Abstract
Linezolid showed MIC50s and MIC90s of 1 μg/ml (for both) against Staphylococcus aureus. Two S. aureus strains exhibited higher MICs (4 to 8 μg/ml) caused by cfr and/or target site mutations, including the first detection of cfr in Poland. Linezolid (MIC50 and MIC90, 0.5 and 1 μg/ml) had potent MICs against coagulase-negative staphylococci (CoNS). Four CoNS had MICs of 16 to 128 μg/ml due to alterations in 23S rRNA and/or L3/L4. Linezolid inhibited all enterococci and streptococci at ≤2 μg/ml, except for one Enterococcus faecium strain (MIC, 8 μg/ml; G2576T [Escherichia coli numbering] mutation).
TEXT
The oxazolidinone linezolid has been clinically available for nearly 15 years (approved by the Food and Drug Administration in April 2000) and has become an important agent in the antimicrobial armamentarium against Gram-positive organisms. Linezolid represents one of the few options approved by the regulatory agencies for treatment of infections caused by vancomycin-resistant Enterococcus faecium and Enterococcus faecalis and is the only orally developed alternative (1, 2). Other approved indications for linezolid are the treatment of nosocomial and community-acquired pneumonia and uncomplicated and complicated (including diabetic foot infections) skin and skin-structure infections (1).
The spectrum and activity of linezolid has been monitored through the Linezolid Experience and Accurate Determination of Resistance (LEADER) Program (United States) and the Zyvox Annual Appraisal of Potency and Spectrum (ZAAPS) Program (ex-U.S.) as postmarketing surveillance studies (3, 4). These programs have demonstrated consistent activity of linezolid against targeted Gram-positive isolates worldwide and have also assisted in detecting isolates with elevated MICs, as well as newer and emergent (i.e., cfr) resistance mechanisms and outbreaks (5, 6). In this ZAAPS (ex-U.S.) study, we report the in vitro activity and spectrum of linezolid (and comparator agents) by applying centralized testing using the broth microdilution method against 7,967 isolates collected in 2013. Moreover, this report provides molecular characterization for associated resistance mechanisms and epidemiological typing.
This investigation included Gram-positive strains collected from 73 medical centers on five continents (33 countries). Isolates included in this study originated from the following countries (number of medical sites): in North America, Canada (2) and Mexico (2); in South America, Argentina (2), Brazil (4), and Chile (2); in Europe and surrounding countries, Belgium (1), Czech Republic (1), France (2), Germany (6), Greece (1), Hungary (1), Ireland (2), Israel (1), Italy (4), Poland (1), Portugal (1), Russia (3), Slovenia (1), Spain (3), Sweden (2), Turkey (2), Ukraine (1), and United Kingdom (3); in the Asia-Pacific (APAC) region, Australia (6), China (8), Hong Kong (1), Japan (2), South Korea (2), Malaysia (1), New Zealand (2), Singapore (1), Taiwan (1), and Thailand (1).
Participating centers selected consecutive unique isolates associated with documented infections (per local guidelines) in hospitalized patients. These isolates were recovered mostly from blood (25.2%), wound (33.3%), and lower respiratory tract (22.5%) specimens. Overall, each site submitted 250 to 500 isolates to reach a minimum target of 200 Gram-positive organisms per country except for China (600) and Japan (400). JMI Laboratories (North Liberty, IA, USA) and Women's and Children's Hospital (Adelaide, Australia), which processed isolates from Australia and New Zealand only, confirmed organism identification and performed MIC testing. Isolates were primarily identified by the participating laboratory, and identifications were confirmed by the monitoring laboratory (JMI Laboratories or Women's and Children's Hospital) by standard algorithms and matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS; Bruker Daltonics, Bremen, Germany).
Isolates were tested for susceptibility by broth microdilution following Clinical and Laboratory Standards Institute (CLSI) document M07-A9 (7). MIC testing was performed using panels manufactured by Thermo Fisher Scientific (Cleveland, OH, USA) containing cation-adjusted Mueller-Hinton broth (2.5 to 5% lysed horse blood added for testing streptococci). Bacterial inoculum density was monitored by colony counts to ensure an adequate number of cells for each testing event. Validation of the MICs was performed by concurrent testing of CLSI-recommended quality control reference strains (Staphylococcus aureus ATCC 29213, E. faecalis ATCC 29212, and Streptococcus pneumoniae ATCC 49619) (8). MIC interpretations were based on the CLSI M100-S24 (2014) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoint criteria (8, 9). Isolates processed by JMI Laboratories or Women's and Children's Hospital with linezolid MICs at ≥4 μg/ml were submitted for additional testing using customized frozen-form broth microdilution panels for MIC confirmation, molecular characterization of resistance mechanisms, and epidemiological typing, as previously described (10–12).
Linezolid had MIC50s of 1 or 0.5 μg/ml when tested against a collection of S. aureus strains and other staphylococcal species (coagulase-negative staphylococci [CoNS]), respectively, regardless of the methicillin resistance phenotype (Tables 1 and 2). Staphylococcal isolates displaying higher linezolid MICs (4 to 128 μg/ml) carried either cfr (S. aureus) or mutations in the 23S rRNA (other species) (Table 3), as well as amino acid alterations in ribosomal protein L3 or L4. Linezolid in vitro potency against MRSA (>99.9% susceptible) was comparable to those observed for teicoplanin, vancomycin, and trimethoprim-sulfamethoxazole (TMP-SMX), with an overall activity of ≥95.8% (Table 2). However, the TMP-SMX susceptibility rates varied from 97.6 to 100.0% among MRSA from Europe, South America, and North America, while a lower percentage (92.9%) of isolates from the APAC region were susceptible (data not shown). These variations in TMP-SMX susceptibility are likely due to the higher prevalence of MRSA ST239 in the APAC region, which is usually resistant to this combination (13, 14). Linezolid (MIC50 and MIC90, 0.5 and 1 μg/ml) was 2-fold more active than vancomycin (MIC50 and MIC90, 1 and 2 μg/ml) against CoNS, while other agents had limited coverage (Table 2).
TABLE 1.
Linezolid MIC distributions when tested against species and groups of Gram-positive cocci isolated from five continents
| Organism (no. tested)a | Number (cumulative %) of isolates inhibited at linezolid MIC (μg/ml) of: |
MIC (μg/ml) |
||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| ≤0.12 | 0.25 | 0.5 | 1 | 2 | 4 | 8 | >8 | 50% | 90% | |
| S. aureus (3,885) | 3 (0.1) | 13 (0.4) | 597 (15.8) | 2,923 (91.0) | 347 (99.9) | 1 (>99.9) | 1 (100.0) | 1 | 1 | |
| Oxacillin susceptible (2,674) | 1 (0.0) | 6 (0.3) | 339 (12.9) | 2,074 (90.5) | 254 (100.0) | 1 | 1 | |||
| Oxacillin resistant (1,211) | 2 (0.2) | 7 (0.7) | 258 (22.0) | 849 (92.2) | 93 (99.8) | 1 (99.9) | 1 (100.0) | 1 | 1 | |
| CoNSb (1,045) | 1 (0.1) | 135 (13.0) | 720 (81.9) | 184 (99.5) | 1 (99.6) | 0 (99.6) | 0 (99.6) | 4c (100.0) | 0.5 | 1 |
| Enterococcus spp. (757) | 0 (0.0) | 3 (0.4) | 126 (17.0) | 577 (93.3) | 50 (99.9) | 0 (99.9) | 1 (100.0) | 1 | 1 | |
| E. faecalis (434) | 0 (0.0) | 3 (0.7) | 58 (14.1) | 336 (91.5) | 37 (100.0) | 1 | 1 | |||
| E. faecium (299) | 0 (0.0) | 0 (0.0) | 63 (21.1) | 223 (95.7) | 12 (99.7) | 0 (99.7) | 1 (100.0) | 1 | 1 | |
| VRE (106) | 0 (0.0) | 0 (0.0) | 27 (25.5) | 77 (98.1) | 1 (99.1) | 0 (99.1) | 1 (100.0) | 1 | 1 | |
| S. pneumoniae (1,144) | 1 (0.1) | 21 (1.9) | 436 (40.0) | 666 (98.3) | 20 (100.0) | 1 | 1 | |||
| VGS (518) | 7 (1.4) | 35 (8.1) | 250 (56.4) | 223 (99.4) | 3 (100.0) | 0.5 | 1 | |||
| BHS (618) | 0 (0.0) | 2 (0.3) | 210 (34.3) | 406 (100.0) | 1 | 1 | ||||
CoNS, coagulase-negative staphylococci; VRE, vancomycin-resistant enterococci; VGS, viridans group streptococci; BHS, beta-hemolytic streptococci. Four vancomycin-resistant E. faecalis strains were observed, which had linezolid MICs of 0.5 to 1 µg/ml.
78.7% of isolates were methicillin-resistant. Linezolid MIC50s and MIC90s were 0.5 and 1 μg/ml, respectively, against both methicillin-susceptible and -resistant groups.
MICs between 16 and 128 μg/ml (Table 3).
TABLE 2.
Comparative activity of linezolid tested against Gram-positive cocci from 33 nations in the ZAAPS Program (2013)
| Organism (no. tested) and antimicrobial agentb | MIC (μg/ml) |
% susceptible/resistanta |
||
|---|---|---|---|---|
| 50% | 90% | CLSI | EUCAST | |
| MRSA (1,211) | ||||
| Linezolid | 1 | 1 | 99.9/0.1 | 99.9/0.1 |
| Clindamycin | ≤0.25 | >2 | 55.0/44.9 | 54.7/45.0 |
| Erythromycin | >16 | >16 | 26.0/69.0 | 26.5/71.8 |
| Gentamicin | ≤1 | >8 | 64.0/35.4 | 62.5/37.5 |
| Levofloxacin | >4 | >4 | 21.5/77.9 | 21.5/77.9 |
| Tetracycline | ≤0.25 | >32 | 68.9/29.3 | 68.0/31.5 |
| TMP-SMX | ≤0.5 | ≤0.5 | 95.8/4.2 | 95.8/4.1 |
| Teicoplanin | ≤2 | ≤2 | 99.9/0.0 | 98.3/1.7 |
| Vancomycin | 1 | 1 | 100.0/0.0 | 100.0/0.0 |
| MSSA (2,674) | ||||
| Linezolid | 1 | 1 | 100.0/0.0 | 100.0/0.0 |
| Clindamycin | ≤0.25 | ≤0.25 | 96.2/3.6 | 96.0/3.8 |
| Erythromycin | 0.25 | >16 | 83.7/14.5 | 83.8/15.7 |
| Gentamicin | ≤1 | ≤1 | 96.5/3.1 | 95.8/4.2 |
| Levofloxacin | 0.25 | 0.25 | 95.8/3.9 | 95.8/3.9 |
| Tetracycline | 0.25 | 0.25 | 92.4/7.0 | 92.1/7.7 |
| TMP-SMX | ≤0.5 | ≤0.5 | 99.6/0.4 | 99.6/0.3 |
| Teicoplanin | ≤2 | ≤2 | 100.0/0.0 | >99.9/<0.1 |
| Vancomycin | 1 | 1 | 100.0/0.0 | 100.0/0.0 |
| CoNSc (1,045) | ||||
| Linezolid | 0.5 | 1 | 99.6/0.4 | 99.6/0.4 |
| Oxacillin | >2 | >2 | 21.3/78.7 | 21.3/78.7 |
| Clindamycin | ≤0.25 | >2 | 68.6/30.4 | 67.3/31.4 |
| Erythromycin | >16 | >16 | 35.7/63.0 | 35.8/63.6 |
| Gentamicin | ≤1 | >8 | 58.1/36.5 | 50.8/49.2 |
| Levofloxacin | 1 | >4 | 58.1/34.1 | 52.3/47.7 |
| Tetracycline | 0.5 | 32 | 83.5/14.7 | 78.5/17.7 |
| TMP-SMX | ≤0.5 | >4 | 67.8/32.2 | 67.8/15.8 |
| Teicoplanin | ≤2 | 8 | 96.5/0.4 | 84.1/15.9 |
| Vancomycin | 1 | 2 | 100.0/0.0 | 100.0/0.0 |
| E. faecalis (434) | ||||
| Linezolid | 1 | 1 | 100.0/0.0 | 100.0/0.0 |
| Ampicillin | 1 | 2 | 100.0/0.0 | 100.0/0.0 |
| Erythromycin | >16 | >16 | 6.5/56.5 | —/— |
| Levofloxacin | 1 | >4 | 71.0/28.3 | 71.0/28.3 |
| Vancomycin | 1 | 2 | 99.1/0.7 | 99.1/0.9 |
| Teicoplanin | ≤2 | ≤2 | 99.3/0.7 | 99.3/0.7 |
| Daptomycin | 1 | 2 | 100.0/— | —/— |
| E. faecium (299) | ||||
| Linezolid | 1 | 1 | 99.7/0.3 | 99.7/0.3 |
| Ampicillin | >8 | >8 | 7.0/93.0 | 6.0/93.0 |
| Erythromycin | >16 | >16 | 4.3/86.3 | —/— |
| Levofloxacin | >4 | >4 | 5.0/92.0 | 8.0/92.0 |
| Vancomycin | 1 | >16 | 64.5/34.8 | 64.5/35.5 |
| Teicoplanin | ≤2 | >16 | 69.9/25.1 | 69.2/30.8 |
| Daptomycin | 2 | 2 | 100.0/— | —/— |
| S. pneumoniae (1,144) | ||||
| Linezolid | 1 | 1 | 100.0/— | 100.0/0.0 |
| Amoxicillin-clavulanate | ≤1 | 8 | 85.8/10.4 | —/— |
| Ceftriaxone | ≤0.06 | 2 | 88.0/3.2 | 75.3/3.2 |
| Clindamycin | ≤0.25 | >2 | 68.4/31.2 | 68.8/31.2 |
| Erythromycin | ≤0.12 | >16 | 58.5/41.1 | 58.5/41.1 |
| Levofloxacin | 1 | 1 | 98.4/1.4 | 98.4/1.6 |
| Penicillin | ≤0.06 | 4 | 59.7 (88.8)/21.2 (1.5)d | 59.7/11.2 |
| Tetracycline | 0.25 | >32 | 61.0/38.2 | 61.0/38.2 |
| TMP-SMX | ≤0.5 | >4 | 59.5/31.7 | 64.8/31.7 |
| Vancomycin | 0.25 | 0.5 | 100.0/— | 100.0/0.0 |
| Viridans group streptococcie (518) | ||||
| Linezolid | 0.5 | 1 | 100.0/— | —/— |
| Ceftriaxone | 0.25 | 1 | 92.1/4.6 | 88.4/11.6 |
| Clindamycin | ≤0.25 | >2 | 85.3/13.7 | 86.3/13.7 |
| Erythromycin | ≤0.12 | >16 | 57.9/39.6 | —/— |
| Levofloxacin | 1 | 2 | 93.8/5.8 | —/— |
| Penicillin | ≤0.06 | 1 | 73.7/4.8 | 81.3/4.8 |
| Tetracycline | 0.5 | 32 | 67.1/29.2 | —/— |
| Vancomycin | 0.5 | 1 | 100.0/— | 100.0/0.0 |
| Beta-hemolytic streptococcif (618) | ||||
| Linezolid | 1 | 1 | 100.0/— | 100.0/0.0 |
| Ceftriaxone | ≤0.06 | 0.12 | 100.0/— | 100.0/0.0 |
| Clindamycin | ≤0.25 | >2 | 81.6/18.0 | 82.0/18.0 |
| Erythromycin | ≤0.12 | >16 | 71.6/26.7 | 71.6/26.7 |
| Levofloxacin | 0.5 | 1 | 95.0/4.5 | 91.2/5.0 |
| Penicillin | ≤0.06 | ≤0.06 | 100.0/— | 100.0/0.0 |
| Tetracycline | 0.5 | >32 | 50.2/48.7 | 49.0/49.8 |
| Vancomycin | 0.25 | 0.5 | 100.0/— | 100.0/0.0 |
According to criteria published by the CLSI and EUCAST (2014). —, breakpoint not available.
TMP-SMX, trimethoprim-sulfamethoxazole.
CoNS, coagulase-negative staphylococci. Includes 22 staphylococcal species, among which S. epidermidis comprised 572 (54.7%) isolates.
CLSI 2014 susceptibility breakpoints for oral penicillin V (parenteral [nonmeningitis] in parentheses) were used.
Includes S. anginosus group (178 strains), S. bovis group (30 strains), S. sanguinis group (57 strains), S. mitis/oralis group (185 strains), S. salivarius group (32 strains), S. mutans group (one strain), S. australis (seven strains), S. canis (one strain), S. cristatus (nine strains), S. infantis (15 strains), S. lutetiensis (one strain), S. macedonicus (one strain), and S. urinalis (one strain).
Includes S. agalactiae (236 strains), S. dysgalactiae (89 strains), S. equisimilis (13 strains), S. pyogenes (279 strains), and group G streptococci (one strain).
TABLE 3.
Isolates with elevated or non-susceptible linezolid MICs (≥4 μg/ml) observed during the ZAAPS Program (2013)
| Organism | Countrya | Linezolid MICb (μg/ml) | Resistance mechanism(s) | PFGE typec |
|---|---|---|---|---|
| S. aureus | Spain | 8 | cfr | |
| S. aureus | Poland | 4 | cfr, L4 (A118V) | |
| E. faecium | Poland | 8 | G2576T | |
| S. haemolyticus | Brazil | 16 | G2576T | |
| S. epidermidis | Italy | 16 | G2576T, L3 (M156T) | SEPI75A |
| S. epidermidis | Italy | 32 | G2576T, L3 (M156R) | SEPI75A |
| S. epidermidis | Portugal | 128 | T2504A, L3 (A160P, D159E, G152D) |
Number of nonsusceptible isolates/number tested, by country: Brazil, 1/308 (0.3%); Italy, 2/285 (0.7%); Poland, 2/154 (1.3%); Portugal, 1/158 (0.6%); Spain, 1/281 (0.4%).
Preliminary elevated MICs (≥4 μg/ml) (Thermo Fisher Scientific; dry-form panels) were confirmed by using a customized frozen-form panel with an extended linezolid dilution range (i.e., 1 to 128 μg/ml).
Pulsed-field gel electrophoresis (PFGE) types were assigned according to the organism code and origin of the isolate (medical site number), followed by a capital letter (type) and a number (subtype). PFGE was performed only when multiple same-species isolates were recovered from the same site. Comparisons of PFGE profiles followed the criteria established by Tenover et al. (19). Isolates displaying the SEPI75A PFGE profile were detected during the 2009 and 2010 surveillance (one isolate each year) at this medical center (17).
Overall, linezolid exhibited consistent modal MICs and MIC50s when tested against enterococci, regardless of species or vancomycin resistance phenotype (Table 1). All E. faecalis isolates were susceptible to linezolid, ampicillin, and daptomycin, among which similar MIC50s and MIC90s were observed. However, E. faecium demonstrated multidrug resistance phenotypes and susceptibility only to linezolid (MIC50 and MIC90, 1 and 1 μg/ml) and daptomycin (MIC50 and MIC90, 2 and 2 μg/ml) (Table 2). A single vancomycin-resistant E. faecium isolate from Poland exhibited an elevated linezolid MIC (i.e., 8 μg/ml) and harbored the common G2576T (Escherichia coli numbering) mutation in the 23S rRNA (Table 3).
Streptococcal isolates were inhibited by linezolid at ≤2 μg/ml (Table 1). Linezolid, levofloxacin, and vancomycin were most active against S. pneumoniae (Table 2). Other tested agents (including ceftriaxone) showed low or marginal activity (58.5 to 88.0% susceptible) against this species. In fact, the ceftriaxone susceptibility rates (EUCAST breakpoint, ≤0.5 μg/ml) against S. pneumoniae was lowest in isolates from the APAC region (61.5%), followed by isolates from Latin America (68.3%) and Europe (86.0%). All strains from Canada were susceptible to ceftriaxone (data not shown). Linezolid, ceftriaxone, levofloxacin, and vancomycin were active against viridans group and beta-hemolytic streptococci (BHS), while penicillin also had complete coverage (≥91.2% susceptible; CLSI criteria) against BHS (Table 2).
The MIC50 results presented here corroborate (±1 doubling dilution) those previously reported during the ZAAPS program for 2012 (3) and those observed for linezolid during earlier years (5). A very limited number of non-linezolid-susceptible isolates was observed among enterococci and staphylococci during 2013. Molecular analysis indicated that these isolates appear scattered across surveyed sites and likely reflect random selection due to previous and/or prolonged use of linezolid (15) or other agents when selecting for cfr (5, 16). In contrast, clonally related isolates of linezolid-resistant CoNS have consistently been detected over the years (Italy) (Table 3), suggesting persistence of endemic clones (3, 17, 18). These results support the continued long and stable in vitro potency of linezolid against clinical Gram-positive pathogens causing infections worldwide.
ACKNOWLEDGMENTS
We express appreciation to the following persons for significant contributions to the manuscript: K. Hass, D. J. Farrell, H. S. Sader, P. R. Rhomberg, L. M. Deshpande, J. E. Ross, and M. Castanheira.
This study was supported by Pfizer Inc. via the SENTRY Antimicrobial Surveillance Program platform.
JMI Laboratories, Inc., received research and educational grants in 2011-2013 from Achaogen, Actelion, Affinium, American Proficiency Institute (API), AmpliPhi Bio, Anacor, Astellas, AstraZeneca, Basilea, BioVersys, Cardeas, Cempra, Cerexa, Cubist, Daiichi, Dipexium, Durata, Fedora, Forest Research Institute, Furiex, Genentech, GlaxoSmithKline, Janssen, Johnson & Johnson, Medpace, Meiji Seika Kaisha, Melinta, Merck, Methylgene, Nabriva, Nanosphere, Novartis, Pfizer, Polyphor, Rempex, Roche, Seachaid, Shionogi, Synthes, The Medicines Co., Theravance, ThermoFisher, Venatorx, Vertex, Waterloo, and some other corporations. There are no speakers' bureaus or stock options to declare. P. A. Hogan is an employee of Pfizer Inc.
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