, 0.25, and 0.5 microg/ml, respectively, with the highest MIC for a pneumococcus being 1 microg/ml, recorded for a strain for which penicillin and cefotaxime MICs were 8 and 4 microg/ml. MICs for Lancefield group A, B, C, and G streptococci were < or =0.008 microg/ml; those for viridans group streptococci, including isolates not susceptible to penicillin, were from 0.015 to 0.5 microg/ml. RWJ-54428 did not select resistant mutants of MRSA or enterococci in challenge experiments and has the potential to be useful for the treatment of infections caused by gram-positive cocci.     

In vitro and in vivo antibacterial activities of BO-2727, a new carbapenem.

BO-2727, a new injectable carbapenem, was evaluated for its in vitro and in vivo antibacterial activities in comparison with those of biapenem, meropenem, imipenem, cefpirome, and ceftazidime. BO-2727 had activity comparable to that of imipenem against methicillin-susceptible staphylococci and streptococci, with MICs at which 90% of strains tested (MIC90s) are inhibited being equal to 0.5 microgram/ml or less. Against methicillin-resistant staphylococci, BO-2727 was the most active among the antibiotics tested, with MIC90s ranging from 4 to 8 micrograms/ml. BO-2727 was highly active against members of the family Enterobacteriaceae, Haemophilus influenzae, and Moraxella catarrhalis, with MIC90s ranging from 0.006 to 2 micrograms/ml. BO-2727 was also highly active against Pseudomonas aeruginosa (imipenem-susceptible strains), for which the MIC90 was 2 micrograms/ml, which was lower than those of imipenem, cefpirome, and ceftazidime and comparable to those of biapenem and meropenem. Differences in activity between BO-2727 and the other carbapenems against imipenem-resistant P. aeruginosa were particularly striking (MIC90, 8 micrograms/ml). Furthermore, BO-2727 displayed a high degree of activity against many of the ceftazidime-, ciprofloxacin-, and/or gentamicin-resistant isolates of P. aeruginosa. The in vivo efficacy of BO-2727 against experimental septicemia caused by gram-positive and gram-negative bacteria, including methicillin-resistant Staphylococcus aureus and imipenem-resistant P. aeruginosa, reflected its potent in vitro activity and high levels in plasma.     

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.     

Activity of cephalosporins against coagulase-negative staphylococci

Staphylococcus epidermidis has become an increasingly important pathogen as the cause of serious postoperative infection after heart and orthopedic surgery. We studied the susceptibilities of 80 blood, sternotomy, and hip isolates to vancomycin, cefazolin, cefuroxime, oxacillin, erythromycin, ciprofloxacin, and ofloxacin. The MIC90 of methicillin-susceptible isolates was 4 micrograms/ml for cefazolin and cefamandole, 8 micrograms/ml for cefuroxime, and 4 micrograms/ml for vancomycin. At 48 hr the MIC90 rose to 32 micrograms/ml for cefazolin and greater than 128 micrograms/ml for cefuroxime, and remained at 4 micrograms/ml for cefamandole and vancomycin. The MIC90 of methicillin-resistant isolates at 48 hr was 16 micrograms/ml cefamandole, 64 micrograms/ml cefazolin, greater than 128 micrograms/ml cefuroxime, and 4 micrograms/ml vancomycin. Ciprofloxacin and ofloxacin inhibited the majority of isolates at 1 microgram/ml, and vancomycin at 4 micrograms/ml. The new peptolide, daptomycin, also inhibited S. epidermidis at less than or equal to 1 microgram/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 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.     

In vitro and in vivo activities of novel 2-(thiazol-2-ylthio)-1beta-methylcarbapenems with potent activities against multiresistant gram-positive bacteria

SM-197436, SM-232721, and SM-232724 are new 1beta-methylcarbapenems with a unique 4-substituted thiazol-2-ylthio moiety at the C-2 side chain. In agar dilution susceptibility testing these novel carbapenems were active against methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE) with a MIC(90) of 相似文献   

In vitro activity of ceftobiprole, daptomycin, linezolid, and vancomycin against methicillin-resistant staphylococci associated with endocarditis and bone and joint infection

We tested the in vitro activity of 4 antimicrobial agents against methicillin-resistant Staphylococcus aureus and coagulase-negative staphylococci recovered from patients with endocarditis or bone and joint infection. Ceftobiprole, daptomycin, linezolid, and vancomycin MIC(90) values were 1, 1, 2, and 1 microg/mL, respectively. Ceftobiprole, daptomycin, linezolid, and vancomycin MBC(90) values were 2, 4, > or = 128, and 8 microg/mL, respectively. Ceftobiprole MIC and MBC values were < or = 2 microg/mL for all isolates tested, with the exception of one methicillin-resistant coagulase-negative Staphylococcus spp isolate. Vancomycin lacked bactericidal activity (defined as an MBC/MIC ratio of > or = 32) against 2 methicillin-resistant Staphylococcus aureus (MRSA) isolates from patients with bone and joint infection; one of these isolates was additionally daptomycin nonsusceptible (daptomycin MIC, 2 microg/mL). There was one additional daptomycin nonsusceptible (daptomycin MIC, 2 microg/mL) isolate (MRSA associated with bone and joint infection). Ceftobiprole demonstrated in vitro bactericidal activity against all MRSA and methicillin-resistant coagulase-negative staphylococci tested.     

Antistaphylococcal activities of the new fluoroquinolone JNJ-Q2

The new broad-spectrum fluoroquinolone JNJ-Q2 displays in vitro activity against Gram-negative and Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA) and ciprofloxacin-resistant MRSA isolates. Tested with isogenic methicillin-susceptible S. aureus (MSSA) and MRSA strains bearing quinolone-resistant target mutations, JNJ-Q2 displayed MICs ≤ 0.12 μg/ml, values 16- to 32-fold lower than those determined for moxifloxacin. Overexpression of the NorA efflux pump did not impact JNJ-Q2 MICs. Inhibition of S. aureus DNA gyrase and DNA topoisomerase IV enzymes demonstrated that JNJ-Q2 was more potent than comparators against wild-type enzymes and enzymes carrying quinolone-resistant amino acid substitutions, and JNJ-Q2 displayed equipotent activity against both enzymes. In serial-passage studies comparing resistance selection in parallel MRSA cultures by ciprofloxacin and JNJ-Q2, ciprofloxacin readily selected for mutants displaying MIC values of 128 to 512 μg/ml, which were observed within 18 to 24 days of passage. In contrast, cultures passaged in the presence of JNJ-Q2 displayed MICs ≤ 1 μg/ml for a minimum of 27 days of serial passage. A mutant displaying a JNJ-Q2 MIC of 4 μg/ml was not observed until after 33 days of passage. Mutant characterization revealed that ciprofloxacin-passaged cultures with MICs of 256 to 512 μg/ml carried only 2 or 3 quinolone resistance-determining region (QRDR) mutations. Cultures passaged with JNJ-Q2 selection for up to 51 days displayed MICs of 1 to 64 μg/ml and carried between 4 and 9 target mutations. Established in vitro biofilms of wild-type or ciprofloxacin-resistant MRSA exposed to JNJ-Q2 displayed greater decreases in bacterial counts (7 days of exposure produced 4.5 to >7 log(10) CFU decreases) than biofilms exposed to ciprofloxacin, moxifloxacin, rifampin, or vancomycin.     

In vitro activities of ME1036 (CP5609), a novel parenteral carbapenem, against methicillin-resistant staphylococci

ME1036, formerly CP5609, is a novel parenteral carbapenem with a 7-acylated imidazo[5,1-b]thiazole-2-yl group directly attached to the carbapenem moiety of the C-2 position. The present study evaluated the in vitro activities of ME1036 against clinical isolates of gram-positive and gram-negative bacteria. ME1036 displayed broad activity against aerobic gram-positive and gram-negative bacteria. Unlike other marketed beta-lactam antibiotics, ME1036 maintained excellent activity against multiple-drug-resistant gram-positive bacteria, such as methicillin-resistant staphylococci and penicillin-resistant Streptococcus pneumoniae (PRSP). The MICs of this compound at which 90% of isolates were inhibited were 2 microg/ml for methicillin-resistant Staphylococcus aureus (MRSA), 2 microg/ml for methicillin-resistant coagulase-negative staphylococci, and 0.031 microg/ml for PRSP. In time-kill studies with six strains of MRSA, ME1036 at four times the MIC caused a time-dependent decrease in the numbers of viable MRSA cells. The activity of ME1036 against MRSA is related to its high affinity for penicillin-binding protein 2a, for which the 50% inhibitory concentration of ME1036 was approximately 300-fold lower than that of imipenem. In conclusion, ME1036 demonstrated a broad antibacterial spectrum and high levels of activity in vitro against staphylococci, including beta-lactam-resistant strains.     

Oxazolidinones, a new class of synthetic antibacterial agents: in vitro and in vivo activities of DuP 105 and DuP 721

DuP 721 (p-acetylphenyloxooxazolidinylmethylacetamide) and DuP 105 (a methylsulfinyl derivative) are orally active representatives of the oxazolidinones, a new class of synthetic antibacterial agents. Their antibacterial spectrum includes staphylococci, streptococci, and Bacteroides fragilis strains. The compounds have equal activity against staphylococcal strains susceptible or resistant to beta-lactam antibiotics, including methicillin-resistant strains. The MICs for 90% of the strains (MIC90s) against staphylococcal isolates were 1 to 4 micrograms/ml for DuP 721 and 4 to 16 micrograms/ml for DuP 105, compared with 1 to 2 micrograms/ml for vancomycin, 0.5 microgram/ml for ciprofloxacin, and 2 to greater than 16 micrograms/ml for imipenem. The MIC90s against group D streptococci were 4 micrograms/ml for DuP 721, 16 micrograms/ml for DuP 105, and 2 micrograms/ml for vancomycin, ciprofloxacin, and imipenem. MIC90s against B. fragilis isolates were 4 micrograms/ml for DuP 721, 16 micrograms/ml for DuP 105, and 8 micrograms/ml for cefoxitin. DuP 721 and DuP 105 administered by either the oral or the parenteral route were protective against staphylococcal and streptococcal infections in mice. The 50% effective doses were 2 to 10 mg/kg for DuP 721, 9 to 23 mg/kg for DuP 105, and 2 to 12 mg/kg for vancomycin. These results indicate that further studies of compounds of the oxazolidinone series are warranted.     

In vitro activities of two glycylcyclines.

The in vitro activities of two glycylcyclines, CL 329,998 and CL 331,002 (two new semisynthetic tetracyclines), were evaluated in comparison with those of tetracycline and other available oral antimicrobial agents. A total of 523 recent clinical isolates were studied, including strains resistant to tetracycline. Members of the family Enterobacteriaceae were generally > or = 16-fold more susceptible to the glycylcyclines than to tetracycline (although less difference was seen with Proteus spp.). Pseudomonas aeruginosa was modestly susceptible to both new compounds (MIC for 90% of strains tested [MIC90], 16 micrograms/ml). Tetracycline- and methicillin-susceptible and -resistant strains of Staphylococcus aureus were all susceptible to the glycylcyclines (MIC90 < or = 1 microgram/ml). Streptococci (including Streptococcus pneumoniae) and Enterococcus faecalis and Enterococcus faecium displayed a bimodal distribution of susceptibility to tetracycline yet were uniformly susceptible to the glycylcyclines (MIC90 < or = 0.25 microgram/ml). The glycylcyclines were highly potent against Neisseria, Moraxella, Haemophilus, and Bacteroides spp. (MIC90 < or = 0.5 microgram/ml). Strains of Chlamydia spp. (three C. trachomatis strains and one C. pneumoniae strain) were inhibited by < or = 0.25 microgram of CL 329,998 or CL 331,002 per ml. Two strains of Mycoplasma pneumoniae were inhibited by < or = 0.12 microgram of CL 331,002 per ml and by 1 microgram of CL 329,998 per ml. Mycobacterium tuberculosis and Mycobacterium avium were resistant to the two glycylcyclines (MIC > or = 8 micrograms/ml). These results indicate that the two glycylcyclines have potent in vitro activities against a wide range of clinically important pathogenic bacteria.     

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.     

In vitro activity of Ro 23-9424, a dual-action cephalosporin, compared with activities of other antibiotics.

The in vitro activity of Ro 23-9424, which is desacetyl-cefotaxime linked to fleroxacin, was compared with the activities of cefotaxime, desacetyl-cefotaxime, fleroxacin, ofloxacin, and ciprofloxacin. It inhibited the majority of members of the family Enterobacteriaceae, except for some Serratia marcescens, Citrobacter freundii, and Enterobacter cloacae strains, at less than or equal to 0.25 microgram/ml and had an MIC for 90% of strains tested (MIC90) of 8 micrograms/ml against Pseudomonas aeruginosa. Most group A, B, C, and G streptococci and Streptococcus pneumoniae were inhibited at less than or equal to 0.25 microgram/ml. Ninety percent of the staphylococci were inhibited at less than or equal to 4 micrograms/ml, except for some methicillin-resistant Staphylococcus aureus isolates. The MIC90S of Ro 23-9424 for Enterococcus faecalis and Listeria monocytogenes were greater than or equal to 16 micrograms/ml. Ninety percent of Clostridium perfringens isolates were inhibited by less than or equal to 2 micrograms/ml, whereas Bacteroides fragilis had an MIC90 of 32 micrograms/ml. There was a minimal inoculum size effect. The MICs and MBCs were either identical or within a twofold dilution. The MICs of Ro 23-9424 for Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, Enterobacter cloacae, Citrobacter freundii, Pseudomonas aeruginosa, and Staphylococcus aureus increased 16- to 128-fold after 2 weeks of transfer in the presence of Ro 23-9424, showing that the presence of two agents does not prevent resistance.     

Antimicrobial activity of SM-17466, a novel carbapenem antibiotic with potent activity against methicillin-resistant Staphylococcus aureus.

The in vitro and in vivo antibacterial activities of SM-17466, a new 1 beta-methyl carbapenem, were evaluated against a wide range of clinical bacterial isoaltes and compared with the activities of meropenem, imipenem, vancomycin, and arbekacin. SM-17466 had a broad spectrum of action against gram-positive bacteria, showing especially potent activity against methicillin-resistant staphylococci. The MICs of SM-17466, meropenem, imipenem, vancomycin, and arbekacin at which 90% of clinical isolates of methicillin-resistant Staphylococcus aureus were inhibited were 3.13, 50, 100, 1.56, and 3.13 micrograms/ml, respectively. This activity of SM-17466 was almost equivalent to those of the antibiotics used for the treatment of infections caused by this organism. SM-17466 also showed bactericidal activity against methicillin-resistant S. aureus. In contrast, SM-17466 was less active against gram-negative bacteria, especially against Pseudomonas aeruginosa, compared with the other carbapenems; however, of the carbapenems, SM-17466 exhibited the highest activity against Haemophilus influenzae and Bacteriodes fragilis. SM-17466, at a 50% inhibitory concentration of less than 1 microgram/ml, bound to penicillin-binding proteins 1 to 4 in methicillin-susceptible S. aureus and also had good binding to penicillin-binding protein 2' in a methicillin-resistant strain (50% inhibitory concentration, 5.9 micrograms/ml). This high affinity, which was 10 and 20 times greater than those for meropenem and imipenem, respectively, was reflected in the potent activity of SM-17466 against methicillin-resistant S. aureus. SM-17466 demonstrated excellent in vivo efficacy against methicillin-susceptible and -resistant S. aureus strains in a mouse peritoneal infection model: the efficacy of SM-17466 against methicillin-resistant strains was equal to or one-third that of vancomycin. This activity was comparable to the in vitro activity of SM-17466. The subcutaneous injection of SM-17466 in mice revealed that the half-life of SM-17466 in serum was about 18 min, intermediate between those of vancomycin and arbekacin and 1.5-fold that of imipenem-cilastatin. SM-17466 was resistant to hydrolysis by swine renal dehydropeptidase I, to an extent comparable to the resistance shown by meropenem.     

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.     

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.     

In vitro activities of ceftobiprole, dalbavancin, daptomycin, linezolid, and tigecycline against methicillin-resistant Staphylococcus aureus blood isolates: stratified analysis by vancomycin MIC

The in vitro activities of newer agents against 569 methicillin-resistant Staphylococcus aureus (MRSA) blood isolates stratified by vancomycin MIC values (≤1 versus >1 μg/mL) were evaluated using broth microdilution methods. All agents had good in vitro activities against MRSA regardless of vancomycin MIC values. Some significant correlations between vancomycin and newer agents' MIC values were observed.     

In vitro activity of Ro 23-6240, a new difluoroquinolone derivative, compared with that of other antimicrobial agents.

Ro 23-6240 is a new difluorinated quinolone antimicrobial agent. Its in vitro activity against a wide range of bacteria was compared with those of other quinolones and beta-lactams. Generally, members of the family Enterobacteriaceae were inhibited by low concentrations of Ro 23-6240 (MIC90 [MIC for 90% of isolates tested], less than or equal to 1 microgram/ml). Ninety percent of Staphylococcus aureus (including methicillin-resistant strains) and Neisseria gonorrhoeae isolates were inhibited by 0.5 microgram/ml. Pseudomonas aeruginosa (MIC90, 2 micrograms/ml) and Bacteroides fragilis (MIC90, 4 micrograms/ml) showed intermediate susceptibility, and Streptococcus pneumoniae (MIC90, 8 micrograms/ml) was less susceptible. Strains resistant to nalidixic acid were less susceptible to all the quinolones tested. The protein binding of Ro 23-6240 (5 micrograms/ml) was 27%.     

In vitro and in vivo antibacterial activities of SM-216601, a new broad-spectrum parenteral carbapenem

SM-216601 is a novel parenteral 1beta-methylcarbapenem. In agar dilution susceptibility testing, the MIC of SM-216601 for 90% of the methicillin-resistant Staphylococcus aureus (MRSA) strains tested (MIC(90)) was 2 microg/ml, which was comparable to those of vancomycin and linezolid. SM-216601 was also very potent against Enterococcus faecium, including vancomycin-resistant strains (MIC(90) = 8 microg/ml). SM-216601 exhibited potent activity against penicillin-resistant Streptococcus pneumoniae, ampicillin-resistant Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis, with MIC(90)s of less than 0.5 microg/ml, and intermediate activity against Citrobacter freundii, Enterobacter cloacae, Serratia marcescens, and Pseudomonas aeruginosa. The therapeutic efficacy of SM-216601 against experimentally induced infections in mice caused by S. aureus, E. faecium, E. coli, and P. aeruginosa reflected its in vitro activity and plasma level. Thus, SM-216601 is a promising candidate for nosocomial bacterial infections caused by a wide range of gram-positive and gram-negative bacteria, including multiresistant pathogens.