1 Department of Microbiology and Infectious Diseases, Womens and Childrens Hospital, 72 King William Road, North Adelaide, SA 5006, Australia; 2 Buffalo Clinical Research Center, Buffalo, NY; 3 The Jones Group/JMI Laboratories, North Liberty, IA; 4 Tufts University School of Medicine, Boston, MA, USA
Received 28 July 2002; returned 12 September 2002; revised 31 October 2002; accepted 4 November 2002
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Abstract |
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Keywords: linezolid, Western Pacific region, ZAPS
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Introduction |
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Linezolid is the first of a novel antimicrobial class, the oxazolidinones, which have a unique mechanism of action.6 Oxazolidinones affect bacterial protein synthesis at the ribosomal level by binding to a specific target on the 50S subunit of the ribosome and inhibiting the formation of the initiation complex. This new class of antimicrobial agents has very promising activity against multiply resistant Gram-positive organisms.7,8 It has been approved in the USA, Australia and some European countries for the treatment of serious Gram-positive infections, including those caused by strains resistant to multiple other antimicrobials. Linezolid also has the advantage of being available in both oral and intravenous forms.9
As part of the ZAPS (Zyvox Antimicrobial Potency Study) programme worldwide,10 the activity of linezolid, a new oxazolidinone, was evaluated against a range of clinically important Gram-positive species isolated in clinical laboratories across the Western Pacific region.
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Materials and methods |
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Eighteen hospital-based laboratories from six countries in the Western Pacific region participated in the study: Australia (six sites), China (Hong Kong; two sites), Korea (three sites), Japan (three sites), Singapore (two sites) and Taiwan (three sites).
Isolates
Each laboratory was required to collect prospectively, for up to 6 months in the years 19992000, isolates from wounds and soft tissue, abdominal cavity, bone or joint specimens, upper respiratory sinuses, middle ear, lower respiratory tract, body cavities, cerebrospinal fluid and blood cultures. The following species were collected at each site: S. aureus (oxacillin resistant, n = 20; oxacillin susceptible, n = 30); coagulase-negative Staphylococcus spp. (CoNS; oxacillin resistant, n = 20; oxacillin susceptible, n = 15); Enterococcus faecalis (n = 30), Enterococcus faecium (n = 10) or Enterococcus spp. unspecified (n = 40); S. pneumoniae (n = 20); and other Streptococcus spp. (n = 5). No repeat isolates were allowed from the same patient.
Susceptibility testing
All Streptococcus species, including S. pneumoniae, were tested by stable gradient diffusion (Etest) against ceftriaxone, erythromycin, linezolid, penicillin, quinupristindalfopristin and trovafloxacin. Staphylococci and enterococci were tested by either broth microdilution (Microscan; Dade Behring, Sacramento, CA, USA) or disc diffusion using NCCLS methods11,12 against ampicillin, cefazolin, ceftriaxone, chloramphenicol, clindamycin, doxycycline, erythromycin, linezolid, oxacillin, quinupristindalfopristin, teicoplanin, trovafloxacin and vancomycin. NCCLS breakpoint criteria (M100-S12, 2002)13 were used to define susceptibility categories for all strains, where available.
Confirmatory testing
All isolates with possible resistance to linezolid (MIC > 4 mg/L) or zone diameters of 20 mm were referred to the regional coordinating laboratory (Womens and Childrens Hospital) for confirmation of the organism identification and susceptibility test result. Strains of Streptococcus or Staphylococcus spp. with suspected resistance to vancomycin were also sent to the coordinating laboratory for confirmation. Streptococci with a trovafloxacin MIC > 1 mg/L, any species (except E. faecalis) with a quinupristindalfopristin MIC > 1 mg/L (
18 mm), staphylococci with a vancomycin MIC
4 mg/L (
14 mm) or teicoplanin MIC > 8 mg/L (
10 mm), or enterococci with vancomycin MIC > 4 mg/L (
14 mm) or teicoplanin MIC > 8 mg/L (
10 mm) were also referred to the coordinating laboratory for confirmation. All referred staphylococci were tested for the presence of mecA and nuc genes by multiplex PCR.14 Enterococci were identified and vancomycin genotype determined using PCR techniques.15 All referred isolates were tested by both susceptibility test methods.
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Results |
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Table 1 lists the susceptibility patterns of 351 pneumococci from six countries. For the Western Pacific region, only 46.7% of isolates were penicillin susceptible (MIC 0.06 mg/L) and high-level resistance was observed in 16.2% of pneumococci. A wide susceptibility variation was noted between nations with a range of susceptibility from 12% (Taiwan) and 18% (Korea) to 78% (Australia). Similarly, the macrolide resistance rates paralleled the penicillin pattern, with
80% resistance found in three countries (China, Korea and Taiwan), but only 20% in Australia. Resistance to ceftriaxone (1.7%), quinupristindalfopristin (0.0%) and trovafloxacin (0.0%) was very rare. Linezolid was active against all S. pneumoniae strains at
2 mg/L and against 99.4% of these isolates at
1 mg/L.
The 83 strains of other streptococci were also very susceptible to linezolid (Table 2) with a MIC range of 0.252 mg/L and an MIC90 of 1 mg/L. Only 7.2% of these Streptococcus spp. isolates were not susceptible to penicillin, and the erythromycin resistance was 424% depending on the nation sampled (data not shown).
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Table 3 summarizes the in vitro activity of linezolid and nine comparison agents tested against 1520 isolates of staphylococci. Among the oxacillin-susceptible S. aureus, the most common resistance pattern was erythromycin resistance usually without concurrent clindamycin resistance (so-called M-phenotype). The exception was the isolates from Taiwan, where most (5973%) macrolide-resistant isolates were co-resistant to clindamycin and chloramphenicol. In contrast, oxacillin-resistant S. aureus were often resistant to erythromycin (82100%), clindamycin (5487%) and the tetracyclines (887%). As observed with oxacillin-susceptible strains, the oxacillin-resistant S. aureus were more likely to be resistant to chloramphenicol in Taiwan. Linezolid, quinupristindalfopristin and the two tested glycopeptides inhibited all S. aureus strains; no so-called VISA strains were discovered.5
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Linezolid, quinupristindalfopristin and vancomycin were active against all CoNS isolates and the activity was not influenced by resistance to oxacillin or other monitored agents (Table 3). The linezolid MIC range for the staphylococci was 0.54 mg/L with an MIC50 and MIC90 result of 2 mg/L for both S. aureus and CoNS (Table 2).
Linezolid activity against enterococci
Table 4 shows the activity of linezolid tested against 630 isolates of E. faecalis and E. faecium from the Western Pacific region. Resistance to glycopeptides was not observed among the E. faecalis isolates, but 14 vancomycin-resistant E. faecium were confirmed from Australia [three strains (7%); both a vanB pattern] and Korea [11 strains (27%); nine with a vanA phenotype]. Ampicillin was effective in vitro against E. faecalis (98.3% susceptible), but not against E. faecium (17.4% susceptible). Quinupristindalfopristin was active only against E. faecium; however, 9.6% of vancomycin-susceptible isolates had intermediate in vitro testing results.
The activity of other alternative agents against E. faecium or E. faecalis included chloramphenicol (8.7% and 26.0% resistance, respectively), doxycycline (22.4% and 29.5% resistance, respectively) and new fluoroquinolones such as trovafloxacin (15.8% and 50.3% resistance, respectively). All E. faecium tested were susceptible to linezolid and only one isolate of E. faecalis was resistant (equates to 0.2% resistance). This isolate had a zone diameter of 20 mm, being only 1 mm below the NCCLS breakpoint.13 Only 0.8% of enterococci had an intermediate result for linezolid, all were E. faecalis strains. The range of linezolid MICs among the enterococci was 0.54 mg/L (MIC90 2 mg/L; Table 2).
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Discussion |
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Enterococci were largely susceptible as well, although a few strains of enterococci fell into the intermediate range. This was not unexpected and was understood at the time that the NCCLS breakpoints for enterococci were established.13
The study provides a valuable baseline for linezolid for the Western Pacific region before its clinical usage. It confirms the potency of linezolid against the major community and nosocomial Gram-positive pathogens, including activity against strains that have become resistant to other oral or parenteral agents. Oxacillin-resistant S. aureus is a particular problem in many countries in the Western Pacific region,1 and the availability of an agent that can be administered for serious infections to in-patients, or for ongoing outpatient therapy orally, represents a major advance in the management of infections caused by this pathogen and glycopeptide refractory species.4,5,9
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Acknowledgements |
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Footnotes |
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ZAPS Western Pacific Regional Participants are listed in the Acknowledgements.
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References |
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