High-level aminoglycoside resistance was noted in 30.0% of Enterococcus faecalis and 25.2% of Enterococcus faecium isolates. Only 3.3% and 2.1% of E. faecalis isolates had elevated daptomycin MIC (≥2 mg/liter) and vancomycin resistance, respectively. In contrast, 37.4% to 40.3% of E. faecium isolates exhibited these phenotypes. Tedizolid inhibited 98.9% to 100.0% of enterococci causing serious invasive infections, including resistant subsets.
KEYWORDS: Enterococcus faecalis, Enterococcus faecium, high-level aminoglycoside resistance (HLAR), vancomycin-resistant enterococci (VRE)
ABSTRACT
High-level aminoglycoside resistance was noted in 30.0% of Enterococcus faecalis and 25.2% of Enterococcus faecium isolates. Only 3.3% and 2.1% of E. faecalis isolates had elevated daptomycin MIC (≥2 mg/liter) and vancomycin resistance, respectively. In contrast, 37.4% to 40.3% of E. faecium isolates exhibited these phenotypes. Tedizolid inhibited 98.9% to 100.0% of enterococci causing serious invasive infections, including resistant subsets. Oxazolidinone resistance was mainly driven by G2576T; however, optrA and poxtA genes were also detected, including poxtA in the United States and Turkey.
INTRODUCTION
Enterococcus faecalis and Enterococcus faecium isolates are commensals of the human gastrointestinal flora, but these organisms are also well-known opportunistic pathogens that cause health care-associated infections (HAIs). Treating invasive infections caused by Enterococcus species, mainly E. faecium, remains challenging because of intrinsic resistance to various antimicrobials and acquisition of resistance traits, such as altered penicillin-binding protein 5 (PBP5), aminoglycoside, and glycopeptide resistance genes (1, 2). Currently, invasive E. faecium infections are commonly treated with a limited number of agents, including oxazolidinones (linezolid and tedizolid) and daptomycin (3, 4).
Daptomycin was approved for treating adult and pediatric patients with complicated skin and skin structure infections (cSSSIs) caused by Gram-positive cocci, such as E. faecalis (vancomycin-susceptible isolates only) and Staphylococcus aureus bloodstream infections (BSIs) in adults, including right-sided infective endocarditis, and has been the drug of choice for treating serious infections caused by E. faecium isolates (5, 6). However, cases of clinical failure have been reported when treating serious infections caused by E. faecium isolates displaying elevated daptomycin MICs (≥2 mg/liter) (5, 7). In addition, pharmacodynamic studies reported that even when the daptomycin dose was maximized at 12 mg/kg daily, the probability of target attainment was suboptimal for isolates showing MIC values of 4 mg/liter (8, 9).
Tedizolid is an oxazolidinone derivative compound that possesses greater in vitro potency than its first-in-class predecessor linezolid (10, 11). Tedizolid received clinical approval by the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), and other regulatory bodies for treating acute bacterial SSSIs (12). In this study, the in vitro activities of tedizolid and comparator agents were evaluated against a collection of E. faecalis and E. faecium isolates causing serious infections (bloodstream [BSI] and intra-abdominal [IAI]), including resistant subsets, such as those with high-level aminoglycoside resistance (HLAR), vancomycin-resistant enterococci (VRE), isolates displaying elevated daptomycin MIC values, and combinations of these phenotypes. (In addition, isolates nonsusceptible to oxazolidinones were molecularly characterized to elucidate the resistance mechanism, as well as genetic background.)
Enterococcus spp. causing BSI (27,523 isolates) and IAI (5,051 isolates) in the United States and Europe were collected as part of the SENTRY Antimicrobial Surveillance Program in North America and Europe during 2016 to 2018. Each participating center was requested to collect a specific number of consecutive organisms (bacteria and fungi) determined to be clinically significant by local criteria as the probable cause of BSI or IAI. Only 1 isolate per patient infection episode was included in the study. Isolates that met the inclusion criteria were submitted to a coordinating center (JMI Laboratories, North Liberty, IA) for storage, identification, susceptibility, and molecular testing.
A randomized subset of 1,342 E. faecalis (1,047 from BSI and 295 from IAI) and 916 E. faecium (642 from BSI and 274 from IAI) isolates recovered from 33 U.S. and 40 European medical centers were included in this study. Identification was performed by matrix-assisted laser desorption ionization–time of flight mass spectrometry (Bruker Daltonics, Billerica, MA). Tedizolid and comparators were tested by broth microdilution according to CLSI guidelines (13). Categorical interpretations and a VRE subset were established following CLSI interpretative criteria (14). EUCAST criteria were applied for HLAR (gentamicin) screening (15). An additional subset (E. faecium with a daptomycin MIC of ≥2 mg/liter) was selected based on published studies that showed clinical and pharmacodynamics challenges when treating invasive infections caused by these organisms (5–8).
Isolates that showed elevated MICs for oxazolidinones (linezolid MIC, ≥4 mg/liter, and/or tedizolid MIC, ≥1 mg/liter) were selected for molecular characterization of resistance mechanisms and epidemiological typing. Selected isolates had their genomes sequenced on a MiSeq sequencer following the manufacturer’s instructions (Illumina, San Diego, CA). Assembled genomes were subjected to a proprietary software (JMI Laboratories) to screen for the presence of cfr, cfr(B), cfr(C), optrA, and poxtA genes. DNA sequences associated with the 23S rRNA and ribosomal proteins (L3, L4, and L22) were analyzed for the presence of mutations (16–18). These isolates were also subjected to multilocus sequence typing (MLST).
Enterococcus spp. were the fifth and seventh most common pathogens recovered from patients with BSI in Europe (1,094; 7.8% of all BSI isolates) and the United States (870; 6.4% of all BSI isolates), respectively. Among isolates deemed to cause IAI in Europe (2,495 isolates) and the United States (2,556 isolates), Enterococcus spp. were the third (339; 13.6%) and fourth (310; 12.1%) aerobic pathogens more frequently observed, respectively. The majority of E. faecalis isolates recovered from BSIs and IAIs were susceptible to the agents tested (67.1%) (data not shown). HLAR (30.0%) was the most common resistance phenotype observed among E. faecalis isolates, followed by small proportions of isolates showing elevated daptomycin MIC (3.3%), VRE (2.1%), or both VRE and HLAR phenotypes (1.6%) (Table 1). Tedizolid showed consistent activity (MIC50) against E. faecalis isolates within the following resistance subsets: HLAR (MIC50/MIC90, 0.25/0.25 mg/liter), VRE (MIC50/MIC90, 0.25/0.5 mg/liter), VRE-HLAR (MIC50/MIC90, 0.25/0.25 mg/liter), and the elevated daptomycin MIC subset (MIC50/MIC90, 0.25/0.25 mg/liter) (Tables 1 and 2). Ampicillin was also active against E. faecalis infection. Moreover, tedizolid inhibited all E. faecalis isolates except for one (isolate no. 1061298) at the current susceptible breakpoint (≤0.5 mg/liter). The latter isolate (ST28) was recovered from a patient from Rome and showed tedizolid and linezolid MIC values of 2 and 16 mg/liter, respectively (see Table S1 in the supplemental material). This isolate carried G2576T substitutions within the 23S rRNA. A second E. faecalis isolate (isolate no. 973450; ST 775) collected in a hospital in Paris was linezolid nonsusceptible (MIC, 4 mg/liter), while displaying a susceptible tedizolid MIC (0.25 mg/liter). This isolate harbored optrA.
TABLE 1.
Antimicrobial activity of tedizolid tested against resistant phenotypes of E. faecalis and E. faecium causing invasive infections in hospitalized patients in U.S. and European medical centers, 2015 to 2017
| Organism and phenotypea | No. tested | No. (cumulative %) of isolates inhibited at MIC (mg/liter) of: |
MIC (mg/liter) |
|||||||
|---|---|---|---|---|---|---|---|---|---|---|
| 0.03 | 0.06 | 0.12 | 0.25 | 0.5 | 1 | >1 | MIC50 | MIC90 | ||
| E. faecalis | 1,342 | 1 (0.1) | 16 (1.3) | 394 (30.6) | 813 (91.2) | 117 (99.9) | 0 (99.9) | 1 (100) | 0.25 | 0.25 |
| HLAR | 402 | 1 (0.2) | 5 (1.5) | 147 (38.1) | 235 (96.5) | 13 (99.8) | 0 (99.8) | 1 (100) | 0.25 | 0.25 |
| VRE | 28 | 1 (3.6) | 0 (3.6) | 11 (42.9) | 13 (89.3) | 3 (100) | 0.25 | 0.5 | ||
| VRE-HLAR | 21 | 1 (4.8) | 0 (4.8) | 8 (42.9) | 11 (95.2) | 1 (100) | 0.25 | 0.25 | ||
| Daptomycinb | 44 | 0 (0) | 11 (25) | 31 (95.5) | 2 (100) | 0.25 | 0.25 | |||
| E. faecium | 916 | 3 (0.3) | 29 (3.5) | 340 (40.6) | 442 (88.9) | 97 (99.5) | 5 (100) | 0.25 | 0.25 | |
| HLAR | 231 | 7 (3) | 89 (41.6) | 110 (89.2) | 23 (99.1) | 2 (100) | 0.25 | 0.5 | ||
| VRE | 343 | 2 (0.6) | 16 (5.2) | 140 (46.1) | 158 (92.1) | 26 (99.7) | 1 (100) | 0.25 | 0.25 | |
| HLAR-VRE | 75 | 1 (1.3) | 34 (46.7) | 32 (89.3) | 8 (100) | 0.25 | 0.5 | |||
| Daptomycinb | 369 | 1 (0.3) | 6 (1.9) | 109 (31.4) | 208 (87.8) | 41 (98.9) | 4 (100) | 0.25 | 0.5 | |
| VRE and daptomycinb | 115 | 2 (1.7) | 44 (40) | 58 (90.4) | 10 (99.1) | 1 (100) | 0.25 | 0.25 | ||
| HLAR-VRE and daptomycinb | 30 | 13 (43.3) | 14 (90.0) | 4 (100) | 0.25 | 0.25 | ||||
HLAR, high-level aminoglycoside resistance; VRE, vancomycin-resistant enterococci.
Daptomycin MIC, ≥2 mg/liter.
TABLE 2.
Antimicrobial activities of tedizolid and comparator agents against 1,342 E. faecalis, 916 E. faecium, and resistant phenotypes from bloodstream and intra-abdominal infections in European and U.S. hospitalized patients
| Organism/phenotype and antimicrobial agenta | MIC (mg/liter) |
Susceptibility (%) according tob: |
||||
|---|---|---|---|---|---|---|
| CLSI |
EUCAST |
|||||
| MIC50 | MIC90 | S | R | S | R | |
| Enterococcus faecalis (n = 1,342) | ||||||
| Ampicillin | 1 | 1 | 100 | 0.0 | 100 | 0.0 |
| Daptomycin | 0.5 | 1 | 99.6 | 0.0 | – | – |
| Gentamicin | ≤128 | >256 | – | – | 70.0 | 30.0 |
| Linezolid | 1 | 2 | 99.9 | 0.1 | 99.9 | 0.1 |
| Tedizolid | 0.25 | 0.25 | 99.9 | – | – | – |
| Vancomycin | 1 | 2 | 97.8 | 2.1 | 97.8 | 2.2 |
| HLAR (n = 402) | ||||||
| Ampicillin | 1 | 2 | 100 | 0.0 | 100 | 0.0 |
| Daptomycin | 0.5 | 1 | 99.8 | 0.0 | – | – |
| Gentamicin | >256 | >256 | – | – | 0.0 | 100 |
| Linezolid | 1 | 2 | 99.5 | 0.2 | 99.8 | 0.2 |
| Tedizolid | 0.25 | 0.25 | 99.8 | – | – | – |
| Vancomycin | 1 | 1 | 94.5 | 5.2 | 94.5 | 5.5 |
| VRE (n = 28) | ||||||
| Ampicillin | 1 | 2 | 100 | 0.0 | 100 | 0.0 |
| Daptomycin | 0.5 | 1 | 100 | 0.0 | – | – |
| Gentamicin | >256 | >256 | – | – | 25.0 | 75.0 |
| Linezolid | 1 | 2 | 100 | 0.0 | 100 | 0.0 |
| Tedizolid | 0.25 | 0.5 | 100 | – | – | – |
| Vancomycin | >16 | >16 | 0.0 | 100 | 0.0 | 100 |
| VRE-HLAR (n = 21) | ||||||
| Ampicillin | 1 | 2 | 100 | 0.0 | 100 | 0.0 |
| Daptomycin | 0.5 | 1 | 100 | 0.0 | – | – |
| Gentamicin | >256 | >256 | – | – | 0.0 | 100 |
| Linezolid | 1 | 2 | 100 | 0.0 | 100 | 0.0 |
| Tedizolid | 0.25 | 0.25 | 100 | – | – | – |
| Vancomycin | >16 | >16 | 0.0 | 100 | 0.0 | 100 |
| Daptomycin (MIC, ≥2 mg/liter) (n = 44) | ||||||
| Ampicillin | 1 | 1 | 100 | 0.0 | 100 | 0.0 |
| Daptomycin | 2 | 4 | 88.6 | – | – | – |
| Gentamicin | ≤128 | >256 | – | – | 75.0 | 25.0 |
| Linezolid | 1 | 2 | 100 | 0.0 | 100 | 0.0 |
| Tedizolid | 0.25 | 0.25 | 100 | – | – | – |
| Vancomycin | 1 | 2 | 100 | 0.0 | 100 | 0.0 |
| Enterococcus faecium (n = 916) | ||||||
| Ampicillin | >16 | >16 | 15.8 | 84.2 | 14.6 | 84.2 |
| Daptomycin | 1 | 2 | 99.8c | 0.2 | – | – |
| Gentamicin | ≤128 | >256 | – | – | 74.8 | 26.2 |
| Linezolid | 1 | 2 | 99.1 | 0.4 | 99.6 | 0.4 |
| Tedizolid | 0.25 | 0.5 | – | – | – | – |
| Vancomycin | 1 | >16 | 61.9 | 37.4 | 61.9 | 38.1 |
| HLAR (n = 231) | ||||||
| Ampicillin | >16 | >16 | 4.3 | 95.7 | 3.5 | 95.7 |
| Daptomycin | 1 | 2 | 99.6c | 0.4 | – | – |
| Gentamicin | >256 | >256 | – | – | 0 | 100 |
| Linezolid | 1 | 2 | 98.7 | 0.9 | 99.1 | 0.9 |
| Tedizolid | 0.25 | 0.5 | – | – | – | – |
| Vancomycin | 1 | >16 | 66.2 | 32.5 | 66.2 | 33.8 |
| VRE (n = 343) | ||||||
| Ampicillin | >16 | >16 | 1.2 | 98.8 | 0.6 | 98.8 |
| Daptomycin | 1 | 2 | 99.4c | 0.6 | – | – |
| Gentamicin | ≤128 | >256 | – | – | 78.1 | 21.9 |
| Linezolid | 1 | 2 | 99.4 | 0.3 | 99.7 | 0.3 |
| Tedizolid | 0.25 | 0.25 | – | – | – | – |
| Vancomycin | >16 | >16 | 0 | 100 | 0 | 100 |
| VRE-HLAR (n = 75) | ||||||
| Ampicillin | >16 | >16 | 0 | 100 | 0 | 100 |
| Daptomycin | 1 | 2 | 98.7c | 1.3 | – | – |
| Gentamicin | >256 | >256 | – | – | 0 | 100 |
| Linezolid | 1 | 2 | 100 | 0 | 100 | 0 |
| Tedizolid | 0.25 | 0.5 | – | – | – | – |
| Vancomycin | >16 | >16 | 0 | 100 | 0 | 100 |
| Daptomycin (MIC, ≥2 mg/liter) (n = 369) | ||||||
| Ampicillin | >16 | >16 | 15.7 | 84.3 | 14.1 | 84.3 |
| Daptomycin | 2 | 2 | 99.5c | 0.5 | – | – |
| Gentamicin | ≤128 | >256 | – | – | 71.3 | 28.7 |
| Linezolid | 1 | 2 | 98.4 | 0.8 | 99.2 | 0.8 |
| Tedizolid | 0.25 | 0.5 | – | – | – | – |
| Vancomycin | 1 | >16 | 68.3 | 31.2 | 68.3 | 31.7 |
| VRE and daptomycin (MIC, ≥2 mg/liter) (n = 115) | ||||||
| Ampicillin | >16 | >16 | 1.7 | 98.3 | 0.9 | 98.3 |
| Daptomycin | 2 | 2 | 98.3c | 1.7 | – | – |
| Gentamicin | ≤128 | >256 | – | – | 73.9 | 26.1 |
| Linezolid | 1 | 2 | 98.3 | 0.9 | 99.1 | 0.9 |
| Tedizolid | 0.25 | 0.25 | – | – | – | – |
| Vancomycin | >16 | >16 | 0 | 100 | 0 | 100 |
| HLAR-VRE and daptomycin (MIC, ≥2 mg/liter) (n = 30) | ||||||
| Ampicillin | >16 | >16 | 0 | 100 | 0 | 100 |
| Daptomycin | 2 | 2 | 96.7c | 3.3 | – | – |
| Gentamicin | >256 | >256 | – | – | 0.0 | 100 |
| Linezolid | 1 | 2 | 100 | 0 | 100 | 0 |
| Tedizolid | 0.25 | 0.25 | – | – | – | – |
| Vancomycin | >16 | >16 | 0 | 100 | 0 | 100 |
A total of 40.3% of E. faecium isolates had elevated daptomycin MICs (Tables 1 and 2), and this phenotype was more common in Europe (44.6%) than in the United States (35.0%) (data not shown). Moreover, 25.2% and 37.4% of E. faecium isolates displayed HLAR and VRE phenotypes, respectively. Tedizolid inhibited 99.5% of E. faecium isolates at the E. faecalis susceptible breakpoint (≤0.5 mg/liter). Tedizolid (MIC50/90, 0.25/0.5 mg/liter) and linezolid (MIC50/90, 1/2 mg/liter) retained activity against isolates demonstrating elevated daptomycin MICs (n = 369) and inhibited 98.9% and 98.4% of isolates at ≤0.5 and ≤2 mg/liter, respectively (Tables 1 and 2). Vancomycin inhibited only 68.3% of isolates with elevated daptomycin MICs at the current susceptible breakpoint. Tedizolid (99.1% susceptible) and linezolid (98.3% susceptible) were the only active compounds against the challenging VRE subset exhibiting elevated daptomycin MIC (115 invasive isolates; 12.6% of E. faecium).
A total of 7 (0.8%) E. faecium isolates were linezolid nonsusceptible (MIC, 4 to 8 mg/liter), and among these isolates, 5 were also tedizolid nonsusceptible (MIC, 1 mg/liter). All but 2 E. faecium isolates had G2576T mutations (n = 5; 71.4%), whereas poxtA was detected in 1 isolate from New York and 1 isolate from Ankara harbored both poxtA and optrA. cfr gene variants and mutations in ribosomal proteins (L3, L4, and L22) were not detected in any linezolid-nonsusceptible enterococci (see Table S1). All E. faecium isolates were associated with clonal complex 17 (CC17).
The occurrences of enterococci causing BSIs observed here agree with those in published data by the European Centre for Disease Prevention and Control, the Centers for Disease Control and Prevention, and the SENTRY Program, where Enterococcus spp. were among the most frequent pathogens in Europe (8.0% to 8.2%) and the United States (8.8% of BSI and 15.2% of central line-associated BSI) (19, 20). These pathogens were also among the most common isolates causing complicated IAI (cIAI) in a compiled evaluation of data from three randomized prospective trials for cIAI that included a total of 1,237 microbiologically confirmed infections (21–23). Those studies showed that Escherichia coli, followed by Streptococcus spp. and Enterococcus spp., was the most frequent causative agent of cIAI. The latter was higher than that observed here; however, a direct comparison is not possible because the data set presented here includes complicated and uncomplicated IAIs (23).
Overall, E. faecalis isolates remained susceptible to several agents, and a few isolates showed VRE, HLAR, or elevated daptomycin MIC phenotypes, which still allowed for more standard treatment approaches. In contrast, lower susceptibility results were observed for ampicillin (15.8%) and vancomycin (61.9%) against E. faecium infection (Table 2). Also, patients with enterococcal invasive infections are often critically ill and present several comorbidities, such as impaired renal function, oncological disease, and/or immunosuppression (24); which, consequently, further limits the options for treating these invasive infections that usually require prolonged courses (2 to 6 weeks) in a population with higher risks of an adverse event.
Among the antimicrobial agents tested, only daptomycin and the oxazolidinones exhibited activity against E. faecium isolates. Note that clinical trials have not yet evaluated daptomycin for treating E. faecium for the BSI and IAI indications (6). The daptomycin dosage of 4 mg/kg daily remains the only regimen approved by the FDA for treating vancomycin-susceptible E. faecalis in cSSSI (6). More recent evidence showed that the standard daptomycin regimen for treating S. aureus bacteremia (6 mg/kg daily) applied against VRE bacteremia was associated with a high rate of clinical failure (3, 5, 25). Based on these findings and other evidence (26, 27), CLSI revisited the interpretive breakpoint for daptomycin against E. faecium and other Enterococcus spp. (14, 28, 29). Although using a higher daptomycin dose is suggested for treating serious E. faecium infections and/or infections caused by isolates with elevated daptomycin MICs (2 to 4 mg/liter), recent evidence indicates that even higher doses (8 to 12 mg/kg daily) may not be satisfactory (4, 5, 30).
Linezolid is the first drug of the oxazolidinone class approved by the FDA and the EMA for treating VRE infections, including cases with concurrent bacteremia (31). However, its prolonged use may result in myelosuppression or peripheral neuropathy and potentially severe drug interactions (29, 31). In addition, the linezolid efficacy for treating severe VRE infections was recently questioned in large retrospective cohort studies that showed higher failure rates with linezolid than with daptomycin (32, 33). Linezolid displayed high susceptibility rates against E. faecium isolates (99.1%) and the subsets of HLAR, VRE, and elevated daptomycin MIC (98.4% to 99.4%) and against isolates showing resistance to multiple agents (98.3% to 100.0%). Similarly, tedizolid demonstrated a high rate of activity against E. faecium infection (MIC50/90, 0.25/0.5 mg/liter), including resistant subsets (MIC50/90, 0.25/0.25 to 0.5 mg/liter) (Table 1 and 2).
This study showed a low number (7/916; 0.8%) of E. faecium clinical isolates nonsusceptible to oxazolidinones, and this result is in accordance with those of previous large surveillance studies (17, 34). Although 23S rRNA alteration remains the main mechanism of linezolid resistance among E. faecium isolates (16, 17), detection of the poxtA gene in isolates from New York and Ankara (1 each) raises concern regarding the dissemination of this novel transferable mechanism that can reduce the susceptibility of oxazolidinones and other compounds (tetracyclines and phenicols) among Gram-positive cocci (18). In addition, 1 poxtA-carrying E. faecium isolate also had an optrA gene, which was previously reported among isolates from Pakistan (35) and E. faecalis isolates from swine (36). Moreover, all linezolid-nonsusceptible E. faecium isolates were associated with the globally disseminated CC17. Isolates associated with this lineage are a well-adapted nosocomial resistant population that emerged in various institutions worldwide (37), and linezolid-nonsusceptible isolates belonging to this lineage were previously reported in other surveillance studies (17, 38).
In summary, Enterococcus spp. isolates are a frequent cause of invasive infections in U.S. and European medical centers. While E. faecalis isolates remained susceptible to common clinically available agents, E. faecium isolates exhibited a contrasting resistance phenotype. Although ampicillin resistance is well known among E. faecium infections, HLAR and VRE were also frequently observed, with subtle differences between regions. The HLAR rate was higher among European hospitals, while VRE isolates were more commonly observed in the United States. This study showed a high rate of E. faecium isolates displaying elevated daptomycin MICs and causing invasive infections. Resistance to oxazolidinones appears to be driven mainly by 23S rRNA alterations in E. faecium isolates; however, ribosomal protection plasmid-mediated ABC superfamily-encoding genes (optrA and poxtA) seem to be emerging among U.S. and European enterococci (16). These findings warrant continued surveillance to avoid dissemination of these resistant isolates/genes. Oxazolidinones remained active in vitro against the challenge subsets included here and may constitute a therapeutic option for treating serious infectious caused by E. faecium. Further clinical evidence is required to better understand the role of tedizolid in these challenging invasive infection cases.
Supplementary Material
ACKNOWLEDGMENTS
Funding for this research was provided by Merck & Co., Inc., Kenilworth, NJ.
JMI Laboratories contracted to perform services in 2018 for Achaogen, Inc., Albany College of Pharmacy and Health Sciences, Allecra Therapeutics, Allergan, AmpliPhi Biosciences Corp., Amplyx, Antabio, American Proficiency Institute, Arietis Corp., Arixa Pharmaceuticals, Inc., Astellas Pharma, Inc., Athelas, Basilea Pharmaceutica Ltd., Bayer AG, Becton, Dickinson and Company, bioMérieux SA, Boston Pharmaceuticals, Bugworks Research, Inc., CEM-102 Pharmaceuticals, Cepheid, Cidara Therapeutics, Inc., CorMedix, Inc., DePuy Synthes, Destiny Pharma, Discuva Ltd., Falk Pharma GmbH, Emery Pharma, Entasis Therapeutics, Eurofarma Laboratorios SA, U.S. Food and Drug Administration, Fox Chase Chemical Diversity Center, Inc., Gateway Pharmaceutical LLC, GenePOC, Inc., Geom Therapeutics, Inc., GlaxoSmithKline plc, Harvard University, Helperby, HiMedia Laboratories, F. Hoffmann-La Roche Ltd., ICON plc, Idorsia Pharmaceuticals Ltd., Iterum Therapeutics plc, Laboratory Specialists, Inc., Melinta Therapeutics, Inc., Merck & Co., Inc., Microchem Laboratory, Micromyx, MicuRx Pharmaceuticals, Inc., Mutabilis Co., Nabriva Therapeutics plc, NAEJA-RGM, Novartis AG, Oxoid Ltd., Paratek Pharmaceuticals, Inc., Pfizer, Inc., Polyphor Ltd., Pharmaceutical Product Development, LLC, Prokaryotics Inc., Qpex Biopharma, Inc., Ra Pharmaceuticals, Inc., Roivant Sciences, Ltd., Safeguard Biosystems, Scynexis, Inc., SeLux Diagnostics, Inc., Shionogi and Co., Ltd., SinSa Labs, Spero Therapeutics, Summit Pharmaceuticals International Corp., Synlogic, T2 Biosystems, Inc., Taisho Pharmaceutical Co., Ltd., TenNor Therapeutics Ltd., Tetraphase Pharmaceuticals, The Medicines Company, Theravance Biopharma, University of Colorado, University of Southern California-San Diego, University of North Texas Health Science Center, VenatoRx Pharmaceuticals, Inc., Vyome Therapeutics, Inc., Wockhardt, Yukon Pharmaceuticals, Inc., Zai Lab, Zavante Therapeutics, Inc.
We have no speakers’ bureaus or stock options to declare.
Footnotes
Supplemental material is available online only.
REFERENCES
- 1.Arias CA, Murray BE. 2012. The rise of the Enterococcus: beyond vancomycin resistance. Nat Rev Microbiol 10:266–278. doi: 10.1038/nrmicro2761. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Patel R, Gallagher JC. 2015. Vancomycin-resistant enterococcal bacteremia pharmacotherapy. Ann Pharmacother 49:69–85. doi: 10.1177/1060028014556879. [DOI] [PubMed] [Google Scholar]
- 3.Narayanan N, Rai R, Vaidya P, Desai A, Bhowmick T, Weinstein MP. 2019. Comparison of linezolid and daptomycin for the treatment of vancomycin-resistant enterococcal bacteremia. Ther Adv Infect Dis 6:2049936119828964. doi: 10.1177/2049936119828964. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Baddour LM, Wilson WR, Bayer AS, Fowler VG, Tleyjeh IM, Rybak MJ, Barsic B, Lockhart PB, Gewitz MH, Levison ME, Bolger AF, Steckelberg JM, Baltimore RS, Fink AM, O'Gara P, Taubert KA, American Heart Association Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young, Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, Stroke Council . 2015. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association. Circulation 132:1435–1486. doi: 10.1161/CIR.0000000000000296. [DOI] [PubMed] [Google Scholar]
- 5.Shukla BS, Shelburne S, Reyes K, Kamboj M, Lewis JD, Rincon SL, Reyes J, Carvajal LP, Panesso D, Sifri CD, Zervos MJ, Pamer EG, Tran TT, Adachi J, Munita JM, Hasbun R, Arias CA. 2016. Influence of minimum inhibitory concentration in clinical outcomes of Enterococcus faecium bacteremia treated with daptomycin: is it time to change the breakpoint? Clin Infect Dis 62:1514–1520. doi: 10.1093/cid/ciw173. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Merck and Co., Inc. 2017. Cubicin (daptomycin for injection) package insert. Merck and Co., Inc., Whitehouse Station, NJ. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021572s059lbl.pdf.
- 7.Munita JM, Mishra NN, Alvarez D, Tran TT, Diaz L, Panesso D, Reyes J, Murray BE, Adachi JA, Bayer AS, Arias CA. 2014. Failure of high-dose daptomycin for bacteremia caused by daptomycin-susceptible Enterococcus faecium harboring LiaSR substitutions. Clin Infect Dis 59:1277–1280. doi: 10.1093/cid/ciu642. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Avery LM, Kuti JL, Weisser M, Egli A, Rybak MJ, Zasowski EJ, Arias CA, Contreras GA, Chong PP, Aitken SL, DiPippo AJ, Wang JT, Britt NS, Nicolau DP. 2018. Pharmacodynamic analysis of daptomycin-treated Enterococcal bacteremia: it is time to change the breakpoint. Clin Infect Dis 68:1650–1657. doi: 10.1093/cid/ciy749. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Kidd JM, Abdelraouf K, Asempa TE, Humphries RM, Nicolau DP. 2018. Pharmacodynamics of daptomycin against Enterococcus faecium and Enterococcus faecalis in the murine thigh infection model. Antimicrob Agents Chemother 62:e00506. doi: 10.1128/AAC.00506-18. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Pfaller MA, Flamm RK, Jones RN, Farrell DJ, Mendes RE. 2016. Activities of tedizolid and linezolid determined by the reference broth microdilution method against 3,032 Gram-positive bacterial isolates collected in Asia-Pacific, Eastern Europe, and Latin American countries in 2014. Antimicrob Agents Chemother 60:5393–5399. doi: 10.1128/AAC.00881-16. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Zhanel GG, Love R, Adam H, Golden A, Zelenitsky S, Schweizer F, Gorityala B, Lagace-Wiens PR, Rubinstein E, Walkty A, Gin AS, Gilmour M, Hoban DJ, Lynch JP III, Karlowsky JA. 2015. Tedizolid: a novel oxazolidinone with potent activity against multidrug-resistant Gram-positive pathogens. Drugs 75:253–270. doi: 10.1007/s40265-015-0352-7. [DOI] [PubMed] [Google Scholar]
- 12.Cubist Pharmaceuticals U.S. 2014. Sivextro (tedizolid phosphate) package insert. Cubist Pharmaceuticals U.S., Lexington, MA. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205435s000lbl.pdf.
- 13.Clinical and Laboratory Standards Institute. 2018. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard—11th ed. CLSI document MO7. Clinical and Laboratory Standards Institute, Wayne, PA. [Google Scholar]
- 14.Clinical and Laboratory Standards Institute. 2019. Performance standards for antimicrobial susceptibility testing; 29th informational supplement. CLSI document M100. Clinical and Laboratory Standards Institute, Wayne, PA. [Google Scholar]
- 15.EUCAST. 2019. Breakpoint tables for interpretation of MICs and zone diameters, version 9.0, January 2019. http://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Breakpoint_tables/v_9.0_Breakpoint_Tables.pdf.
- 16.Deshpande LM, Castanheira M, Flamm RK, Mendes RE. 2018. Evolving oxazolidinone resistance mechanisms in a worldwide collection of enterococcal clinical isolates: results from the SENTRY Antimicrobial Surveillance Program. J Antimicrob Chemother 73:2314–2322. doi: 10.1093/jac/dky188. [DOI] [PubMed] [Google Scholar]
- 17.Mendes RE, Deshpande L, Streit JM, Sader HS, Castanheira M, Hogan PA, Flamm RK. 2018. ZAAPS programme results for 2016: an activity and spectrum analysis of linezolid using clinical isolates from medical centres in 42 countries. J Antimicrob Chemother 73:1880–1887. doi: 10.1093/jac/dky099. [DOI] [PubMed] [Google Scholar]
- 18.Antonelli A, D'Andrea MM, Brenciani A, Galeotti CL, Morroni G, Pollini S, Varaldo PE, Rossolini GM. 2018. Characterization of poxtA, a novel phenicol-oxazolidinone-tetracycline resistance gene from an MRSA of clinical origin. J Antimicrob Chemother 73:1763–1769. doi: 10.1093/jac/dky088. [DOI] [PubMed] [Google Scholar]
- 19.Weiner LM, Webb AK, Limbago B, Dudeck MA, Patel J, Kallen AJ, Edwards JR, Sievert DM. 2016. Antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2011–2014. Infect Control Hosp Epidemiol 37:1288–1301. doi: 10.1017/ice.2016.174. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Diekema DJ, Hsueh PR, Mendes RE, Pfaller MA, Rolston KV, Sader HS, Jones RN. 2019. The microbiology of bloodstream infection: 20-year trends from the SENTRY Antimicrobial Surveillance Program. Antimicrob Agents Chemother 63:e00355. doi: 10.1128/AAC.00355-19. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Solomkin JS, Reinhart HH, Dellinger EP, Bohnen JM, Rotstein OD, Vogel SB, Simms HH, Hill CS, Bjornson HS, Haverstock DC, Coulter HO, Echols RM. 1996. Results of a randomized trial comparing sequential intravenous/oral treatment with ciprofloxacin plus metronidazole to imipenem/cilastatin for intra-abdominal infections. The Intra-Abdominal Infection Study Group. Ann Surg 223:303–315. doi: 10.1097/00000658-199603000-00012. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Solomkin JS, Wilson SE, Christou NV, Rotstein OD, Dellinger EP, Bennion RS, Pak R, Tack K. 2001. Results of a clinical trial of clinafloxacin versus imipenem/cilastatin for intraabdominal infections. Ann Surg 233:79–87. doi: 10.1097/00000658-200101000-00013. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Solomkin JS, Mazuski JE, Bradley JS, Rodvold KA, Goldstein EJC, Baron EJ, O'Neill PJ, Chow AW, Dellinger EP, Eachempati SR, Gorbach S, Hilfiker M, May AK, Nathens AB, Sawyer RG, Bartlett JG. 2010. Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Surg Infect (Larchmt) 11:79–109. doi: 10.1089/sur.2009.9930. [DOI] [PubMed] [Google Scholar]
- 24.O’Driscoll T, Crank CW. 2015. Vancomycin-resistant enterococcal infections: epidemiology, clinical manifestations, and optimal management. Infect Drug Resist 8:217–230. doi: 10.2147/IDR.S54125. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Chong PP, van Duin D, Bangdiwala A, Ivanova A, Miller WC, Weber DJ, Gilligan PH, Shea TC. 2016. Vancomycin-resistant enterococcal bloodstream infections in hematopoietic stem cell transplant recipients and patients with hematologic malignancies: impact of daptomycin MICs of 3 to 4 mg/L. Clin Ther 38:2468–2476. doi: 10.1016/j.clinthera.2016.09.011. [DOI] [PubMed] [Google Scholar]
- 26.Diaz L, Tran TT, Munita JM, Miller WR, Rincon S, Carvajal LP, Wollam A, Reyes J, Panesso D, Rojas NL, Shamoo Y, Murray BE, Weinstock GM, Arias CA. 2014. Whole-genome analyses of Enterococcus faecium isolates with diverse daptomycin MICs. Antimicrob Agents Chemother 58:4527–4534. doi: 10.1128/AAC.02686-14. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Munita JM, Panesso D, Diaz L, Tran TT, Reyes J, Wanger A, Murray BE, Arias CA. 2012. Correlation between mutations in liaFSR of Enterococcus faecium and MIC of daptomycin: revisiting daptomycin breakpoints. Antimicrob Agents Chemother 56:4354–4359. doi: 10.1128/AAC.00509-12. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Reissier S, Saleh-Mghir A, Guerin F, Massias L, Ghout I, Sinel C, Cattoir V, Cremieux AC. 2018. In vivo daptomycin efficacy against experimental vancomycin-resistant Enterococcus faecium endocarditis. J Antimicrob Chemother 73:981–986. doi: 10.1093/jac/dkx499. [DOI] [PubMed] [Google Scholar]
- 29.Hall AD, Steed ME, Arias CA, Murray BE, Rybak MJ. 2012. Evaluation of standard- and high-dose daptomycin versus linezolid against vancomycin-resistant Enterococcus isolates in an in vitro pharmacokinetic/pharmacodynamic model with simulated endocardial vegetations. Antimicrob Agents Chemother 56:3174–3180. doi: 10.1128/AAC.06439-11. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Gonzalez-Ruiz A, Seaton RA, Hamed K. 2016. Daptomycin: an evidence-based review of its role in the treatment of Gram-positive infections. Infect Drug Resist 9:47–58. doi: 10.2147/IDR.S99046. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Pfizer, Inc. 2008. Zyvox (linezolid) package insert. Pfizer, Inc., New York: https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021130s016,021131s013,021132s014lbl.pdf. [Google Scholar]
- 32.Britt NS, Potter EM, Patel N, Steed ME. 2017. Effect of continuous and sequential therapy among veterans receiving daptomycin or linezolid for vancomycin-resistant Enterococcus faecium bacteremia. Antimicrob Agents Chemother 61:e02216. doi: 10.1128/AAC.02216-16. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Britt NS, Potter EM, Patel N, Steed ME. 2015. Comparison of the effectiveness and safety of linezolid and daptomycin in vancomycin-resistant Enterococcal bloodstream infection: a national cohort study of Veterans Affairs patients. Clin Infect Dis 61:871–878. doi: 10.1093/cid/civ444. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Pfaller MA, Mendes RE, Streit JM, Hogan PA, Flamm RK. 2017. Five-year summary of in vitro activity and resistance mechanisms of linezolid against clinically important Gram-positive cocci in the United States from the LEADER Surveillance Program (2011 to 2015). Antimicrob Agents Chemother 61:e00609. doi: 10.1128/AAC.00609-17. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Wardenburg KE, Potter RF, D’Souza AW, Hussain T, Wallace MA, Andleeb S, Burnham CD, Dantas G. 2019. Phenotypic and genotypic characterization of linezolid-resistant Enterococcus faecium from the USA and Pakistan. J Antimicrob Chemother 74:3445–3452. doi: 10.1093/jac/dkz367. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Hao W, Shan X, Li D, Schwarz S, Zhang SM, Li XS, Du XD. 2019. Analysis of a poxtA- and optrA-co-carrying conjugative multiresistance plasmid from Enterococcus faecalis. J Antimicrob Chemother 74:1771–1775. doi: 10.1093/jac/dkz109. [DOI] [PubMed] [Google Scholar]
- 37.Freitas AR, Tedim AP, Francia MV, Jensen LB, Novais C, Peixe L, Sanchez-Valenzuela A, Sundsfjord A, Hegstad K, Werner G, Sadowy E, Hammerum AM, Garcia-Migura L, Willems RJ, Baquero F, Coque TM. 2016. Multilevel population genetic analysis of vanA and vanB Enterococcus faecium causing nosocomial outbreaks in 27 countries (1986–2012). J Antimicrob Chemother 71:3351–3366. doi: 10.1093/jac/dkw312. [DOI] [PubMed] [Google Scholar]
- 38.Pfaller MA, Mendes RE, Streit JM, Hogan PA, Flamm RK. 2017. ZAAPS program results for 2015: an activity and spectrum analysis of linezolid using clinical isolates from medical centres in 32 countries. J Antimicrob Chemother 72:3093–3099. doi: 10.1093/jac/dkx251. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.