Trends in linezolid susceptibility patterns: report from the 2002-2003 worldwide Zyvox Annual Appraisal of Potency and Spectrum (ZAAPS) Program.

Linezolid is an important oxazolidinone antimicrobial for the treatment of infections caused by Gram-positive cocci, especially vancomycin-resistant enterococci and oxacillin-resistant Staphylococcus aureus (ORSA). Since its introduction, however, ribosomal mutations have been detected that produce resistance; thus, longitudinal surveillance remains necessary to monitor for emerging resistance in all geographic areas of oxazolidinone use. The 2003 Zyvox Annual Appraisal of Potency and Spectrum (ZAAPS) Program compared linezolid minimum inhibitory concentration (MIC) results with 13-15 comparator antimicrobial agents (8089 isolates) and also with results from an earlier surveillance period (2002). Sampling institutions in the United States of America (USA), Canada, Europe (seven nations), South America (three nations) and the Asia-Pacific (three nations) referred 200 Gram-positive cocci to the central laboratory for MIC processing and identification confirmation. Linezolid resistance (MIC > or = 8 mg/L) was established by alternative susceptibility testing methods as well as by ribosomal target characterisation. Concurrent drug use data were collected. Linezolid activity against the six major organism groups did not vary between years or geographic areas. In contrast, penicillin resistance increased 2% in Streptococcus pneumoniae; macrolide resistance was stable among beta-haemolytic streptococci (19-21%), but increased in S. pneumoniae (+2%); ORSA rates increased 4%; and vancomycin resistance in enterococci was present, but varied markedly by region. Non-clonal linezolid-resistant isolates were detected, each having the same G2576U 23S rRNA target mutation. Furthermore, the first linezolid-resistant, non-USA isolate (S. aureus in Greece) was observed, apparently related to linezolid use. In 2003, near complete activity for linezolid against Gram-positive isolates was again documented (99.93% susceptible) in the ZAAPS Program. Rare linezolid-resistant isolates were identified among enterococci, limited to USA strains. Limited correlations of linezolid resistance to drug use continues, with an average consumption rate of 0.63DDD/100 patient days (a 50% increase since 2002), and indicates the important role of hospital hygiene practice in preventing the dissemination of oxazolidinone resistances, should they be detected.

Trends in linezolid susceptibility patterns in 2002: report from the worldwide Zyvox Annual Appraisal of Potency and Spectrum Program.

Oxazolidinones have become reliable clinical and candidate antimicrobial agents to be utilized for infections caused by multidrug-resistant Gram-positive cocci, especially vancomycin-resistant enterococci and methicillin-resistant staphylococci. However, mutational resistance of the ribosomal target has been described for several species. Longitudinal surveillance remains necessary to monitor for this evolving linezolid resistance pattern. A survey of linezolid and several comparison Gram-positive focused agents was initiated in 2002 (7971 strains, >99.0% compliance) for 54 participating sites in the United States, Canada, Europe (6 nations), Latin America (2 nations), and the Asia Pacific (2 nations). The 5 and 25 sites in Canada and the United States, respectively, submitted 200 strains each to a central laboratory for organism identification/confirmation and reference MIC processing. The 10 remaining nations had 200 strain samples from 1 to 4 separate institutions. Linezolid resistance (MIC >/= 8 microg/mL) was confirmed by alternative susceptibility testing methods (Etest, AB BIO Disk, Solna, Sweden; disk diffusion method) and target mutation characterization by PCR and sequence analysis. Linezolid activity against the 6 major organism groups did not vary between geographic areas. A total of 98.1% of linezolid MIC values were between 0.5 and 2 microg/mL, and only 0.5% of results were at 4 microg/mL, which included 32 Staphylococcus aureus (0.9%) and 5 (0.5%) enterococcal isolates. Linezolid resistance was detected in only 4 isolates (0.05%): 1 each Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecium, and a viridans group Streptococcus. All 4 isolates had a G2576U mutation in the 23S rRNA target. Linezolid activity as outlined by these Zyvox Annual Appraisal of Potency and Spectrum (ZAAPS) Program results demonstrate sustained, near complete activity against contemporary Gram-positive isolates on 4 monitored continents and in centers utilizing oxazolidinones. Rare linezolid-resistant strains were identified in the United States only (0.05% resistance overall).

Quality control guidelines for testing gram-negative control strains with polymyxin B and colistin (polymyxin E) by standardized methods.

An eight-laboratory study addressed the urgent need for quality control (QC) ranges for susceptibility determination when testing colistin (polymyxin E) and polymyxin B, two polycationic peptide antimicrobial agents, against multidrug-resistant gram-negative bacilli. For Escherichia coli ATCC 25922l, the QC ranges were as follows: for colistin, 0.25 to 1 microg/ml (11 to 17 mm), and for polymyxin B, 0.25 to 2 microg/ml (13 to 19 mm). For Pseudomonas aeruginosa ATCC 27853, the QC ranges were as follows: for colistin, 0.25 to 2 microg/ml (11 to 17 mm), and for polymyxin B, 0.25 to 2 mug/ml (14 to 18 mm). More than 97% of all reported QC results were within these proposed ranges.

Bactericidal activity of garenoxacin tested by kill-curve methodology against wild type and QRDR mutant strains of Streptococcus pneumoniae.

Kill-curve bactericidal assays over 24 hours were determined for garenoxacin, a novel des-F(6) quinolone, and levofloxacin at achievable serum drug concentrations ranging from 2 to 8 microg/mL. Tested strains included 4 wild type and 2 target quinolone resistance-determining region (QRDR) mutant Streptococcus pneumoniae. Garenoxacin was 16-fold to 32-fold more active than levofloxacin, and mutant strains (3 QRDR sites) had garenoxacin minimum inhibitory concentration (MIC) values at 1 microg/mL (levofloxacin MIC >32 microg/mL, resistant), but equal to the levofloxacin potency against wild type strains. Garenoxacin killed mutant pneumococci with comparable rapidity, as did levofloxacin versus strains without target alterations. Garenoxacin appears to be a widely usable and highly active agent against S. pneumoniae resistant to other quinolones such as levofloxacin.

Disk diffusion quality control guidelines for NVP-PDF 713: a novel peptide deformylase inhibitor.

NVP-PDF713 is a peptide deformylase inhibitor that has emerged as a candidate for treating Gram-positive infections and selected Gram-negative species that commonly cause community-acquired respiratory tract infections. This report summarizes the results of a multi-center (seven participants) disk diffusion quality control (QC) investigation for NVP PDF-713 using guidelines of the National Committee for Clinical Laboratory Standards and the standardized disk diffusion method. A total of 420 NVP-PDF 713 zone diameter values were generated for each QC organism. The proposed zone diameter ranges contained 97.6-99.8% of the reported participant results and were: Staphylococcus aureus ATCC 25923 (25-35 mm), Streptococcus pneumoniae ATCC 49619 (30-37 mm), and Haemophilus influenzae ATCC 49247 (24-32 mm). These QC criteria for the disk diffusion method should be applied during the NVP-PDF 713 clinical trials to maximize test accuracy.

Preliminary susceptibility testing guidelines for AZD2563, a long-acting oxazolidinone.

Rapid expansion of antimicrobial resistance has led to the development of new antimicrobial agents. AZD2563 is a novel oxazolidinone that has activity similar to linezolid and the potential for extended dosing intervals. Recent Gram-positive clinical organisms (1572 strains) were tested including four oxazolidinone-resistant enterococci. Strains processed were: 313 Staphylococcus aureus, 299 coagulase-negative staphylococci, 305 enterococci, 305 Streptococcus pneumoniae, 300 other streptococci (beta-haemolytic and viridans group) and 50 other rarely isolated Gram-positive species. The methods (agar and broth dilution, disk diffusion) of the National Committee for Clinical Laboratory Standards (NCCLS; M7-A6, M2-A8) were followed and linezolid was used as a control agent. A tentative MIC breakpoint (or=20 mm), intermediate at 4 mg/l (17-19 mm) and resistant at >or=8 mg/l (

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 evaluation of AZD2563, a novel oxazolidinone, against 603 recent staphylococcal isolates.

AZD2563, a novel oxazolidinone, and a selection of comparator drugs that included linezolid, erythromycin, clindamycin, quinolones, and gentamicin were tested against 384 Staphylococcus aureus (176 oxacillin-resistant S. aureus [ORSA]) and 219 coagulase-negative staphylococci (CoNS; 162 oxacillin resistant) by reference microdilution (all strains) and agar dilution (30 strains) methods. The following results were noted for AZD2563. (Note that, for comparison only, a breakpoint of < or =4 microg/ml [the breakpoint of linezolid] was used for this study, although a susceptibility breakpoint for AZD2563 has not been determined.) For S. aureus, the MIC at which 50% of the isolates tested are inhibited (MIC(50)) was 1 microg/ml, the MIC(90) was 2 microg/ml, and the percent susceptibility was 100%. For CoNS, the MIC(50) was 0.5 microg/ml, the MIC(90) was 1 microg/ml, and the percent susceptibility was 100%. ORSA and OR-CoNS strains were equally inhibited by AZD2563 and linezolid. AZD2563 demonstrated antistaphylococcal activity comparable to that of linezolid.

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.

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.