In vitro evaluation of AZD2563, a new oxazolidinone, tested against unusual gram-positive species

The recently introduced oxazolidinone, linezolid, has a spectrum and potency directed against Gram-positive organisms, including antimicrobial-resistant isolates. The newest agent in this class, AZD2563 was tested against uncommonly isolated Gram-positive species to establish the breadth of its spectrum. By reference broth microdilution methods, 120 strains were tested (48 Corynebacterium spp., 10 species; 27 Listeria spp., 2 species; 11 Micrococcus spp., 2 species; 23 Bacillus spp., 3 species; 6 Stomatococcus mucilaginosus and one strain each of 5 other species) against AZD2563 and compared to eight other agents. The AZD2563/linezolid MIC(50;) % inhibited at < or =4 microg/mL were: for corynebacteria (0.25/0.25 microg/mL; 100/100%), Listeria spp. (2/2 microg/mL; 100/100%), Micrococcus spp. (1/1 microg/mL; 100/100%), Bacillus spp. (0.5/1 microg/mL; 100/100%), and S mucilaginosus (0.5/1 microg/mL; 100/100%). Using the MIC(90) values, AZD2563 was slightly more potent than linezolid (two-fold). Only four genus- species groups had AZD2563 MICs of strains at 2 microg/mL (Aerococcus, Leuconostoc, Listeria, Rhodococcus), all other isolates were inhibited by < or = 1 microg/mL. The AZD2563 potency and spectrum versus these rarer species was at least equal to linezolid, including some strains resistant to penicillins, macrolides-lincosamides, and fluoroquinolones.     

In vitro evaluation of AZD2563, a new oxazolidinone,tested against beta-haemolytic and viridans group streptococci

Linezolid was the first clinically applied agent from the oxazolidinone class, and AZD2563, a new agent, is described here. Five hundred and twenty-five streptococcal isolates were tested, including beta-haemolytic (266) and viridans group (259) species. MIC(50)/MIC(90)/% susceptible (susceptibility breakpoint <2 mg/L of AZD2563) results were, for beta-haemolytic species: AZD2563 (1/2/100), linezolid (1/2/100), quinupristin-dalfopristin (0.25/0.25/100), vancomycin (0.25/0.5/100) and levofloxacin (0.5/1/99); for viridans group species: AZD2563 (0.5/1/100), linezolid (1/1/100), quinupristin-dalfopristin (0.5/1/99), vancomycin (0.5/0.5/100) and levofloxacin (1/1/98). The modal MICs of AZD2563 and linezolid were 0.5 or 1 mg/L and 1 mg/L, respectively. AZD2563 activity screening against these non-pneumococcal streptococci indicated a slightly greater potency of AZD2563 when compared with linezolid. All AZD2563 MICs were <2 mg/L.     

Activity of AZD2563, a novel oxazolidinone, against Staphylococcus aureus strains with reduced susceptibility to vancomycin or linezolid

The susceptibilities of clinical vancomycin-intermediate Staphylococcus aureus (VISA), heterogeneous VISA, and laboratory-generated linezolid-resistant S. aureus strains to the new oxazolidinone AZD2563 were assessed by agar dilution MIC determination. All clinical strains were susceptible to linezolid, and the linezolid MICs for them were equal to or twofold higher than those of AZD2563. Cross-resistance with linezolid was seen in laboratory-generated mutants, and for these strains the MIC of AZD2563 was twofold higher than that of linezolid.     

Zyvox Annual Appraisal of Potency and Spectrum Program Results for 2006: an activity and spectrum analysis of linezolid using clinical isolates from 16 countries

The Zyvox Annual Appraisal of Potency and Spectrum Program has completed its fifth year of monitoring for emerging resistance to linezolid and other Gram-positive active agents on the continents of Europe, Asia, Australia, and Latin America. In 2006, 4216 Gram-positive isolates from 16 nations were submitted for analysis from 6 organism groups including Staphylococcus aureus (54.0%), coagulase-negative staphylococci (CoNS) (14.6%), enterococci (10.0%), Streptococcus pneumoniae (9.4%), viridans group streptococci (5.0%), and beta-hemolytic streptococci (7.0%). Linezolid retained potent activity against S. aureus (MIC(50) and MIC(90), 2 microg/mL; 39.8% methicillin resistant) and CoNS (MIC(50) and MIC(90), 1 microg/mL; 74.3% methicillin resistant). Despite endemicity of vancomycin-resistant enterococci (up to 30.0%) in several nations, linezolid inhibited >99% of strains at 相似文献   

A multicenter evaluation of linezolid antimicrobial activity in North America

Overall, 141 centers in North America enrolled in this international surveillance study designed to evaluate the in vitro antimicrobial activity and spectrum of linezolid, a new oxazolidinone. Each participant tested the susceptibility of clinical isolates of staphylococcal species (n = 85) against 12 drugs, and enterococcal species (n = 40) against 6 drugs using reference broth microdilution trays; and of streptococcal species (n = 25) against 6 drugs using Etests (AB BIODISK, Solna, Sweden). Quality control testing was conducted using recommended strains, and verification of resistance to linezolid and select other agents was performed by a regional monitor. Of the 20,161 isolates collected from sites across the United States (US; n = 132) and Canada (n = 9), 18,307 were included in this analysis. Oxacillin resistance occurred in 38.7 and 70.6% of Staphylococcus aureus and coagulase-negative staphylococcal (CoNS) isolates, respectively. Vancomycin resistance was reported in 65.9 and 2.6% of Enterococcus faecium and E. faecalis, respectively. Penicillin resistance occurred in 37.2% of Streptococcus pneumoniae, 17.5% constituting high-level resistance (MIC, > or =2 microg/ml). The MIC(90) for linezolid was 1 microg/ml for streptococci, 2 microg/ml for enterococci and CoNS isolates, and 4 microg/ml for S. aureus. Using the US FDA-recommended susceptible breakpoints for linezolid, there were no confirmed reports of linezolid resistance (i.e., MIC > or =8 microg/ml). The occurrence of linezolid MICs was unimodal and generally varied between, 1-4 microg/ml for staphylococci (94% of recorded results), 1-2 microg/ml for enterococci (93%), and 0.5-1 microg/ml for streptococci (85%). Susceptibility to linezolid was not influenced by susceptibility to other antiicrobials such as vancomycin, beta-lactams or macrolides. Only linezolid was universally active against essentially all tested Gram-positive specimens. The unimodal susceptibility pattern is indicative of excellent and near complete activity against key Gram-positive pathogens including multiply resistant strains, but surveillance for emerging resistances (rare) and the performance of routine susceptibility tests to guide patient therapy seems prudent.     

Worldwide assessment of dalbavancin activity and spectrum against over 6,000 clinical isolates

Continuing emergence of new antimicrobial resistance mechanisms and the increased frequency of existing resistances, requires the development of alternative antimicrobial agents. Dalbavancin is an amide glycopeptide derivative with a markedly extended serum elimination half-life. Dalbavancin and selected comparators were tested against 6,339 recent clinical isolates (2002) from the Americas and Europe using reference susceptibility testing methods. The general characteristics of this Gram-positive organism collection were: oxacillin (OXA)-resistant Staphylococcus aureus (ORSA) at 39% of strains; vancomycin-resistant enterococci (VRE) at 10%; and penicillin-nonsusceptible pneumococci at 28%. The overall distribution of dalbavancin minimum inhibitory concentration (MIC) values ranged from < or = 0.015 to > 32 microg/ml, but > 99% of MIC results were at < or =1 microg/ml. S. aureus and coagulase-negative staphylococci were extremely susceptible to dalbavancin (MIC90, 0.06 microg/ml) despite resistance patterns to other agents. Dalbavancin was the most potent compound (by weight) against vancomycin-susceptible Enterococcus faecalis and E. faecium (MIC90, 0.06 and 0.12 microg/ml, respectively); however, VRE strains showed decreased dalbavancin susceptibility (MIC50, 4 or 8 microg/ml). All streptococcal isolates were inhibited at < or =0.25 microg/ml of dalbavancin. This reported dalbavancin activity indicates that the new glycopeptide has significant activity, superior to available agents in the class, and a potency that was uniform across geographically sampled organisms. Some VRE were inhibited by very low dalbavancin concentrations (< or = 1 microg/ml; Van B phenotypes). Further clinical development seems warranted for this once-weekly administered agent.     

Antimicrobial Activity of Ceftaroline Tested against Staphylococci with Reduced Susceptibility to Linezolid,Daptomycin, or Vancomycin from U.S. Hospitals, 2008 to 2011

Vancomycin, linezolid, and daptomycin are very active against staphylococci, but isolates with decreased susceptibility to these antimicrobial agents are isolated sporadically. A total of 19,350 Staphylococcus aureus isolates (51% methicillin resistant [MRSA]) and 3,270 coagulase-negative staphylococci (CoNS) were collected consecutively from 82 U.S. medical centers from January 2008 to December 2011 and tested for susceptibility against ceftaroline and comparator agents by the reference broth microdilution method. Among S. aureus strains, 14 isolates (0.07%) exhibited decreased susceptibility to linezolid (MIC, ≥8 μg/ml), 18 (0.09%) to daptomycin (MIC, ≥2 μg/ml), and 369 (1.9%) to vancomycin (MIC, ≥2 μg/ml; 368 isolates at 2 μg/ml and 1 at 4 μg/ml). Fifty-one (1.6%) CoNS were linezolid resistant (MIC, ≥8 μg/ml), and four (0.12%) were daptomycin nonsusceptible (MIC, ≥2 μg/ml). Ceftaroline was very active against S. aureus overall (MIC_50/90, 0.5/1 μg/ml; 98.5% susceptible), including MRSA (MIC_50/90, 0.5/1 μg/ml; 97.2% susceptible). All daptomycin-nonsusceptible and 85.7% of linezolid-resistant S. aureus isolates were susceptible to ceftaroline. Against S. aureus isolates with a vancomycin MIC of ≥2 μg/ml, 91.9, 96.2, and 98.9% were susceptible to ceftaroline, daptomycin, and linezolid, respectively. CoNS strains were susceptible to ceftaroline (MIC_50/90, 0.25/0.5 μg/ml; 99.1% inhibited at ≤1 μg/ml), including methicillin-resistant (MIC_50/90, 0.25/0.5 μg/ml), linezolid-resistant (MIC_50/90, 0.5/0.5 μg/ml), and daptomycin-nonsusceptible (4 isolates; MIC range, 0.03 to 0.12 μg/ml) strains. In conclusion, ceftaroline demonstrated potent in vitro activity against staphylococci with reduced susceptibility to linezolid, daptomycin, or vancomycin, and it may represent a valuable treatment option for infections caused by these multidrug-resistant staphylococci.     

Comparative activities of the oxazolidinone AZD2563 and linezolid against selected recent North American isolates of Streptococcus pneumoniae

The activity of AZD2563 against 250 highly resistant pneumococci and 267 drug-susceptible isolates was determined. The AZD2563 MICs for 50 and 90% of the strains tested were 1 and 2 micro g/ml and 0.5 and 1 micro g/ml, respectively, for the two isolate groups. These MICs were within 1 log(2) dilution of those of linezolid.     

Anti-anaerobic activity of AZD2563, a new oxazolidinone,compared with eight other agents

The anti-anaerobic activity of AZD2563, a new oxazolidinone, was compared with that of eight other agents against 201 Gram-positive and 99 Gram-negative anaerobes. MIC(50) and MIC(90) values (mg/L) for the 201 Gram-positive organisms were as follows: AZD2563, 1.0/4.0; linezolid, 1.0/4.0; quinupristin/dalfopristin, 0.5/1.0; amoxicillin, 0.25/1.0; clindamycin, 0.25/8.0; metronidazole, 0.5/>16.0; vancomycin, 0.5/2.0; teicoplanin, 0.125/0.25; and meropenem, 0.06/1.0. AZD2563, linezolid, vancomycin, teicoplanin and quinupristin/dalfopristin were mainly active against Gram-positive anaerobes, with no useful activity against Gram-negative anaerobes.     

AZD2563, a new oxazolidinone: bactericidal activity and synergy studies combined with gentamicin or vancomycin against staphylococci and streptococcal strains

AZD2563, a novel oxazolidinone, was tested against 10 well characterized multiple-resistant strains of staphylococci and viridans group or beta-hemolytic streptococci using kill curve kinetic methods. Generally, AZD2563 demonstrated bacteriostatic action and modest concentration-dependent cidal activity against a minority of strains of both genera. When combined with gentamicin (MIC/4 concentration), rapid bactericidal action was observed against all streptococci tested, but not against the staphylococci. No enhanced activity was noted when AZD2563 was added to subinhibitory concentrations of vancomycin. Linezolid used as a control, showed the same characteristics, confirming that AZD2563 possesses activity comparable to other agents in the oxazolidinone class. AZD2563 remained active (MIC, < or = 1 microg/ml) against all 10 strains tested.     

Antipneumococcal activity of AZD2563, a new oxazolidinone,compared with nine other agents

The in vitro activity of AZD2563, a new oxazolidinone, was compared with that of linezolid, vancomycin, quinupristin/dalfopristin, amoxicillin, levofloxacin, penicillin, erythromycin, azithromycin and clindamycin against a range of pneumococci by microdilution and time-kill studies. Against 300 pneumococci (99 penicillin susceptible, 86 penicillin intermediate, 115 penicillin resistant, 185 erythromycin resistant, 35 quinolone resistant), both oxazolidinones remained active against isolates less susceptible to other agents, with MICs ranging between 0.125 and 2 mg/L; AZD2563 MICs were generally one dilution lower than those of linezolid. Both quinupristin/dalfopristin and vancomycin were active against all groups (MIC ranges 0.125-2 and 0.125-0.25 mg/L, respectively). Apart from 35 isolates with levofloxacin MICs > or= 8 mg/L, levofloxacin MICs were < or =0.25-4 mg/L. MICs of amoxicillin and erythromycin rose with penicillin G MICs; most macrolide-resistant isolates were either penicillin-intermediate or -resistant. Against 16 organisms with differing beta-lactam, macrolide and quinolone MICs, time-kill studies showed that AZD2563 was bactericidal (99.9% killing) at 4 x MIC against nine strains at 24 h, with 90% killing of all 16 strains at 2 x MIC after 12 h. Similar results were obtained with linezolid. Both oxazolidinones were bacteriostatic at the MIC against all 16 strains. Amoxicillin, levofloxacin and vancomycin, at 2 x MIC, were bactericidal against 15 of the 16 strains after 24 h. Quinupristin/dalfopristin yielded the most rapid killing, with bactericidal activity against 13 of 16 strains at the MIC after 3 h and against 15 strains at 2 x MIC after 24 h. Erythromycin was bactericidal against all 10 strains with MICs < or= 8 mg/L at 4 x MIC after 24 h.     

In Vitro Activity of PNU-100766 (Linezolid), a New Oxazolidinone Antimicrobial, against Nocardia brasiliensis

The in vitro activity of a novel oxazolidinone, linezolid, was studied by comparing the activity of linezolid with those of amikacin, trimethoprim-sulfamethoxazole, and amoxicillin-clavulanic acid against 25 strains of Nocardia brasiliensis isolated from patients with mycetoma. All N. brasiliensis strains tested were sensitive to linezolid (MIC at which 90% of strains are inhibited [MIC(90)], 2 microg/ml; MIC(50), 1 microg/ml). This antimicrobial might constitute a good alternative for treatment of actinomycetoma.     

Determination of disk diffusion and MIC quality control parameters for AZD2563, a novel long-acting oxazolidinone

AZD2563 is a new, long-acting oxazolidinone that possesses potent antimicrobial activity against Gram-positive organisms. This report summarizes the results of broth microdilution MIC and disk diffusion quality control (QC) investigations for AZD2563. All tests or methods (M2-A7 and M7-A5) and QC study designs (M23-A2) were those published by the National Committee for Clinical Laboratory Standards. QC strains tested against AZD2563 included: Staphylococcus aureus ATCC 25923 and ATCC 29213, Enterococcus faecalis ATCC 29212 and Streptococcus pneumoniae ATCC 49619. In the eight-center QC trial, 320 and 480 results were generated for MIC and disk diffusion tests, respectively. The selected 7-mm ranges for the two disk diffusion QC organisms contained > or = 98.5% of reported results. Proposed 3 or 4 log(2) dilution MIC ranges contained all reported participant results. AZD2563 disk diffusion zone diameters were generally 2-3 mm smaller than the corresponding linezolid zone diameters. In conclusion, QC ranges for AZD2563 MIC and disk diffusion methods were established and appear acceptable in preparation for the clinical trials use.     

In vitro activity of the new oxazolidinone AZD2563 against Enterococci

The activity of a new oxazolidinone antimicrobial, AZD2563, was assessed against >500 clinical isolates of enterococci representing six species. All isolates, including those resistant to other antibiotic classes, were inhibited by AZD2563 at concentrations 相似文献   

Activities of linezolid against rapidly growing mycobacteria

Linezolid is an oxazolidinone available as an oral drug which has activity against most gram-positive bacteria. However, few species of the genus Mycobacterium have been studied. We tested 249 clinical isolates and 10 reference strains of rapidly growing mycobacteria for susceptibility to linezolid by broth microdilution. Clinical species included the Mycobacterium fortuitum group (n = 74), M. abscessus (n = 98), M. chelonae (n = 50), M. mucogenicum (n = 10), and M. fortuitum third biovariant complex (10). The modal MIC for M. mucogenicum was 1.0 microg/ml, and the MIC at which 90% of the isolates tested are inhibited (MIC(90)) was 4 microg/ml; the modal MIC for the M. fortuitum group was 4 microg/ml, and the MIC(90) was 16 microg/ml; the modal MIC for the M. fortuitum third biovariant complex was 4 microg/ml, and the MIC(90) was 8 microg/ml; the modal MIC for M. chelonae was 8 microg/ml, and the MIC(90) was 16 microg/ml; and the modal MIC for M. abscessus was 32 microg/ml, and the MIC(90) was 64 microg/ml. Based on peak levels of linezolid in serum of 15 to 20 microg/ml, we propose the following broth MIC breakpoints for these species: susceptible, < or = 8 microg/ml; moderately susceptible, 16 microg/ml; and resistant, > or =32 microg/ml). These studies demonstrate the excellent potential of linezolid for therapy of rapidly growing mycobacteria.     

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.     

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 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.     

In vitro activity of linezolid against Clostridium difficile

We examined the in vitro activity of linezolid against Clostridium difficile, including isolates with reduced susceptibility to metronidazole or vancomycin. The MIC at which 50% of the isolates were inhibited (MIC50) and MIC90 were 0.5 and 2 microg/ml, respectively (range, 0.03 to 4 microg/ml). MICs were always 相似文献   

Antistaphylococcal activity of CB-181963 (CAB-175), an experimental parenteral cephalosporin

Among 265 methicillin-susceptible and -resistant staphylococci, CB-181963 (CAB-175) had a 50% minimum inhibitory concentration of 2 microg/ml and a 90% minimum inhibitory concentration of 4 microg/ml. All strains except two vancomycin-resistant S. aureus and 5 vancomycin-intermediate S. aureus strains were also susceptible to vancomycin and teicoplanin, and all were susceptible to linezolid, ranbezolid, tigecycline, and quinupristin-dalfopristin. Most methicillin-resistant strains were levofloxacin resistant. CB-181963 was bactericidal against all six methicillin-resistant strains at four times the MIC after 24 h.