JAC Advance Access originally published online on December 2, 2005
Journal of Antimicrobial Chemotherapy 2006 57(2):279-287; doi:10.1093/jac/dki437
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Oxazolidinone susceptibility patterns in 2004: report from the Zyvox® Annual Appraisal of Potency and Spectrum (ZAAPS) Program assessing isolates from 16 nations
1 JMI Laboratories, Inc., 345 Beaver Kreek Centre, Suite A, North Liberty, IA 52317, USA; 2 Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA
* Corresponding author. Tel: +1-319-665-3370; Fax: +1-319-665-3371; E-mail: ronald-jones{at}jmilabs.com
Received 8 September 2005; returned 27 October 2005; revised 3 November 2005; accepted 6 November 2005
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Objectives: To investigate the activity of linezolid (an oxazolidinone), a potent choice for community- and hospital-acquired infections, via a worldwide surveillance network called the Zyvox® Annual Appraisal of Potency and Spectrum (ZAAPS) Program.
Methods: A total of 4098 Gram-positive strains were collected from 42 laboratories located in North America (five sites in Canada), South America (10 sites), Europe (16 sites) and the Far East (11 sites). Each country or site submitted 200 isolates (Canada submitted 200 isolates for each of five sites; total 1000) for confirmation of organism identification and reference MIC processing. Nearly 25 comparator agents were tested along with quality control strains, and interpretative criteria from the CLSI, formerly the NCCLS, M100-S15 were applied. No linezolid resistance was detected in strains from 16 monitored countries in 2004.
Results: Linezolid remained highly active against Streptococcus pneumoniae, viridans group and ß-haemolytic streptococci (MIC90, 1 mg/L). Against Staphylococcus aureus, linezolid showed 99.5% of results at 0.5–2 mg/L with only one isolate at 4 mg/L. Oxacillin-resistant S. aureus rates varied between nations and ranged from 1.4% in Sweden to 29.5% in the UK to 65.2% in Mexico. Linezolid MIC values were generally one log2 dilution step lower for coagulase-negative staphylococci (CoNS) when compared with S. aureus. No CoNS strains produced a linezolid result at 4 mg/L. Compared with ZAAPS 2002 and 2003 results for enterococci where seven resistant strains were identified, the 2004 data revealed no resistance and 98.1% of linezolid MIC results were at 1 or 2 mg/L. Vancomycin-resistant enterococci (5.3% overall) varied markedly by country including a high of 47.2% in Korea.
Conclusions: Linezolid continues to be effective in vitro against Gram-positive pathogens from five continents and no oxazolidinone-resistant strains were identified among the 4098 systemically collected strains (2004) or among 20 158 non-United States isolates for the entire ZAAPS Program (2002–04).
Keywords: linezolid , MRSA , VRE , surveillance
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Introduction |
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Linezolid was the first clinically applied oxazolidinone and has become a welcome addition to those agents used to treat infections caused by antimicrobial-resistant Gram-positive cocci.1–6 Treatment success has been reported for a wide range of serious clinical infections including endocarditis,7 meningitis,8 complicated skin and soft tissue infections (cSSTI),9 for nosocomial pneumonias caused by oxacillin-resistant and methicillin-resistant Staphylococcus aureus (MRSA),10 and in the compassionate-use trials against multidrug-resistant Gram-positive pathogens.11 These observations have been supported by favourable pharmacokinetic (PK)/pharmacodynamic studies among patients with SSTI12 and in the compassionate-use population PK analyses,13 as well as in the model of catheter-related bloodstream infection.14 However, resistance to linezolid has been observed, particularly among S. aureus and enterococci,15–19 but the occurrence rates have been classified as rare16,17,20 and usually have been associated with prolonged therapy, indwelling device infections and high-use in the clinical setting.16,21,22 Some oxazolidinone-resistant strains have emerged in patients without prior drug exposure, each event attributed to clonal spread of strains from other exposed patients in the hospital environment.23–25
The mechanism of oxazolidinone action has been suggested to be inhibition of protein synthesis by the binding to domain V of 23S rRNA.5,26,27 Modifications of the target have been widely described,15,16,20,28,29 the level of resistance (MICs at 
8 mg/L) noted to be associated with ‘gene dosage’,30 and the mutation may or may not be stable.26,31 More recently, Wolter et al.32 described linezolid resistance mediated by a 6 bp deletion in the gene encoding riboprotein L4 of two Streptococcus pneumoniae clinical strains. These resistance patterns have most often been described in the United States,16,20,32 but some isolates have been detected in Europe33 and the Far East.34
As linezolid use increases, both in the current prescription environment and geographically into new areas, the need for activity and resistance rate monitoring also becomes critical. In vitro studies of linezolid activity (ZAPS protocols) before release by the USA-Food and Drug Administration (USA-FDA) indicated that an excellent spectrum of activity could be expected against Gram-positive pathogens isolated in North America (23 261 strains), Latin America (2640 strains), Europe (5598 strains) and the Western Pacific (2143 strains).34–38 The occurrence of linezolid-resistant isolates in the ZAPS international studies was extremely rare (one case in the Western Pacific region) and when local laboratories detected linezolid resistance by MIC or disc diffusion methods, the local test method result was found to be erroneous by follow-up procedures performed in reference laboratories.34 Recently, the College of American Pathologists Surveys Program utilized a MRSA strain as an unknown challenge, an organism that also had an elevated linezolid MIC (>8 mg/L, e.g. resistant).39 In the USA, only 299 of 2427 laboratories (12.3%) reporting susceptibility results actually tested and reported linezolid information.39 Most disturbing was the fact that 18.7–18.9% of MIC and disc diffusion method users incorrectly categorized this strain as linezolid-susceptible. These cited data and the potential for continuing increases in oxazolidinone resistance in nations where the drug (linezolid) has been introduced, requires well constructed and executed resistance surveillance protocols [ZAPS and the Zyvox® Annual Appraisal of Potency and Spectrum (ZAAPS) Programs] using reference MIC methods to assure accuracy of the findings, in contrast to using potentially-flawed networks that rely totally on results derived from rapid, commercial systems.6,40,41
This report summarizes the results of the 2004 ZAAPS Program for 16 nations (Table 1). These data were compared with the ZAAPS Program findings for 2002–03,40,41 when the USA was a contributing nation. All tests were performed in a good laboratory practices (GLP) reference laboratory using CLSI, formerly the NCCLS, broth microdilution methods and recently published interpretive criteria.42,43
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Materials and methods |
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Study design
The central monitoring site (JMI Laboratories, North Liberty, IA, USA) collected a total of 4098 isolates for the 2004 ZAAPS Program from sites in Latin America (4 nations/10 sites), Europe (6 nations/16 sites), the Far East (5 nations/11 sites) and North America (Canada only/5 sites; see Table 1). Each participating site or country forwarded a target total of 200 consecutive, non-duplicate patient isolates originating from patients having infections of the bloodstream, respiratory tract, urinary tract or wounds/skin and soft tissue.
Organisms tested
The collection included S. aureus (1422 isolates), S. pneumoniae (796 isolates), coagulase-negative staphylococci (CoNS; 652 isolates), enterococci (719 isolates), ß-haemolytic streptococci (313 isolates) and viridans group streptococci (196 isolates). This represented a compliance rate of >100% (target number was 4000 strains). All isolates were identified by the submitting laboratory and confirmed by the central monitor using standard biochemical algorithms and/or commercial methods (Vitek System; bioMerieux, Hazelwood, MO, USA). The results for the 2004 ZAAPS Program were similar to the numbers tested for the year 2002–03 ZAAPS Program excluding the USA, for a total of 20 158 Gram-positive cocci processed during the first 3 years of the ZAAPS oxazolidinone resistance surveillance Program.40,41
Susceptibility test methods
Antimicrobial susceptibility testing was performed on all isolates using the reference broth microdilution method as described in the CLSI/NCCLS documents (2003 and 2005). The validated, dry-form microdilution panels and cation-adjusted Mueller–Hinton broth (with 2–5% lysed horse blood added for testing of streptococci) were prepared by and/or purchased from TREK Diagnostics (Cleveland, OH, USA). Interpretations of quantitative MIC results and quality control strains (S. aureus ATCC 29213, Enterococcus faecalis ATCC 29212 and S. pneumoniae ATCC 49619) were in accordance with the CLSI tables42 and previously published control criteria by our group.44
All isolates were tested against antimicrobial agents active against Gram-positive organisms, including (but not limited to) linezolid, amoxicillin/clavulanic acid, ampicillin, cefepime, ceftriaxone, chloramphenicol, ciprofloxacin, clindamycin, erythromycin, gentamicin, levofloxacin, oxacillin, penicillin, quinupristin/dalfopristin, rifampicin, streptomycin, teicoplanin, tetracycline, trimethoprim/sulfamethoxazole and vancomycin (Table 2).
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Activity of linezolid against S. aureus
A total of 1422 S. aureus strains were tested by reference methods with sample sizes varying from 49 (France) to 257 (Canada) isolates per country (Tables 1 and 2). MRSA rates were quite different between nations and continents (data not shown). Examples of differences within a continent or region are as follows: for Europe MRSA ranged from 1.4–7.1% (Sweden and Germany) to 29.5–30.0% (UK and Italy); for Latin America MRSA rates were more uniformly high at 32.6–65.2% (highest in Mexico); for the Far East the MRSA rate in Australia was lower (17.1%) compared with the other four monitored nations (40.0–75.0%); and finally, Canada had a modest MRSA occurrence rate of only 14.0%.
The linezolid results for S. aureus showed a narrow distribution of MIC values across all regions and nations with 99.5% of results at 0.5–2 mg/L (Table 3). All regional results were combined to compare linezolid activity with other tested agents (Table 2). The MIC50 and MIC90 of linezolid for all monitored isolates was 2 mg/L. This was also true for every country except Italy where the MIC50 was 1 mg/L. Only one isolate was observed to have a reproducible linezolid MIC at 4 mg/L (at breakpoint concentration). These results are unchanged from ZAAPS Program reports in 2002 and 2003 for non-USA S. aureus strains.40,41 In fact, earlier reports (2002) documented one occurrence each of a linezolid-resistant S. aureus and CoNS, both USA isolates. Also the modal linezolid MIC (2 mg/L; 1042 of 1422 results) remains unchanged and the percentages of strains with a linezolid MIC at 4 mg/L has remained stable or decreasing (0.53, 0.87 and 0.07% for 2002, 2003 and 2004, respectively).
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Activity of linezolid against CoNS
Among the 652 isolates of CoNS tested, the variations in resistance rates to the listed drugs and from earlier reports were minimal. Examples include the oxacillin resistance (OR) rates that only varied from 63.2 (Sweden) to 93.2% (Italy), but 14 of the 16 countries had OR rates between 71.1 and 85.0% (average, 77.5%). This compares favourably with the USA (prior years data) and Canada (76.9% in this report; data not shown).
Linezolid MIC values were generally one log2 dilution step lower for CoNS when compared with the S. aureus results (Tables 2 and 3). The linezolid modal MIC, MIC50 and MIC90 for CoNS was 1 mg/L with a range of only 0.25–2 mg/L. These results were characteristic for all countries (results combined for comparisons; Table 2) except Sweden, UK and Korea where the MIC90 was slightly higher at 2 mg/L. Like vancomycin, linezolid was active against all staphylococci at 
4 mg/L. Teicoplanin was less active against CoNS with 0.5% of isolates being frankly resistant (MIC, >16 mg/L; Table 2).
Activity of linezolid against enterococci
A total of 719 enterococci were tested against linezolid and numerous other antimicrobials (Table 2). Among these isolates, E. faecalis (486 strains) and E. faecium (164 strains) predominated, accounting for 90.4% of strains tested. Vancomycin resistance (VRE) overall was only 5.3% (includes intermediate category), but the rates by nation were not uniform (data not shown). Chile, Mexico, Germany, Spain, Sweden, Australia, Hong Kong and Taiwan did not have any VRE isolates identified during the monitored interval. In contrast, moderate rates of VRE occurrence were detected in Canada (3.0%), Argentina (5.0%), Brazil (3.6%), France (6.7%; all intermediate), Italy (14.3%), UK (9.5%) and Japan (4.4%). The VRE rate was 47.2% in Korea, the highest rate ever recorded for a national sample in the ZAPS or ZAAPS Programs.40,41
Although VRE appears to be endemic/epidemic in several nations and compromises treatment, linezolid resistance was not observed. Linezolid modal MIC, MIC50 and MIC90 results were 2 mg/L (Table 2). The range of linezolid MIC values reported was only 0.5–2 mg/L with 98.1% of MIC results at either 1 or 2 mg/L. Five national samples of enterococci had an MIC50 result that varied from the all-nation average by being one log2 dilution lower at 1 mg/L (Mexico, Italy, Spain, Australia and Korea). All prior linezolid-resistant enterococci (seven strains) documented by the ZAAPS Program were detected in the USA (2002–03).40,41 No change in the linezolid MIC distribution was found when comparing these 2004 results with previously reported survey years.
Teicoplanin (95.8% susceptible) results compared with vancomycin susceptibility data indicate that 20.8% of VRE were of the VanB resistance phenotype. Only 76.8 and 78.6% of strains were susceptible to ampicillin and chloramphenicol, respectively.40,41 High-level aminoglycoside resistance was consistently >30%.
Activity of linezolid against S. pneumoniae
The combined, all-region population of pneumococci (796 strains) had overall penicillin and erythromycin resistance rates of 22.6 and 41.0%, respectively (Table 2). These rates, however, varied greatly between nations. The highest penicillin resistance (2 mg/L) rates were observed in the Far East (Hong Kong at 52.3%, Japan at 34.9%, Korea at 62.9% and Taiwan at 64.4%) and in France at 30.0%. The lowest penicillin resistance rates were found in Canada (5.5%), Argentina (7.3%), Italy (4.9%), Sweden (4.0%) and the UK (4.3%). Similarly, macrolide resistance has markedly escalated for some participating nations in the ZAAPS Program (overall resistance rate at 41.0% for erythromycin). The countries with the highest erythromycin resistance rates were Taiwan (91.1%) > Japan (77.1%) > Korea (75.7%) > Hong Kong (72.7%) > France (55.0%) > Spain (51.5%) > Italy (51.5%). The fluoroquinolones (0.6–1.6% resistant), ceftriaxone (0.3% resistant), cefepime (0.3% resistant), quinupristin/dalfopristin (0.0% resistant), rifampicin (0.1% resistant) and vancomycin (0.0% resistant) remained very active against this international collection of S. pneumoniae.
Linezolid activity versus S. pneumoniae was excellent (Table 2). The clear modal MIC was 1 mg/L and this value was also the MIC50 and MIC90. For this distribution of linezolid MIC values, 98.5% of results were at 0.5 or 1 mg/L. No significant variation in linezolid potency was noted between countries, and these results were unchanged from the 2002 and 2003 ZAAPS reports.40,41 The glycopeptides, quinupristin/dalfopristin, rifampicin, gatifloxacin and levofloxacin all inhibited 98.4% of strains at current CLSI breakpoints.42
A smaller sample of viridans group streptococci (196 strains) was tested and the results for linezolid and comparison drugs are found in Table 2. These 
-haemolytic species had an overall penicillin-resistant (MIC 4 mg/L) rate of 5.1% and a non-susceptibility rate of 31.1%. Many countries had smaller samples because of fewer cases of bacteraemias with these species, however, among those nations with 10 isolates collected, the penicillin resistance rates varied from 0.0% (Germany, Sweden and Japan) to 15.8–18.2% (France and Taiwan; data not shown).
Linezolid was very active against viridans group streptococci with an overall MIC mode, MIC50 and MIC90 of 1 mg/L. Again, a narrow range of oxazolidinone MIC values was observed (0.12–2 mg/L), with 94.4% of MIC values at 0.5 or 1 mg/L. No variation from this pattern of linezolid activity was detected in any monitored nation. In 2002, a single linezolid-resistant S. oralis was found (USA isolate) with a high MIC (>8 mg/L) and a documented G2576U 23S rRNA mutation. No other linezolid-resistant streptococci have been discovered in the 2003 or 2004 ZAAPS samples.40,41
Table 2 lists the activity of linezolid and comparators tested against 313 isolates of ß-haemolytic Streptococcus spp. The dominant serotypes were group A (S. pyogenes, 170 strains) and group B (S. agalactiae, 102 strains) that accounted for 86.9% of tested isolates. Penicillin remained active against all strains, but macrolide resistance was observed in 22.7% of the organisms. Where national samples consisted of 10 strains, the resistance rates for erythromycin varied from 5.9% (Germany) to 41.0% (Spain). The countries with macrolide resistance at 20.0% were as follows: Canada, 22.7%; France, 25.0%; Spain, 41.0%; Korea, 20.0%; and Taiwan, 29.6% (data not shown).
Linezolid activity against ß-haemolytic streptococci was similar to that described earlier for S. pneumoniae, viridans group streptococci and CoNS (MIC50 and MIC90, 1 mg/L; Table 2). None of the national samples varied from the all-linezolid activity results. The range of linezolid MIC values against ß-haemolytic streptococci was 0.25–2 mg/L, and 98.4% of MIC results were either 0.5 or 1 mg/L (86.3% at 1 mg/L). No variation in linezolid activity was observed within this 2004 sample compared with prior years (2002 or 2003) potencies against this organism group.40,41
Activity of linezolid against all monitored Gram-positive organisms
Across six groups of Gram-positive pathogens isolated in 16 nations (not USA), the linezolid activity remains stable and without significant occurrence of strains with MICs of 4 mg/L (Table 3). The limited range of linezolid MIC values (Figure 1) for each organism group was also unchanged from earlier reports from ZAPS34–38 and ZAAPS (2002 and 2003),40,41 thus indicating no significant ‘creep’ in the MIC results for the wild-type, susceptible Gram-positive organism population.
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Discussion |
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Linezolid, as the initial clinically used member of the oxazolidinone class, has demonstrated in vitro activity against a wide range of Gram-positive organisms,2,17,45–48 specifically including multidrug-resistant isolates like MRSA,49 strains with genetic resistances to protein synthesis inhibitors,50 isolates from bite wound infections51 and penicillin-resistant S. pneumoniae.52 More contemporary study results have documented linezolid PAE at 1.8–3.0 h for staphylococci, enterococci and pneumococci; and that antimicrobial combinations generally had an indifferent action with synergy or antagonism being a rare occurrence.53,54 Other in vitro studies of linezolid combinations indicate that fusidic acid, gentamicin or rifampicin used as co-drugs prevented selection of oxazolidinone-resistant mutants55 in MRSA strains, but slight antagonism was observed when combined with vancomycin and ciprofloxacin in the rabbit endocarditis model.56 The choice of linezolid and imipenem proved to be synergistic and bactericidal against MRSA in vitro and in the rabbit endocarditis model,57 illustrating that prudent choices of linezolid combinations can produce favourable or superior results to linezolid used alone in vivo against methicillin-susceptible S. aureus.7,58
The value of linezolid to address serious emerging resistances among Gram-positive cocci has been well documented3 and can facilitate the action plans promulgated by the EU,59 WHO60 and individual nations for limiting resistance occurrences. Antimicrobial resistance problems where linezolid appears therapeutically suited continue to be severe MRSA infections (pneumonias and cSSTI),9,10,61 enterococci resistant to glycopeptides or quinupristin/dalfopristin,62 multidrug-resistant or fluoroquinolone-resistant S. pneumoniae,63 and glycopeptide-intermediate or -resistant staphylococci.64,65 These positive features must be balanced against the safety profile of this oxazolidinone66,67 and the possibility of emerging linezolid resistance. The most concerning linezolid adverse event has been optical or peripheral neuropathy and the cytopenias,68 however, the latter can be reversed with the use of vitamin B6,69 a regimen needing further investigation.
The threat of emerging linezolid resistance on chemotherapy (prolonged) has become very real,16,20 especially in the USA. Although rare or undetected outside the USA, following introduction into various nations, linezolid-resistant strains (usually enterococci) have been isolated.33 This indicates the need for continued resistance surveillance for linezolid on the global or national levels via ZAAPS Program protocols and by local, hospital-based antibiograms.40,41 Past experience with the ZAPS Program34–38 would dictate a possibility of false-resistant linezolid MIC values secondary to so called ‘trailing MIC endpoints’, but the recent experience of the CAP Microbiology Surveys Program (2005) where false-susceptible linezolid results were reported by a significant number of medical centres and also the limited reporting of linezolid results to the local medical staff members, was not anticipated. Clearly more attention must be directed to accurately assess newer agents and classes of antimicrobials (oxazolidinones) in the intervals immediately before, and after approvals by national or regional regulatory authorities (USA-FDA, etc.). These studies for linezolid represented by the ZAAPS Program (2004) exhibit the sustained value of this new oxazolidinone as monitored by accurate reference methods and resistance rates that continue to be well below 1% overall.
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No declarations were made by the authors of this paper.
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Acknowledgements |
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This Program was sponsored by an educational/research grant from Pfizer, Inc. The co-authors acknowledge the excellent contributions of the following individuals at JMI Laboratories for their technical skills and assistance in preparation of this manuscript: K. L. Meyer and M. G. Stilwell. The co-authors would also like to acknowledge the dedicated participation from the following ZAAPS sites: University of Alberta Hospitals (Edmonton, Alberta, Canada); Health Sciences Centre (Winnipeg, Manitoba, Canada); Queen Elizabeth II Health Sciences Centre (Halifax, Nova Scotia, Canada); Ottawa Hospital, General Campus (Ottawa, Ontario, Canada); Vancouver Hospital and Health Sciences Centre (Vancouver, British Columbia, Canada); Microbiology Laboratory C.E.M.I.C. (Buenos Aires, Argentina); Sanatorio Parque-Rosario (Buenos Aires, Argentina); Laboratorio Medico Santa Luzia (Florianopolis, Brazil); Hospital Sao Paulo (Sao Paulo, Brazil); Hospital de Clinicas de Porto Alegre (Porto Alegre, Brazil); Hospital de Base do Distrito Federal (Brasilia-DF, Brazil); Catholic University Hospital (Macul Santiago, Chile); Universidad de Chile (Santiago, Chile); Instituto Nacional de la Nutricion Salvador Z (Mexico City, Mexico); Instituto de Pathologia Infecciosa (Guadalajara, Mexico); A. Calmette Hospital (Lille Cedex, France); Hospital Edouard Herriot (Lyon, France); Hospital Henri Mondor (Creteil Cedex, France); Hospital Cote de Nacre (Cedex, France); Centre Hospitalier Regional de Metz (Metz, France); University of Leipzig School of Medicine (Leipzig, Germany); Labor Dres Ballies (Kiel, Germany); San Martino-Instituto Di Microbiologia (Genoa, Italy); Azienda Policlinico Universita di Catania (Catania, Italy); Policlinico Agostino Gemelli (Roma, Italy); University Hospital V. de Marcarena (Seville, Spain); Hospital Ramon y Cajal (Madrid, Spain); University Hospital (Linkoping, Sweden); Central Hospital (Vaxjo, Sweden); Guy's, Kings and St Thomas' School of Medicine (London, UK); Southmead Hospital (Bristol, UK); Institute of Medical and Veterinary Science (Adelaide, Australia); Princess Alexandra Hospital (Woolloongabba, Australia); Royal Perth Hospital (Perth, Australia); Women's and Children's Hospital (North Adelaide, Australia); Queen Mary Hospital (Hong Kong); Teikyo University School of Medicine (Tokyo, Japan); Nagasaki University School of Medicine (Nagasaki, Japan); Kitasato University School of Medicine (Kanagawa, Japan); SungKyunKwan University School of Medicine (Seoul, Korea); Yonsei University College of Medicine (Seoul, Korea); National Taiwan University Hospital (Taipei, Taiwan).
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