Abstract
This study summarizes the linezolid susceptibility testing results for 7,429 Gram-positive pathogens from 60 U.S. sites collected during the 2012 sampling year for the LEADER Program. Linezolid showed potent activity when tested against 2,980 Staphylococcus aureus isolates, inhibiting all but 3 at ≤2 μg/ml. Similarly, linezolid showed coverage against 99.5% of enterococci, as well as for all streptococci tested. These results confirm a long record of linezolid activity against U.S. Gram-positive isolates since regulatory approval in 2000.
TEXT
During more than a decade of clinical use, linezolid has demonstrated clinical effectiveness for treating infections caused by a variety of Gram-positive pathogens (1–4). The clinical data have been supported by the LEADER Surveillance Program established in 2004, which has monitored the activity, spectrum and susceptibility/resistance rates of this oxazolidinone in the United States for eight consecutive years (5, 6). Table 1 summarizes the linezolid nonsusceptibility rates documented during the 8-year LEADER Program, which illustrates the low rates observed for the monitored species and groups of Gram-positive organisms. In this study, we report the results obtained during the ninth consecutive (2012) year of the LEADER Program by applying centralized testing by reference microdilution methods.
TABLE 1.
Summary of the linezolid nonsusceptibility rates documented during the 9-year LEADER surveillance program
| Organism (no. of isolates tested) | % with linezolid nonsusceptibility ina: |
||||||||
|---|---|---|---|---|---|---|---|---|---|
| 2004 | 2005 | 2006 | 2007 | 2008 | 2009 | 2010 | 2011 | 2012 | |
| S. aureus (27,827) | 0.00 | 0.03 | 0.03 | 0.06 | 0.10 | 0.15 | 0.06 | 0.10 | 0.03 |
| CoNSb (6,984) | 0.20 | 1.13 | 1.61 | 1.76 | 1.64 | 1.47 | 1.48 | 1.18 | 0.93 |
| Enterococci (7,608) | 0.80 | 0.64 | 1.83 | 1.13 | 0.55 | 0.49 | 1.10 | 0.34 | 0.53 |
| S. pneumoniae (6,311) | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.12c | 0.00 | 0.00 |
| Viridans group streptococci (2,381) | NT | NT | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.19c | 0.00 |
| Beta-hemolytic streptococci (3,980) | NT | NT | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 |
| Total (54,911) | 0.14 | 0.24 | 0.45 | 0.44 | 0.36 | 0.34 | 0.38 | 0.19 | 0.17 |
A total of 7,429 Gram-positive pathogens cultured in 60 U.S. medical centers (in 37 states) located in all nine U.S. Census Bureau Regions, including 7 medical centers specializing in children's health care, were submitted to JMI Laboratories (North Liberty, IA). Isolates were primarily identified by the participating laboratory, and the identifications were confirmed by the reference monitoring laboratory (JMI Laboratories) by using standard algorithms and Vitek 2 (bioMérieux, Hazelwood, MO), supported by 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 the methods in Clinical and Laboratory Standards Institute (CLSI) document M07-A9 (7). Testing was performed using panels manufactured by Thermo Fisher Scientific (Cleveland, OH). Isolates with initial linezolid MIC results at ≥4 μg/ml were submitted to additional testing using customized frozen-form panels, molecular characterization of resistance mechanisms, and epidemiology typing, as previously described (8–10). Bacterial inoculum density was monitored by colony counts to ensure an adequate number of cells for each testing event. Validation of the MIC values was performed by concurrent testing of CLSI-recommended quality control reference strains (Staphylococcus aureus ATCC 29213, Enterococcus faecalis ATCC 29212, and Streptococcus pneumoniae ATCC 49619) (11). MIC interpretations were based on the CLSI document M100-S23 (2013) breakpoint criteria, as available (11). Isolates resistant to erythromycin but susceptible to clindamycin were subjected to the CLSI broth microdilution inducible clindamycin resistance screening test (11).
All S. aureus isolates tested (2,980) were inhibited by linezolid at ≤2 μg/ml, except for two and one isolates displaying MIC values at 4 and 32 μg/ml, respectively (Tables 2, 3, and 4). The former isolates carried the cfr gene, while the latter strain had mutations in the 23S rRNA and the L3 ribosomal protein (Table 4). Daptomycin, vancomycin, gentamicin, and trimethoprim-sulfamethoxazole demonstrated high levels of antimicrobial coverage (≥97.0% susceptible) when tested against methicillin-resistant S. aureus (MRSA), while ciprofloxacin (66.1% resistance), erythromycin (88.4%), and clindamycin (25.4 and 12.3% constitutive and inducible resistance, respectively) showed high resistance rates (Table 3). Nearly all (99.1%) coagulase-negative staphylococci (CoNS) were also inhibited by linezolid at ≤2 μg/ml, whereas seven (0.9%) isolates displayed MIC values of 16 to 128 μg/ml (Tables 2 and 4). Linezolid and daptomycin, followed by vancomycin, were the most potent agents tested against CoNS. Other agents had limited activities (36.5 to 85.0% susceptible) (Table 3).
TABLE 2.
Linezolid MIC distribution when tested against species and groups of Gram-positive cocci isolated in the United States and submitted to the LEADER Surveillance Program, 2012
| Organisma (no. of isolates [n = 7,429]) | No. (cumulative %) of isolates inhibited at linezolid MIC (μg/ml) of: |
MIC (μg/ml) |
||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| ≤0.12 | 0.25 | 0.5 | 1 | 2 | 4 | 8 | >8 | MIC50 | MIC90 | |
| S. aureus (2,980) | 1 (0.0) | 5 (0.2) | 290 (9.9) | 2,354 (88.9) | 327 (99.9) | 2 (>99.9) | 0 (>99.9) | 1 (100.0) | 1 | 2 |
| Oxacillin susceptible (1,537) | 0 (0.0) | 3 (0.2) | 140 (9.3) | 1,207 (87.8) | 186 (99.9) | 0 (99.9) | 0 (99.9) | 1 (100.0) | 1 | 2 |
| Oxacillin resistant (1,443) | 1 (0.1) | 2 (0.2) | 150 (10.6) | 1,147 (90.1) | 141 (99.9) | 2 (100.0) | 1 | 1 | ||
| CoNS (753) | 2 (0.3) | 106 (14.3) | 449 (74.0) | 184 (98.4) | 5 (99.1) | 0 (99.1) | 0 (99.1) | 7 (100.0) | 0.5 | 1 |
| Enterococcus spp. (937) | 0 (0.0) | 9 (1.0) | 112 (12.9) | 695 (87.1) | 116 (99.5) | 1 (99.6) | 3 (99.9) | 1 (100.0) | 1 | 2 |
| E. faecalis (640) | 0 (0.0) | 8 (1.3) | 71 (12.3) | 482 (87.7) | 78 (99.8) | 1 (100.0) | 1 | 2 | ||
| E. faecium (259) | 0 (0.0) | 1 (0.4) | 32 (12.8) | 185 (84.5) | 37 (98.8) | 0 (98.8) | 3 (99.6) | 1 (100.0) | 1 | 2 |
| S. pneumoniae (1,273) | 6 (0.5) | 36 (3.3) | 408 (35.3) | 800 (98.2) | 23 (100.0) | 1 | 1 | |||
| VGS (526) | 12 (2.3) | 26 (7.2) | 217 (48.5) | 260 (97.9) | 11 (100.0) | 1 | 1 | |||
| BHS (960) | 1 (0.1) | 2 (0.3) | 258 (27.2) | 699 (100.0) | 1 | 1 | ||||
CoNS, coagulase-negative staphylococci; VGS, viridans group streptococci; BHS, beta-hemolytic streptococci.
TABLE 3.
Antimicrobial activities and spectra of linezolid and comparator agents when tested against species and groups of Gram-positive cocci isolated in the United States and submitted to the LEADER Surveillance Program, 2012
| Organism(s), antimicrobial agent (no. of isolates tested [n = 7,429]) | MIC (μg/ml) |
%S/%I/%R by CLSI criteriaa | ||
|---|---|---|---|---|
| MIC50 | MIC90 | Range | ||
| S. aureus isolates | ||||
| Oxacillin resistant (1,443) | ||||
| Linezolid | 1 | 2 | 0.25–4 | 100.0/0.0/0.0 |
| Ciprofloxacin | >4 | >4 | 0.06–>4 | 32.5/1.4/66.1 |
| Clindamycin | ≤0.25 | >2 | ≤0.25–>2 | 74.4/0.2/25.4 (12.3)b |
| Erythromycin | >16 | >16 | ≤0.12–>16 | 9.6/2.0/88.4 |
| Gentamicin | ≤1 | ≤1 | ≤1–>8 | 97.0/0.1/2.9 |
| Trimethoprim-sulfamethoxazole | ≤0.5 | ≤0.5 | ≤0.5–>4 | 98.3/0.0/1.7 |
| Daptomycin | 0.25 | 0.5 | 0.06–2 | 99.9/—/— |
| Vancomycin | 1 | 1 | 0.25–2 | 100.0/0.0/0.0 |
| Oxacillin susceptible (1,537) | ||||
| Linezolid | 1 | 2 | 0.25–>8 | 99.9/0.0/0.1 |
| Ciprofloxacin | 0.25 | >4 | ≤0.03–>4 | 87.2/1.9/10.9 |
| Clindamycin | ≤0.25 | ≤0.25 | ≤0.25–>2 | 94.3/0.2/5.5 (13.8)b |
| Erythromycin | 0.25 | >16 | ≤0.12–>16 | 63.3/4.4/32.7 |
| Gentamicin | ≤1 | ≤1 | ≤1–>8 | 99.0/0.3/0.7 |
| Trimethoprim-sulfamethoxazole | ≤0.5 | ≤0.5 | ≤0.5–>4 | 99.5/0.0/0.5 |
| Daptomycin | 0.25 | 0.5 | ≤0.06–2 | 99.9/—/— |
| Vancomycin | 1 | 1 | 0.25–2 | 100.0/0.0/0.0 |
| CoNSc (753) | ||||
| Linezolid | 0.5 | 1 | ≤0.12–>8 | 99.1/0.0/0.9 |
| Oxacillin | 1 | >2 | ≤0.25–>2 | 36.5/0.0/63.5 |
| Ciprofloxacin | 0.25 | >4 | ≤0.03–>4 | 62.2/0.5/37.3 |
| Clindamycin | ≤0.25 | >2 | ≤0.25–>2 | 73.4/2.8/23.8 (9.6)b |
| Erythromycin | >16 | >16 | ≤0.12–>16 | 39.6/2.1/58.3 |
| Gentamicin | ≤1 | >8 | ≤1–>8 | 85.0/2.5/12.5 |
| Trimethoprim-sulfamethoxazole | ≤0.5 | >4 | ≤0.5—>4 | 72.6/0.0/27.4 |
| Daptomycin | 0.25 | 0.5 | ≤0.06–2 | 99.9/—/— |
| Vancomycin | 1 | 2 | ≤0.12–4 | 100.0/0.0/0.0 |
| Enterococcid (937) | ||||
| Linezolid | 1 | 2 | 0.25–>8 | 99.5/0.1/0.4 |
| Ampicillin | 1 | >8 | 0.5–>8 | 74.3/0.0/25.7 |
| Ciprofloxacin | 2 | >4 | 0.25–>4 | 49.1/6.8/44.1 |
| Piperacillin-tazobactam | 4 | >64 | 1–>64 | 74.3/—/— |
| Daptomycin | 1 | 2 | ≤0.06–4 | 100.0/—/— |
| Teicoplanin | ≤2 | >16 | ≤2–>16 | 77.7/1.0/21.3 |
| Vancomycin | 1 | >16 | 0.25–>16 | 76.6/0.5/22.9 |
| S. pneumoniae (1,273) | ||||
| Linezolid | 1 | 1 | ≤0.12–2 | 100.0/—/— |
| Amoxicillin-clavulanic acid | ≤1 | 4 | ≤1–>8 | 86.4/3.7/9.9 |
| Ceftriaxone | ≤0.06 | 1 | ≤0.06–8 | 91.5/7.3/1.2 |
| Ciprofloxacin | 1 | 2 | 0.12–>4 | —/—/— |
| Clindamycin | ≤0.25 | >2 | ≤0.25–>2 | 82.2/0.7/17.1 (1.3)b |
| Erythromycin | ≤0.12 | >16 | ≤0.12–>16 | 57.4/0.7/41.9 |
| Levofloxacin | 1 | 1 | 0.25–>4 | 99.2/0.1/0.7 |
| Penicilline | ≤0.06 | 4 | ≤0.06–8 | 57.7/24.1/18.2 |
| Vancomycin | 0.25 | 0.5 | ≤0.12–0.5 | 100.0/—/— |
| Viridans group streptococcif (526) | ||||
| Linezolid | 1 | 1 | ≤0.12–2 | 100.0/—/— |
| Ceftriaxone | 0.25 | 0.5 | ≤0.06–8 | 95.8/2.5/1.7 |
| Ciprofloxacin | 1 | 4 | ≤0.03–>4 | —/—/— |
| Clindamycin | ≤0.25 | >2 | ≤0.25–>2 | 87.6/0.6/11.8 |
| Erythromycin | 0.5 | 16 | ≤0.12–>16 | 48.5/2.8/48.7 |
| Levofloxacin | 1 | 2 | ≤0.12–>4 | 93.1/1.2/5.7 |
| Penicillin | ≤0.06 | 0.5 | ≤0.06–>8 | 73.6/24.1/2.3 |
| Vancomycin | 0.5 | 1 | ≤0.12–1 | 100.0/—/— |
| Beta-hemolytic streptococcig (960) | ||||
| Linezolid | 1 | 1 | ≤0.12–1 | 100.0/—/— |
| Ceftriaxone | ≤0.06 | 0.12 | ≤0.06–0.5 | 100.0/—/— |
| Ciprofloxacin | 0.5 | 1 | 0.12–>4 | —/—/— |
| Clindamycin | ≤0.25 | >2 | ≤0.25–>2 | 80.0/0.6/19.4 (5.5)b |
| Erythromycin | ≤0.12 | >16 | ≤0.12–>16 | 60.7/1.3/38.0 |
| Levofloxacin | ≤0.5 | 1 | ≤0.12–>4 | 98.9/0.2/0.9 |
| Penicillin | ≤0.06 | ≤0.06 | ≤0.06–0.12 | 100.0/—/— |
| Vancomycin | 0.5 | 0.5 | ≤0.12–1 | 100.0/—/— |
Criteria as published by the CLSI (11). %S, percent susceptible; %I, percent intermediate; %R, percent resistant; —, breakpoint not available.
Inducible clindamycin resistance rate among erythromycin-resistant, clindamycin-susceptible isolates as determined by the CLSI broth microdilution inducible clindamycin resistance screening test (11).
Includes [organism (no. of isolates)] S. auricularis (1), S. capitis (35), S. caprae (9), S. cohnii (5), S. epidermidis (462), S. haemolyticus (30), S. hominis (53), S. intermedius (5), S. lugdunensis (78), S. pasteuri (2), S. pettenkoferi (9), S. saprophyticus (35), S. schleiferi (2), S. simulans (13), S. warneri (12), and coagulase-negative staphylococci whose species was not determined (2).
Includes [organism (no. of isolates)] E. avium (9), E. casseliflavus (6), E. faecalis (640), E. faecium (259), E. gallinarum (7), E. gilvus (1), E. hirae (4), and E. raffinosus (11).
Criteria used were as published by the CLSI for “Penicillin oral penicillin V” (susceptible, ≤0.06 μg/ml; intermediate, 0.12 to 1 μg/ml; and resistant, ≥2 μg/ml) (11).
Includes 27 species.
Includes [organism (no. of isolates)] S. dysgalactiae (20), S. equisimilis (1), group A Streptococcus (S. pyogenes; 332), group B Streptococcus (S. agalactiae; 451), group C Streptococcus species (51), group F Streptococcus (9), and group G Streptococcus species (96).
TABLE 4.
Isolates with elevated or nonsusceptible linezolid MICsa observed during the 2012 LEADER Surveillance Program
| Organism | Isolate | City | State | Linezolid MIC (μg/ml) | Resistance mechanism(s) | PFGEb |
|---|---|---|---|---|---|---|
| S. aureus | 002-3143 | Indianapolis | IN | 4 | cfr | |
| S. aureus | 464-7136 | Maywood | IL | 4 | cfr | |
| S. aureus | 015-26753 | New York | NY | 32 | G2576T; L3 (ΔS145) | |
| S. epidermidis | 052-3560 | Burlington | MA | 16 | L3 (V154L, A157R); L4 (71G72 ins) | |
| S. epidermidis | 129-8096 | New Brunswick | NJ | 32 | G2576T; L3 (H146R, V154L, M156T); L4 (71G72 insc) | SEPI129Bd |
| S. epidermidis | 003-13587 | Detroit | MI | 128 | G2576T; L3 (G137S, H146P, F147Y, M156T); L4 (71G72 ins) | SEPI3K |
| S. epidermidis | 404-14750 | Philadelphia | PA | 16 | L3 (H146Q, V154L, A157R); L4 (71G72 ins) | |
| S. epidermidis | 454-15674 | Winston-Salem | NC | 128 | G2576T; L3 (G137S, H146P, M156T); L4 (71G72 ins) | SEPI454E |
| S. epidermidis | 454-15678 | Winston-Salem | NC | 128 | G2576T; L3 (G137S, H146P, M156T); L4 (71G72 ins) | SEPI454E |
| S. epidermidis | 412-45728 | Memphis | TN | 16 | L3 (H146Q, V154L, A157R); L4 (71G72 ins) | SEPI412Ce |
| E. faecalis | 417-36420 | Wauwatosa | WI | 4 | G2576T | |
| E. faecium | 448-18200 | New Orleans | LA | 4 | G2576T | EFM448A |
| E. faecium | 448-18203 | New Orleans | LA | 8 | G2576T; cfr | EFM448B |
| E. faecium | 460-11256 | Lansing | MI | 8 | G2576T | |
| E. faecium | 116-51168 | Houston | TX | 8 | G2576T |
Preliminary elevated or nonsusceptible MICs (≥4 μg/ml) (Thermo Fisher Scientific) 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, comprised of the origin of the isolate (medical site number), followed by a capital letter (type) and a number (subtype), when applicable. Comparisons of PFGE profiles followed the criteria established by Tenover et al. (22).
71G72 ins, 71G72 insertion.
Three, two, one, and one linezolid-resistant S. epidermidis isolates exhibiting an SEPI129B PFGE type were collected from this medical site during 2006, 2007, 2008, and 2009 sampling, respectively.
One linezolid-resistant S. epidermidis isolate exhibiting an SEPI412C PFGE type was collected from this medical site in 2010.
Linezolid was equally potent when tested against both E. faecalis and E. faecium (MIC50/90, 1/2 μg/ml for both) (Table 2), and linezolid-nonsusceptible enterococci showed a 23S rRNA mutation at position G2576 (Table 4). In addition, one E. faecium isolate from New Orleans was cfr positive, which represents the first detection of cfr in enterococci in the United States. All E. faecalis isolates except one remained susceptible to ampicillin, and totals of 73.7% (191/259) and 3.6% (23/640) of the E. faecium and E. faecalis isolates, respectively, were vancomycin resistant (data not shown). Overall, linezolid (MIC50/90, 1/2 μg/ml) and daptomycin (MIC50/90, 1/2 μg/ml) were equally potent when tested against the U.S. collection of enterococci, whereas other agents showed narrower antimicrobial coverage (49.1 to 77.7% susceptible) (Table 3). Linezolid (MIC50/90, 1/1 μg/ml) showed uniform potency when tested against S. pneumoniae and other streptococcal groups of organisms (Tables 2 and 3). Moreover, ceftriaxone, levofloxacin, and vancomycin had good antimicrobial coverage (≥91.5% susceptible).
The linezolid resistance mechanisms detected among selected isolates corroborate those documented in previous LEADER reports (5, 6, 12–15), including cfr and G2576 alterations in S. aureus, multiple mutations in 23S rRNA and ribosomal proteins in CoNS, which translate into higher linezolid MIC values, and the G2576 modification in enterococci. The presence of cfr in S. aureus remains of particular importance due to the role of this species in causing community- and hospital-acquired infections and the fact that these organisms often display a linezolid MIC result at the CLSI and European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoint for susceptibility (i.e., ≤4 μg/ml) (11, 16). This may further facilitate the spread of this mobile resistance determinant, emphasizing the importance of active surveillance. Additional genetic analysis demonstrated the presence of clonally related S. epidermidis isolates in a single site in North Carolina, as well as isolates with pulsed-field gel electrophoresis (PFGE) profiles similar to those observed during previous years of the LEADER Program, suggesting persistence of resistant lineages within institutions (New Jersey and Tennessee) (see Table 4).
This report confirms high susceptibility rates for linezolid when tested against isolates from U.S. hospitals during 2012 and sustained rates compared with the rates in previous surveillance years (Table 1). The low number of isolates nonsusceptible to linezolid relates to the fact that target site modifications, which are still the main mechanism of resistance, develop slowly due to the redundancy of rRNA in bacteria (17). The development (target site mutation) and acquisition (cfr) of resistance have been associated with linezolid exposure and/or prolonged treatment (8, 18, 19). Moreover, selection of isolates related to persistent clones within a given institution has also been described (10, 20). In addition, occasional outbreaks of cfr-carrying isolates, which have usually been contained after implementation of infection control measures, have recently been reported (9, 21). Nevertheless, it remains prudent to maintain such national and/or global surveillance programs, not only for monitoring the drug activity and spectrum but also for detecting the development and/or acquisition of resistance, such as cfr in S. aureus and E. faecium.
ACKNOWLEDGMENTS
We express appreciation to the following persons for significant contributions to the manuscript: D. J. Farrell, H. S. Sader, M. G. Stilwell, P. R. Rhomberg, L. M. Deshpande, and M. Castanheira.
This study was supported by Pfizer Inc. via the SENTRY Antimicrobial Surveillance Program platform. R. E. Mendes, R. K. Flamm, J. E. Ross, and R. N. Jones are employees of JMI Laboratories who were paid consultants to Pfizer Inc. in connection with the development of the manuscript. P. A. Hogan is an employee of Pfizer Inc.
JMI Laboratories, Inc., has received research and educational grants in 2011 to 2013 from American Proficiency Institute (API), Anacor, Astellas, AstraZeneca, Bayer, Cempra, Cerexa/Forest, Contrafect, Cubist, Daiichi, Dipexium, Enanta, Furiex, GlaxoSmithKline, Johnson & Johnson (Ortho McNeil), LegoChem Biosciences Inc., Meiji Seika Kaisha, Merck, Nabriva, Novartis, Pfizer, Rempex, Rib-X Pharmaceuticals, Seachaid, Shionogi, The Medicines Company, Theravance, and ThermoFisher. Some JMI employees are advisors/consultants for Astellas, Cubist, Pfizer, Cempra, Cerexa/Forest, J&J, and Theravance.
Footnotes
Published ahead of print 9 December 2013
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