Antimicrobial properties of MX-2401, an expanded-spectrum lipopeptide active in the presence of lung surfactant

MX-2401 is an expanded-spectrum lipopeptide antibiotic selective for Gram-positive bacteria that is a semisynthetic analog of the naturally occurring lipopeptide amphomycin. It was active against Enterococcus spp., including vancomycin-sensitive Enterococcus (VSE), vanA-, vanB-, and vanC-positive vancomycin-resistant Enterococcus (VRE), linezolid- and quinupristin-dalfopristin-resistant isolates (MIC(90) of 4 μg/ml), methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive S. aureus (MSSA) (MIC(90) of 2 μg/ml), coagulase-negative staphylococci, including methicillin-sensitive Staphylococcus epidermidis (MSSE) and methicillin-resistant S. epidermidis (MRSE) (MIC(90) of 2 μg/ml), and Streptococcus spp. including viridans group streptococci, and penicillin-resistant, penicillin-sensitive, penicillin-intermediate and macrolide-resistant isolates of Streptococcus pneumoniae (MIC(90) of 2 μg/ml). MX-2401 demonstrated a dose-dependent postantibiotic effect varying from 1.5 to 2.4 h. Furthermore, MX-2401 was rapidly bactericidal at 4 times the MIC against S. aureus and Enterococcus faecalis, with more than 99.9% reduction in viable bacterial attained at 4 and 24 h, respectively. The MICs of MX-2401 against MRSA, MSSA, VSE, and VRE strains serially exposed for 15 passages to sub- to supra-MICs of MX-2401 remained within three dilutions of the original MIC. In contrast to that of the lipopeptide daptomycin, the antibacterial activity of MX-2401 was not affected in vitro by the presence of lung surfactant, and MX-2401 was active in vivo in the bronchial-alveolar pneumonia mouse model, in which daptomycin failed to show any activity. Moreover, the activity of MX-2401 was not as strongly dependent on the Ca(2+) concentration as is the activity of daptomycin. In conclusion, MX-2401 is a promising new-generation lipopeptide for the treatment of serious infections with Gram-positive bacteria, including hospital-acquired pneumonia.     

In vitro synergy between cefepime and vancomycin against methicillin-susceptible and -resistant Staphylococcus aureus and Staphylococcus epidermidis

The in vitro activity of cefepime combined with vancomycin was assessed by the chequerboard method against 35 clinical isolates of methicillin-susceptible (MSSA, n = 8) or -resistant (MRSA, n = 10) Staphylococcus aureus and methicillin-susceptible (MSSE, n = 9) or -resistant (MRSE, n = 8) Staphylococcus epidermidis and S. aureus ATCC 25923 (MSSA). The combination was synergic against 16 isolates and additive/indifferent against 20. For 10 of the clinical isolates (two MSSA, three MRSA, two MSSE, three MRSE) and the reference strain, the interaction of cefepime and vancomycin was also determined by the time-kill method. Except for one MRSA isolate, synergic killing was demonstrated with clinically achievable concentrations of vancomycin (0.5-1 mg/L) and cefepime (methicillin-susceptible isolates: 0.5-1 mg/L; methicillin-resistant isolates: 2-64 mg/L).     

Staphylococcus aureus versus Staphylococcus epidermidis in periprosthetic joint infection—Outcome analysis of methicillin-resistant versus methicillin-susceptible strains

Periprosthetic joint infections (PJIs) are a major complication in total joint arthroplasty. Staphylococcus aureus and coagulase-negative staphylococci are known to cause the majority of all PJIs. This study aimed to analyze the eradication rates of S. aureus and S. epidermidis with methicillin susceptibility and methicillin resistance in a 2-stage therapy algorithm. Seventy-four patients with PJI caused by methicillin-resistant S. aureus (MRSA), methicillin-resistant coagulase-negative staphylococci (MRSE), methicillin-susceptible S. aureus (MSSA), and methicillin-susceptible coagulase-negative staphylococci (MSSE) were included, and the outcome was analyzed retrospectively. After a minimal follow-up of 2?years, n?=?56 patients (75.7%) were definitively free of infection. The analysis revealed significant differences between the groups, with eradication rates as follows: MSSA (92.6%), MSSE (95.2%), MRSA (80%), and MRSE (54.2%). MRSE showed a significantly lower rate of patients graded as “definitively free of infection” as compared to patients with infections caused by MSSA, MSSE, and MRSA.     

Prevalence of resistance to MLS antibiotics in 20 European university hospitals participating in the European SENTRY surveillance programme. Sentry Participants Group.

Macrolide, lincosamide and streptogramin (MLS) antibiotics are chemically distinct inhibitors of bacterial protein synthesis. Resistance to MLS antibiotics may be constitutive or inducible. The purpose of this study is to update our understanding of the prevalence of different forms of MLS resistance in Europe. The analysis of 3653 clinical pneumococcal, staphylococcal and enterococcal isolates exhibited an average percentage of 21.3% and 6.2% intermediate and high-level penicillin-resistant Streptococcus pneumoniae, 21.8% methicillin-resistant Staphylococcus aureus and 11% vancomycin-resistant Enterococcus faecium. Geographical differences in erythromycin and clindamycin resistance in isolates of S. pneumoniae and S. aureus strongly reflect geographical variations in susceptibility to penicillin and methicillin, respectively. A very narrow range of MICs was obtained with quinupristin/dalfopristin, with no S. pneumoniae, S. aureus and E. faecium isolate having an MIC of > 4 mg/L, indicating a possible role of quinupristin/dalfopristin in the treatment of infections by multi-resistant Gram-positive bacteria.     

Pharmacodynamics of TD-1792, a novel glycopeptide-cephalosporin heterodimer antibiotic used against Gram-positive bacteria, in a neutropenic murine thigh model

TD-1792 is a novel glycopeptide-cephalosporin heterodimer investigational antibiotic that displays potent bactericidal effects against clinically relevant Gram-positive organisms in vitro. The present studies evaluated the in vivo pharmacokinetics (PK) and pharmacodynamics (PD) of TD-1792 in the neutropenic murine thigh infection animal model. TD-1792, dosed subcutaneously (SC), produced dose-dependent reduction in the thigh bacterial burden of several organisms, including methicillin-susceptible and -resistant strains of Staphylococcus aureus and Staphylococcus epidermidis (MSSA, MRSA, MSSE, MRSE, respectively), penicillin-susceptible strains of Streptococcus pneumoniae (PSSP), Streptococcus pyogenes, and vancomycin-intermediate-susceptible Staphylococcus aureus (VISA). In single-dose efficacy studies, the 1-log(10) CFU kill effective dose (ED(1-log kill)) estimates for TD-1792 ranged from 0.049 to 2.55 mg/kg of body weight administered SC, and the bacterial burden was reduced by up to 3 log(10) CFU/g from pretreatment values. Against S. aureus ATCC 33591 (MRSA), the total 24-h log(10) stasis dose (ED(stasis)) and ED(1-logkill) doses for TD-1792 were 0.53 and 1.11 mg/kg/24 h, respectively, compared to 23.4 and 54.6 mg/kg/24 h for vancomycin, indicating that TD-1762 is 44- to 49-fold more potent than vancomycin. PK-PD analysis of data from single-dose and dose-fractionation studies for MRSA (ATCC 33591) demonstrated that the total-drug 24-h area under the concentration-time curve-to-MIC ratio (AUC/MIC ratio) was the best predictor of efficacy (r(2) = 0.826) compared to total-drug maximum plasma concentration of drug-to-MIC ratio (Cmax/MIC ratio; r(2) = 0.715) and percent time that the total-drug plasma drug concentration remains above the MIC (%Time>MIC; r(2) = 0.749). The magnitudes of the total-drug AUC/MIC ratios associated with net bacterial stasis, a 1-log(10) CFU reduction from baseline and near maximal effect, were 21.1, 37.2, and 51.8, respectively. PK-PD targets based on such data represent useful inputs for analyses to support dose selection decisions for clinical studies of patients.     

In vitro evaluation of BAL9141, a novel parenteral cephalosporin active against oxacillin-resistant staphylococci

Community-acquired and nosocomial infections caused by multidrug-resistant Gram-positive pathogens continue to increase in prevalence and have become a serious problem in many parts of the world. BAL9141 is a member of the class of parenteral pyrrolidinone-3-ylidenemethyl cephalosporins, and has a broad spectrum of activity. In the current study, BAL9141 was tested against a large number (n = 2263) of recent isolates from various international surveillance programmes including 1097 Gram-positive strains. Susceptibility to (S) and activity of (mg/L) to BAL9141, based on proposed breakpoints (MIC50/MIC90/% S) were as follows: methicillin-susceptible Staphylococcus aureus (0.5/0.5/100%), methicillin-resistant S. aureus (MRSA) (1/2/100%), methicillin-susceptible coagulase-negative staphylococci (CoNS) (0.12/0.25/100%), methicillin-resistant CoNS (MR-CoNS) (1/2/100%), Streptococcus pneumoniae (< or = 0.015/0.25/100%), viridans group streptococci (0.03/0.5/99%), beta-haemolytic streptococci (< or = 0.015/< or = 0.015/100%), Enterococcus faecalis (0.5/16/90%), Enterococcus faecium (>32/>32/22%), Haemophilus influenzae (0.06/0.06/100%), Moraxella catarrhalis (0.06/0.5/100%), Neisseria gonorrhoeae (0.03/0.06/100%) and Neisseria meningitidis (< or = 0.002/0.004/100%). BAL9141 susceptibility at < pr = 4 mg/L (100% S) surpassed that of ceftriaxone (CRO; 1% S) and quinupristin/dalfopristin (Q-D; 92% S) against MRSA and MR-CoNS (CRO 0.9% S; Q-D 94% S). All S. pneumoniae were inhibited by BAL9141 at < or = 1 mg/L compared with CRO (90% S) and levofloxacin (LVX; 98% S). Susceptibility rates for viridans group streptococci to BAL9141 (>98%) were also higher than to CRO (86%) and LVX (96%). BAL9141 demonstrated excellent activity against most species of wild-type enteric bacilli, with > or = 95% of isolates being susceptible; however, only modest activity was observed for BAL9141 against non-fermentative Gram-negative species and ESBL-producing Escherichia coli or Klebsiella pneumoniae. BAL9141 demonstrated excellent activity against many tested pathogens displaying various resistance phenotypes, and should be particularly valuable in the treatment of MRSA as well as for drug-resistant streptococci, while maintaining a spectrum resembling a 'third-generation' cephalosporin against other clinically important species.     

Increased killing of staphylococci and streptococci by daptomycin compared with cefazolin and vancomycin in an in vitro peritoneal dialysate model

Peritoneal dialysate fluid (PDF) is a bacteriostatic medium that compromises the antibacterial activity of cell wall-active agents. By use of an in vitro static model, methicillin-resistant Staphylococcus aureus (MRSA), methicillin-susceptible S. aureus (MSSA), methicillin-susceptible Staphylococcus epidermidis (MSSE), and Streptococcus sanguis were exposed to daptomycin at concentrations of 10, 30, and 100 mg/liter, cefazolin at 125 mg/liter, and vancomycin at 25 mg/liter in cation-adjusted Mueller-Hinton Broth or Todd Hewitt Broth (for S. sanguis) and PDF at pHs of 5.5 and 7.4. The pH had no effect on antibacterial activity. Neither cefazolin nor vancomycin produced a bactericidal or a bacteriostatic effect versus MRSA, MSSA, MSSE, or S. sanguis in PDF, while all concentrations of daptomycin were bactericidal against all organisms in PDF. Daptomycin did not exhibit concentration-dependent activity in PDF. Daptomycin appears to be a promising agent for use in peritoneal dialysis-associated peritonitis, producing bacterial kill to a greater extent and at a higher rate than cefazolin or vancomycin in PDF.     

In vitro activity of ceftobiprole against frequently encountered aerobic and facultative Gram-positive and Gram-negative bacterial pathogens: results of the CANWARD 2007-2009 study

The in vitro activity of ceftobiprole was evaluated against 15 011 clinical isolates obtained from patients in Canadian hospitals between 2007 and 2009. All Staphylococcus aureus were susceptible to ceftobiprole (MIC(90)'s for methicillin-susceptible Staphylococcus aureus and methicillin-resistant Staphylococcus aureus of ≤ 1 μg/mL and 2 μg/mL, respectively). Ceftobiprole was active against penicillin-susceptible Streptococcus pneumoniae (MIC(90), ≤ 0.06 μg/mL), penicillin-resistant Streptococcus pneumoniae (MIC(90), 0.5 μg/mL), Streptococcus pyogenes (MIC(90), ≤ 0.06 μg/mL), Staphylococcus epidermidis (MIC(90), ≤ 1 μg/mL), and Enterococcus faecalis (MIC(90), ≤ 1 μg/mL). Over 90% of Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes, Citrobacter freundii, Proteus mirabilis, and Serratia marcescens isolates were inhibited by a ceftobiprole concentration of ≤ 1 μg/mL. Ceftobiprole was not active against extended-spectrum β-lactamase-producing Escherichia coli and K. pneumoniae. The in vitro activity of ceftobiprole versus Pseudomonas aeruginosa was similar to that of cefepime (MIC(90), 16 μg/mL). The broad spectrum of activity by ceftobiprole would support further study of this agent in the treatment of hospital-acquired infections.     

In vitro activity of moxifloxacin, a new 8-methoxyquinolone, against gram-positive bacteria

The in vitro activity of moxifloxacin, formerly BAY 12-8039, against gram-positive bacteria was tested by the agar dilution method. A total of 189 isolates that included Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, streptococci, rhodococci, leuconostocs, pediococci, lactobacilli, and diphtheroids were tested. Moxifloxacin showed greater potency than ciprofloxacin against S. aureus, streptococci, and enterococci, having Minimal Inhibitory Concentrations (MICs) lower than those of ciprofloxacin by 2- to 64-fold. This improved activity was most prominent for S. aureus. Moxifloxacin was active against Leuconostoc and Rhodococcus species. Time-kill studies using moxifloxacin at a concentration of 3 micrograms/mL against one isolate each of methicillin-resistant S. aureus (MSSA) (MIC, 0.031 microgram/mL), MRSA (MIC, 1 microgram/mL), two isolates of E. faecalis (MICs, 0.25 and 2 micrograms/mL), and two isolates of vancomycin-resistant E. faecium (MICs, 0.25 and 2 micrograms/mL) revealed an average decrease in colony forming unit (CFU) by 3.8, 0.4, 4.0, 2.0, 4.2, and 1.8 log10 CFU/mL at 24 h, respectively. Moxifloxacin is a new 8-methoxyquinolone with improved in vitro activity against gram-positive bacteria. Further studies of the in vivo activity of this compound appear warranted.     

Comparative antimicrobial activity of gatifloxacin with ciprofloxacin and beta-lactams against gram-positive bacteria.

Gatifloxacin is a new 8-methoxy fluoroquinolone. The in-vitro antibacterial activity of gatifloxacin was compared to that of ciprofloxacin, ceftriaxone, imipenem, piperacillin/tazobactam and amoxicillin/clavulanic acid against 165 streptococcal isolates, 369 staphylococcal isolates, and 50 enterococcal isolates recently recovered from clinical isolates. Gatifloxacin was the most active agent tested against streptococci including penicillin-nonsusceptible Streptococcus pneumoniae (MIC(90) 0.5 microg/mL). Imipenem and gatifloxacin (MIC(90) 0.5 microg/mL) were the most active agents tested against viridans group streptococci. All the agents demonstrated excellent activity against methicillin-susceptible S. aureus. Imipenem, piperacillin/tazobactam, amoxicillin/clavulanic acid, and gatifloxacin had good activity against methicillin-sensitive S. epidermidis. Among the methicillin-sensitive and methicillin-resistant coagulase-negative staphylococci tested, gatifloxacin was the most active agent. Amoxicillin/clavulanic acid and gatifloxacin were the most active agents against E. faecalis. Thus, gatifloxacin possesses equal or superior activity when compared to ciprofloxacin and beta-lactams making it a promising new fluoroquinolone for clinical use in treating Gram-positive infections.     

In vitro activities of two ketolides, HMR 3647 and HMR 3004, against gram-positive bacteria

The in vitro activities of two new ketolides, HMR 3647 and HMR 3004, were tested by the agar dilution method against 280 strains of gram-positive bacteria with different antibiotic susceptibility profiles, including Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, Streptococcus spp. (group A streptococci, group B streptococci, Streptococcus pneumoniae, and alpha-hemolytic streptococci). Seventeen erythromycin-susceptible (EMs), methicillin-susceptible S. aureus strains were found to have HMR 3647 and HMR 3004 MICs 4- to 16-fold lower than those of erythromycin (MIC at which 50% of isolates were inhibited [MIC50] [HMR 3647 and HMR 3004], 0.03 microgram/ml; range, 0.03 to 0.06 microgram/ml; MIC50 [erythromycin], 0.25 microgram/ml; range, 0.25 to 0.5 microgram/ml). All methicillin-resistant S. aureus strains tested were resistant to erythromycin and had HMR 3647 and HMR 3004 MICs of > 64 micrograms/ml. The ketolides were slightly more active against E. faecalis than against E. faecium, and MICs for individual strains varied with erythromycin susceptibility. The MIC50s of HMR 3647 and HMR 3004 against Ems enterococci (MIC < or = 0.5 microgram/ml) and those enterococcal isolates with erythromycin MICs of 1 to 16 micrograms/ml were 0.015 microgram/ml. E. faecalis strains that had erythromycin MICs of 128 to > 512 micrograms/ml showed HMR 3647 MICs in the range of 0.03 to 16 micrograms/ml and HMR 3004 MICs in the range of 0.03 to 64 micrograms/ml. In the group of E. faecium strains for which MICs of erythromycin were > or = 512 micrograms/ml, MICs of both ketolides were in the range of 1 to 64 micrograms/ml, with almost all isolates showing ketolide MICs of < or = 16 micrograms/ml. The ketolides were also more active than erythromycin against group A streptococci, group B streptococci, S. pneumoniae, rhodococci, leuconostocs, pediococci, lactobacilli, and diphtheroids. Time-kill studies showed bactericidal activity against one strain of S. aureus among the four strains tested. The increased activity of ketolides against gram-positive bacteria suggests that further study of these agents for possible efficacy against infections caused by these bacteria is warranted.     

Antimicrobial activity of daptomycin against multidrug-resistant Gram-positive strains collected worldwide

Daptomycin is a cyclic lipopeptide recently released for clinical use in the treatment of serious Gram-positive infections in hospitalized patients. We evaluated the in vitro activity of daptomycin tested against recently isolated multidrug-resistant Gram-positive clinical strains. A total of 386 isolates were selected from a large collection of strains from more than 70 centers located in Europe, North America, and South America. The strains were tested by reference broth microdilution methods in Mueller-Hinton broth with 50 mg/L Ca++ against daptomycin. Daptomycin was the most potent compound tested against penicillin-resistant Streptococcus pneumoniae with MIC50/90 values at < or =0.12 and 0.25 microg/mL, respectively. Daptomycin was also highly active against vancomycin-resistant enterococci and staphylococcal strains with various resistance patterns. Enterococcus faecium showed higher daptomycin MIC values (MIC90, 4 microg/mL) when compared to E. faecalis (MIC90, 1 microg/mL). In summary, resistance to vancomycin, teicoplanin, quinupristin/dalfopristin, or penicillin among the Gram-positive isolates did not adversely influence daptomycin activity. Daptomycin showed a significant potency and spectrum against Gram-positive species, including multidrug-resistant strains, and may represent a reasonable therapeutic option for infections caused by these important pathogens.     

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.     

Comparative in vitro activity of moxifloxacin against Gram-positive clinical isolates

The in vitro activity of moxifloxacin was compared with that of 15 antibacterial agents against 513 Gram-positive microorganisms. The MIC(90) (mg/L) of moxifloxacin was 0.06 for quinolone-susceptible Staphylococcus aureus and Staphylococcus epidermidis, 0.12 for Streptococcus pyogenes and Streptococcus agalactiae; 0.25 for Streptococcus pneumoniae, Streptococcus mitis, Streptococcus bovis, Streptococcus anginosus and Actinomyces pyogenes; 0.5 for Streptococcus sanguis and Listeria monocytogenes, 2 for Corynebacterium jekeium and Bifidobacterium bivius. Over 50% of Enterococcus faecalis, Enterococcus faecium, quinolone-resistant staphylococci, Nocardia steroides and Clostridium difficile were susceptible to 2 mg/L moxifloxacin. Moxifloxacin and trovafloxacin demonstrated comparably high activity towards Gram-positive cocci; moxifloxacin and clinafloxacin were most active against Gram-positive bacilli.     

In vitro and in vivo antibacterial activities of KRM-1648 and KRM-1657, new rifamycin derivatives.

The in vitro and in vivo antibacterial activities of the new rifamycin derivatives KRM-1648 and KRM-1657 were compared with those of rifampin. Rifabutin, ciprofloxacin, and clarithromycin were also tested for reference. The respective MICs of KRM-1648 and KRM-1657 for 90% of the strains tested (MIC90S) were 0.016 and 0.0078 microgram/ml, respectively, for methicillin-susceptible Staphylococcus aureus, 0.016 and 0.0039 microgram/ml, respectively, for methicillin-resistant S. aureus, and 0.0625 and 0.016 microgram/ml, respectively, for methicillin- and quinolone-resistant S. aureus. These MIC90S of KRM-1657 were equal to or 2- to 64-fold lower than those of rifampin. KRM-1648 and KRM-1657 with MIC90S of between 0.002 and 0.078 microgram/ml were 2- to 128-fold more active than rifampin against Staphylococcus epidermidis and Streptococcus species, including Streptococcus pneumoniae and Streptococcus pyogenes. The MIC90S of KRM-1657 for Haemophilus influenzae and Neisseria gonorrhoeae were 0.25 and 0.1 microgram/ml, respectively; KRM-1657 was almost as active as rifampin and was 8- to 16-fold more active than KRM-1648 against these strains. The frequency of occurrence of spontaneous mutations to resistance to KRM-1648 and KRM-1657 was equal to that to rifampin. Against systemic infection with S. aureus in mice, the efficacies of KRM-1648 and KRM-1657 were comparable to that of rifampin.     

Activity of the new quinolones WCK 771, WCK 1152 and WCK 1153 against clinical isolates of Streptococcus pneumoniae and Streptococcus pyogenes

Objectives and methods: The new fluoroquinolones WCK 771, WCK 1152 and WCK 1153 were developed to overcome quinolone resistance in Gram-positive bacteria. The activity of these new quinolones was tested against 159 clinical isolates of Streptococcus pneumoniae and 52 clinical isolates of Streptococcus pyogenes using the microbroth dilution method. RESULTS: MIC50/MIC90 values (mg/L) of WCK 771, WCK 1152 and WCK 1153 for quinolone-susceptible S. pneumoniae (n = 119; 54 penicillin G-susceptible, 53 penicillin G-intermediate, and 12 penicillin G-resistant strains) were 0.25/0.5, 0.03/0.06 and 0.016/0.03, respectively. MIC50/MIC90 values (mg/L) for quinolone-resistant pneumococci (n = 40) increased to 4/16, 0.25/1 and 0.125/0.5, respectively. Against S. pyogenes, WCK 771, WCK 1152 and WCK 1153 were also highly active with MIC50/MIC90 values (mg/L) of 0.25/0.25, 0.03/0.06 and 0.03/0.03, respectively. CONCLUSIONS: Overall, WCK 771 was highly active against quinolone-susceptible, but not against quinolone-resistant S. pneumoniae, whereas WCK 1152 and WCK 1153 were more potent and were able to overcome quinolone resistance in both S. pneumoniae and S. pyogenes.     

In vitro activity of LY264826 compared to other glycopeptides and daptomycin.

LY264826 a new naturally occurring glycopeptide inhibited 90% of methicillin-susceptible and -resistant Staphylococcus aureus at 1 micrograms/ml. LY264826 had similar activity against methicillin-susceptible and -resistant coagulase-negative staphylococci. The LY264826 MIC90 for Streptococcus pyogenes was 0.25 microgram/ml, twofold more active than vancomycin and twofold less active than teicoplanin. LY264826 was eightfold more active than vancomycin and twofold more active than teicoplanin against enterococci. LY264826 inhibited Streptococcus pneumoniae at 0.25 microgram/ml and Listeria monocytogenes at 0.5 microgram/ml. Clostridium were inhibited by less than or equal to 0.25 microgram/ml of LY264826 and peptococci, peptostreptococci, and Fusobacterium were inhibited by less than 0.5 microgram/ml. Bacteroides species were LY284826 -resistant as were all Enterobacteriaceae, Flavobacterium, and Neisseria spp. Minimum bactericidal and inhibitory concentrations (MBCs and MICs) were within a dilution for S. aureus, S. pyogenes, and S. pneumoniae, but greater than or equal to 32-fold greater for enterococci.     

In vitro activities of BAY Y3118, ciprofloxacin, ofloxacin, and fleroxacin against gram-positive and gram-negative pathogens from respiratory tract and soft tissue infections.

BAY Y3118 was highly active against Moraxella catarrhalis, Haemophilus influenzae, Legionella pneumophila, Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus (except quinolone-resistant, methicillin-resistant S. aureus), Staphylococcus epidermidis, Streptococcus pyogenes, Streptococcus agalactiae, and Streptococcus pneumoniae (MIC for 90% of strains tested [MIC90], 0.063 micrograms/ml). For Enterococcus faecalis and Corynebacterium jeikeium, MIC90s were 4 and 2 micrograms/ml, respectively. BAY Y3118 was as active as ciprofloxacin against Pseudomonas aeruginosa (MIC90, 0.5 micrograms/ml) and had potent activity against Bacteroides fragilis (MIC90, 0.5 micrograms/ml).     

In vitro evaluation of BAY Y3118, a new full-spectrum fluoroquinolone.

BAY Y3118, 1-cyclopropyl-7-(2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-8- chloro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride, is a new fluoroquinolone with antibacterial activity against an expanded spectrum of species including Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Enterococcus faecium, Streptococcus pneumoniae, Streptococcus pyogenes, and also anaerobes such as Bacteriodes fragilis and Clostridium perfringens. MIC90s for S. aureus, S. epidermidis, E. faecalis, and S. pneumoniae clinical isolates were 0.125, 0.25, 0.125 and 0.25 micrograms/ml, respectively. Against methicillin- and/or quinolone-resistant S. aureus, MIC50 levels of BAY Y3118 were 10- to 100-fold lower than those of tosufloxacin, sparfloxacin, or ciprofloxacin. The potency of BAY Y3118 against all members of the Enterobacteriaceae generally was equal to or 2-fold greater than that of ciprofloxacin or tosufloxacin. BAY Y3118 was also highly active against Haemophilus influenzae, Moraxella catarrhalis, Acinetobacter spp. and Pseudomonas aeruginosa. Increasing inoculum concentrations had a minimal effect on MIC determinations. The drug was determined to be bactericidal based upon reference MBCs and time-kill curves. From the results presented here, it was concluded that this new compound surpasses other known 4-quinolones both in spectrum and activity and that its further evaluation by in vitro, in vivo, and clinical studies seems warranted.     

In vitro Gram-positive antimicrobial activity of evernimicin (SCH 27899), a novel oligosaccharide, compared with other antimicrobials: a multicentre international trial

The antimicrobial activity of evernimicin (formerly SCH 27899), a novel oligosaccharide antimicrobial of the everninomicin class, was evaluated against four groups of Gram-positive pathogens: (i) Streptococcus pneumoniae (n = 1452); (ii) methicillin- or oxacillin-resistant Staphylococcus aureus (MRSA) and coagulase-negative staphylococci (MR-CoNS; n = 1427); (iii) enterococci (n = 1517); and (iv) non-pneumococcal streptococci (n = 1388), using the Etest method at each study centre throughout Eastern and Western Europe, Scandinavia, South Africa, Turkey and North America. Comparative MICs were determined for a variety of reference compounds, including vancomycin, quinupristin/dalfopristin, chloramphenicol, penicillin, ampicillin, oxacillin, ceftriaxone and ciprofloxacin. Evernimicin was highly active against all strains tested, with MIC90 values < or = 1.0 mg/L, ranging from 0.047 mg/L against S. pneumoniae to 1.0 mg/L against MRSA/MR-CoNS and enterococci. Compared with the reference agents, the MIC90 of evernimicin were lower against all species. Against MRSA and MR-CoNS the MIC90s of evernimicin, quinupristin/dalfopristin and vancomycin (the three most active agents) were 1.0, 1.5 and 3.0 mg/L, respectively. Against all species tested, the relative activities and spectra of these agents were: evernimicin > vancomycin > quinupristin/dalfopristin. The Etest proved to be reliable and reproducible, despite occasional interpretive difficulties caused by observer inexperience. Quality control results were excellent among the 33 participant sites. The results of this in vitro, multicentre, multinational study demonstrate that evernimicin possesses high antimicrobial activity against Gram-positive organisms that compares favourably with established antibacterial treatments and newer agents such as quinupristin/dalfopristin. Further clinical investigations of everninomicin class compounds appear warranted.