ABSTRACT
Relebactam is a non-β-lactam, bicyclic diazabicyclooctane β-lactamase inhibitor of class A and class C β-lactamases, including Klebsiella pneumoniae carbapenemases (KPCs). It is in phase 3 clinical development in combination with imipenem/cilastatin. The in vitro activities of imipenem-relebactam, imipenem, and comparators were determined using the Clinical and Laboratory Standards Institute (CLSI) reference broth microdilution method for isolates of Enterobacteriaceae (n = 3,419) and Pseudomonas aeruginosa (n = 896) collected in 2016 by 21 U.S. hospital laboratories participating in the SMART (Study for Monitoring Antimicrobial Resistance Trends) global surveillance program. Relebactam was tested at a fixed concentration of 4 μg/ml. Imipenem-relebactam MICs were interpreted using CLSI breakpoints for imipenem. Rates of susceptibility to imipenem-relebactam and imipenem for non-Proteeae Enterobacteriaceae (n = 3,143) and P. aeruginosa were 99.1% (3,115/3,143) and 95.9% (3,013/3,143) and were 94.4% (846/896) and 74.7% (669/896), respectively. Relebactam restored imipenem susceptibility to 78.5% (102/130) of imipenem-nonsusceptible non-Proteeae Enterobacteriaceae and to 78.0% (177/227) of imipenem-nonsusceptible P. aeruginosa isolates. Susceptibility to imipenem-relebactam was 98.2% (444/452) and 82.2% (217/264) for multidrug-resistant (MDR) non-Proteeae Enterobacteriaceae and MDR P. aeruginosa, respectively. Given the ability of relebactam to restore susceptibility to imipenem in nonsusceptible isolates of both non-Proteeae Enterobacteriaceae and P. aeruginosa and to demonstrate potent activity against current MDR isolates of both non-Proteeae Enterobacteriaceae and P. aeruginosa, further development of imipenem-relebactam appears warranted.
KEYWORDS: SMART, surveillance, imipenem, relebactam, Gram negative, United States
INTRODUCTION
The emergence and spread of antimicrobial resistance in bacterial pathogens are an ongoing process fostered by selective antimicrobial pressure and imperfect infection control practice. They commonly result from horizontal acquisition of new resistance genes and/or the generation of DNA mutations in target site or regulatory genes which disseminate vertically via clonal expansion. Over time, the appearance of new multidrug-resistant (MDR) phenotypes is inevitable. In the United States, steady increases in rates of extended-spectrum β-lactamase (ESBL)-producing, carbapenem-resistant, and MDR Enterobacteriaceae; MDR Pseudomonas aeruginosa; and other highly resistant nonfermentative Gram-negative bacilli have been observed since 2000 (1–4). The unchecked spread of MDR, extensively drug-resistant, and pan-drug-resistant Gram-negative bacilli is particularly concerning as effective therapeutic choices for such isolates are currently limited and novel agents have been slow to appear (1, 5).
Carbapenems, such as imipenem, are broad-spectrum parenteral antibacterial agents that are generally reserved for use as agents of last resort in the treatment of serious nosocomial infections. Carbapenems are stable to the hydrolytic action of class A and class C (AmpC) β-lactamases. Mechanisms of resistance to carbapenems demonstrated by Gram-negative bacteria include one or more of carbapenemase production, impaired outer membrane permeability (due most commonly to reduced expression of certain outer membrane proteins) in combination with β-lactamase hyperproduction, and efflux across the outer membrane. Carbapenemases include class A β-lactamases such as Klebsiella pneumoniae carbapenemases (KPCs), class B metallo-β-lactamases (e.g., NDM, IMP, and VIM), and class D β-lactamases (e.g., OXA type). Carbapenem resistance in P. aeruginosa most commonly occurs as the result of downregulation of the porin protein OprD in combination with production of the intrinsic, chromosomally encoded AmpC β-lactamase (Pseudomonas-derived cephalosporinase [PDC]).
Relebactam, formerly MK-7655, is a novel piperidine analogue, non-β-lactam bicyclic diazabicyclooctane β-lactamase inhibitor that is active in vitro against class A β-lactamases, including KPC-type carbapenemases, and class C β-lactamases (6). Relebactam is structurally related to avibactam and is not an inducer of AmpC enzymes (7). Relebactam differs from avibactam in that it does not inhibit class D carbapenemases (e.g., OXA-48-like) but does possess inhibitory activity (in the combination imipenem-relebactam) against clinical isolates of K. pneumoniae carrying variant KPC-3 enzymes that are resistant to ceftazidime-avibactam (8, 9).
Relebactam has been combined with the carbapenem/renal dehydropeptidase I inhibitor imipenem/cilastatin, primarily to restore imipenem's clinical activity against KPC-producing K. pneumoniae as well as other carbapenem-resistant Enterobacteriaceae and against P. aeruginosa isolates that demonstrate carbapenem resistance via impermeability arising from porin loss in combination with AmpC expression (6, 9). Imipenem would appear to be an excellent partner for relebactam to treat pseudomonal infections because imipenem, unlike other β-lactams, evades upregulated efflux frequently present in P. aeruginosa (9). Relebactam has been shown to lower imipenem MICs by up to 64-fold for KPC-producing K. pneumoniae and to also demonstrate modest potentiation of imipenem activity against carbapenem-resistant Enterobacteriaceae (CRE) isolates carrying ESBL and AmpC enzymes (8, 10, 11). Imipenem-relebactam, like ceftazidime-avibactam, is inactive against metallo-β-lactamase-producing Gram-negative bacilli (5, 6, 8). The presence of some major OmpK36 mutations (an IS5 promoter insertion or OmpK36 ins AA135–136 GD) has also been reported to be independently associated with higher imipenem-relebactam and imipenem MICs (8), while OmpK35 mutations were not associated with differences in MICs of either agent (8, 12).
The intent of the current study was to determine the in vitro activity of imipenem-relebactam against a current (2016) collection of non-Proteeae Enterobacteriaceae (NPE) and P. aeruginosa isolates from patients with intra-abdominal, lower respiratory tract, and urinary tract infections in the United States. Isolates tested in this study were collected as part of the Study for Monitoring Antimicrobial Resistance Trends (SMART) global surveillance program, which has monitored in vitro antimicrobial susceptibility profiles of clinical isolates of aerobic and facultative Gram-negative bacilli collected by laboratories worldwide from patients with intra-abdominal (since 2002), urinary tract (since 2009), and lower respiratory tract (since 2015) infections (13).
(The results of this report have been presented in part on 26 February 2018 at the 47th Critical Care Congress in San Antonio, TX.)
RESULTS
Of the 3,143 isolates of non-Proteeae Enterobacteriaceae tested, 99.1% (3,115/3,143) were susceptible to imipenem-relebactam, 95.9% (3,013/3,143) were susceptible to imipenem, and 96.1% (3,019/3,143) were susceptible to ertapenem (Table 1). Imipenem-relebactam inhibited all isolates of the 10 most commonly collected species of non-Proteeae Enterobacteriaceae at the susceptible MIC breakpoint for imipenem (1 μg/ml) with three exceptions: K. pneumoniae (99.4% susceptible to imipenem-relebactam), Klebsiella aerogenes (98.4% susceptible), and Serratia marcescens (89.7% susceptible). S. marcescens accounted for only 6.5% (203/3,143) of all isolates of non-Proteeae Enterobacteriaceae tested but contributed the majority (56.2%; 73/130) of imipenem-nonsusceptible isolates (Fig. 1). More than 95% of isolates of non-Proteeae Enterobacteriaceae were susceptible to imipenem with three exceptions: Citrobacter freundii (94.7% susceptible), Enterobacter asburiae (88.6%), and S. marcescens (64.0%) (Table 1). As expected, imipenem showed weak activity against Proteus mirabilis (54.4% susceptible) and Morganella morganii (8.3%), with relebactam increasing percent susceptibility to imipenem by only 11.5 to 16.7%.
TABLE 1.
In vitro activity of imipenem-relebactam, imipenem, and ertapenem against the 12 most common species of Enterobacteriaceae collected as part of the SMART global surveillance program in the United States in 2016
| Species of Enterobacteriaceae | n | % susceptible to drug: |
||
|---|---|---|---|---|
| Imipenem-relebactam | Imipenem | Ertapenem | ||
| Escherichia coli | 1,321 | 100 | 99.6 | 98.8 |
| Klebsiella pneumoniae | 717 | 99.4 | 96.9 | 95.5 |
| Enterobacter cloacae | 276 | 100 | 96.7 | 85.9 |
| Serratia marcescens | 203 | 89.7 | 64.0 | 96.6 |
| Proteus mirabilis | 182 | 65.9 | 54.4 | 98.9 |
| Klebsiella oxytoca | 174 | 100 | 100 | 99.4 |
| Klebsiella aerogenes | 126 | 98.4 | 95.2 | 95.2 |
| Citrobacter freundii | 94 | 100 | 94.7 | 90.4 |
| Morganella morganii | 48 | 25.0 | 8.3 | 100 |
| Enterobacter asburiae | 44 | 100 | 88.6 | 77.3 |
| Klebsiella variicola | 42 | 100 | 100 | 100 |
| Citrobacter koseri | 38 | 100 | 97.4 | 100 |
| All Enterobacteriaceae spp. | 3,419 | 96.1 | 92.2 | 96.3 |
| All non-Proteeae Enterobacteriaceae spp.a | 3,143 | 99.1 | 95.9 | 96.1 |
All non-Proteeae Enterobacteriaceae spp. exclude Proteus spp., Providencia spp., and Morganella spp.
FIG 1.
Species distribution among non-Proteeae Enterobacteriaceae and imipenem-nonsusceptible (IMI-NS), cefepime-nonsusceptible (FEP-NS), ceftazidime-nonsusceptible (CAZ-NS), piperacillin-tazobactam-nonsusceptible (P/T-NS), and MDR (multidrug-resistant) phenotypes.
Table 2 depicts the in vitro activity of imipenem-relebactam, imipenem, and comparator antimicrobial agents against all isolates of non-Proteeae Enterobacteriaceae (n = 3,143) as well as against nonsusceptible and MDR-phenotype subsets of isolates. Figure 2 depicts the prevalence of imipenem-nonsusceptible (4.1%), cefepime-nonsusceptible (11.5%), ceftazidime-nonsusceptible (14.4%), piperacillin-tazobactam-nonsusceptible (10.1%), and MDR (14.4%) phenotypes for non-Proteeae Enterobacteriaceae. Imipenem-relebactam susceptibility was ≥98% for cefepime-nonsusceptible, ceftazidime-nonsusceptible, and piperacillin-tazobactam-nonsusceptible phenotype subsets as well as for MDR isolates (Table 2). Relebactam restored in vitro susceptibility to 78.5% (102/130) for imipenem-nonsusceptible isolates and lowered the imipenem MIC90 by 16-fold. Relebactam also increased percent susceptibility to imipenem by 8.2 to 11.3% for cefepime-nonsusceptible, ceftazidime-nonsusceptible, piperacillin-tazobactam-nonsusceptible, and MDR phenotypes. Of the comparator agents, only amikacin demonstrated in vitro activity comparable to imipenem-relebactam against all isolates of non-Proteeae Enterobacteriaceae. Imipenem-relebactam inhibited 98.2% of all MDR isolates and 100% of seven of the eight most common MDR phenotypes, the exception being the MDR phenotype that included nonsusceptibility to aztreonam, ceftazidime, cefepime, ciprofloxacin, imipenem, and piperacillin-tazobactam, which accounted for only 4.0% of MDR phenotypes and was 88.9% susceptible to imipenem-relebactam (Table 3).
TABLE 2.
In vitro activity of imipenem-relebactam and comparative antimicrobial agents against non-Proteeae Enterobacteriaceae collected as part of the SMART global surveillance program in the United States in 2016
| Phenotype (n) | Antimicrobial agent | MIC determination (μg/ml) |
MIC interpretation |
||||
|---|---|---|---|---|---|---|---|
| MIC50 | MIC90 | MIC range | % susceptible | % intermediate | % resistant | ||
| All (3,143) | Imipenem-relebactama | 0.12 | 0.5 | ≤0.06 to >32 | 99.1 | 0.5 | 0.4 |
| Imipenem | ≤0.5 | 1 | ≤0.5 to >32 | 95.9 | 2.2 | 2.0 | |
| Ertapenem | ≤0.06 | 0.12 | ≤0.06 to >4 | 96.1 | 1.6 | 2.4 | |
| Amikacin | ≤4 | ≤4 | ≤4 to >32 | 99.6 | 0.3 | 0.2 | |
| Aztreonam | ≤1 | >16 | ≤1 to >16 | 83.8 | 1.9 | 14.2 | |
| Cefepimeb | ≤1 | 4 | ≤1 to >32 | 88.5 | 3.8 | 7.8 | |
| Ceftazidime | ≤1 | 16 | ≤1 to >32 | 85.6 | 2.3 | 12.2 | |
| Ceftriaxone | ≤1 | >32 | ≤1 to >32 | 79.8 | 1.9 | 18.2 | |
| Ciprofloxacin | ≤0.25 | >2 | ≤0.25 to >2 | 80.5 | 1.5 | 18.0 | |
| Colistinc | ≤1 | ≤1 | ≤1 to >4 | 91.3 | 8.7 | ||
| Piperacillin-tazobactam | ≤2 | 32 | ≤2 to >64 | 89.9 | 4.6 | 5.5 | |
| Imipenem nonsusceptible (130) | Imipenem-relebactama | 0.5 | 2 | ≤0.06 to >32 | 78.5 | 12.3 | 9.2 |
| Imipenem | 2 | 32 | 2 to >32 | 0 | 52.3 | 47.7 | |
| Ertapenem | ≤0.06 | >4 | ≤0.06 to >4 | 66.9 | 1.5 | 31.5 | |
| Amikacin | ≤4 | 16 | ≤4 to >32 | 97.7 | 1.5 | 0.8 | |
| Aztreonam | ≤1 | >16 | ≤1 to >16 | 64.6 | 1.5 | 33.9 | |
| Cefepimeb | ≤1 | >32 | ≤1 to >32 | 71.5 | 6.9 | 21.5 | |
| Ceftazidime | ≤1 | >32 | ≤1 to >32 | 66.9 | 3.1 | 30.0 | |
| Ceftriaxone | ≤1 | >32 | ≤1 to >32 | 60.8 | 3.9 | 35.4 | |
| Ciprofloxacin | ≤0.25 | >2 | ≤0.25 to >2 | 76.2 | 5.4 | 18.5 | |
| Colistinc | >4 | >4 | ≤1 to >4 | 41.5 | 58.5 | ||
| Piperacillin-tazobactam | ≤2 | >64 | ≤2 to >64 | 67.7 | 5.4 | 26.9 | |
| Cefepime nonsusceptible (363) | Imipenem-relebactama | 0.12 | 0.25 | ≤0.06 to >32 | 98.4 | 0.8 | 0.8 |
| Imipenem | ≤0.5 | 2 | ≤0.5 to >32 | 89.8 | 1.4 | 8.8 | |
| Ertapenem | ≤0.06 | >4 | ≤0.06 to >4 | 76.9 | 8.3 | 14.9 | |
| Amikacin | ≤4 | 16 | ≤4 to >32 | 97.3 | 1.9 | 0.8 | |
| Aztreonam | >16 | >16 | ≤1 to >16 | 8.5 | 7.4 | 84.0 | |
| Cefepimeb | 32 | >32 | 4 to >32 | 0 | 32.8 | 67.2 | |
| Ceftazidime | 16 | >32 | ≤1 to >32 | 17.6 | 14.6 | 67.8 | |
| Ceftriaxone | >32 | >32 | ≤1 to >32 | 1.7 | 0.3 | 98.1 | |
| Ciprofloxacin | >2 | >2 | ≤0.25 to >2 | 24.2 | 6.3 | 69.4 | |
| Colistinc | ≤1 | ≤1 | ≤1 to >4 | 96.1 | 3.9 | ||
| Piperacillin-tazobactam | 16 | >64 | ≤2 to >64 | 60.6 | 11.0 | 28.4 | |
| Ceftazidime nonsusceptible (454) | Imipenem-relebactama | 0.12 | 0.5 | ≤0.06 to >32 | 98.7 | 0.7 | 0.7 |
| Imipenem | ≤0.5 | 1 | ≤0.5 to >32 | 90.5 | 1.8 | 7.7 | |
| Ertapenem | 0.12 | 4 | ≤0.06 to >4 | 78.0 | 7.9 | 14.1 | |
| Amikacin | ≤4 | 8 | ≤4 to >32 | 98.0 | 1.5 | 0.4 | |
| Aztreonam | >16 | >16 | ≤1 to >16 | 5.5 | 5.7 | 88.8 | |
| Cefepimeb | 8 | >32 | ≤1 to >32 | 34.1 | 17.4 | 48.5 | |
| Ceftazidime | 32 | >32 | 8 to >32 | 0 | 15.9 | 84.1 | |
| Ceftriaxone | >32 | >32 | ≤1 to >32 | 1.5 | 1.3 | 97.1 | |
| Ciprofloxacin | >2 | >2 | ≤0.25 to >2 | 42.5 | 5.1 | 52.4 | |
| Colistinc | ≤1 | ≤1 | ≤1 to >4 | 93.4 | 6.6 | ||
| Piperacillin-tazobactam | 32 | >64 | ≤2 to >64 | 48.7 | 24.7 | 26.7 | |
| Piperacillin-tazobactam nonsusceptible (319) | Imipenem-relebactama | 0.12 | 0.5 | ≤0.06 to >32 | 98.1 | 0.9 | 0.9 |
| Imipenem | ≤0.5 | 4 | ≤0.5 to >32 | 86.8 | 2.2 | 11.0 | |
| Ertapenem | 0.25 | >4 | ≤0.06 to >4 | 69.9 | 11.0 | 19.1 | |
| Amikacin | ≤4 | 8 | ≤4 to >32 | 97.5 | 1.6 | 0.9 | |
| Aztreonam | >16 | >16 | ≤1 to >16 | 24.5 | 3.8 | 71.8 | |
| Cefepimeb | 2 | >32 | ≤1 to >32 | 55.2 | 18.2 | 26.7 | |
| Ceftazidime | 32 | >32 | ≤1 to >32 | 27.0 | 4.4 | 68.7 | |
| Ceftriaxone | 32 | >32 | ≤1 to >32 | 21.0 | 0.9 | 78.1 | |
| Ciprofloxacin | ≤0.25 | >2 | ≤0.25 to >2 | 58.9 | 4.7 | 36.4 | |
| Colistinc | ≤1 | ≤1 | ≤1 to >4 | 91.9 | 8.2 | ||
| Piperacillin-tazobactam | >64 | >64 | 32 to >64 | 0 | 45.5 | 54.6 | |
| MDR (452) | Imipenem-relebactama | 0.12 | 0.5 | ≤0.06 to >32 | 98.2 | 0.9 | 0.9 |
| Imipenem | ≤0.5 | 2 | ≤0.5 to >32 | 88.9 | 2.4 | 8.6 | |
| Ertapenem | 0.12 | 4 | ≤0.06 to >4 | 77.9 | 8.0 | 14.2 | |
| Amikacin | ≤4 | 8 | ≤4 to >32 | 97.8 | 1.6 | 0.7 | |
| Aztreonam | >16 | >16 | ≤1 to >16 | 3.3 | 8.2 | 88.5 | |
| Cefepimeb | 16 | >32 | ≤1 to >32 | 26.3 | 20.6 | 53.1 | |
| Ceftazidime | 32 | >32 | ≤1 to >32 | 10.0 | 13.3 | 76.8 | |
| Ceftriaxone | >32 | >32 | ≤1 to >32 | 2.7 | 0.4 | 96.9 | |
| Ciprofloxacin | >2 | >2 | ≤0.25 to >2 | 35.0 | 6.0 | 59.1 | |
| Colistinc | ≤1 | ≤1 | ≤1 to >4 | 91.2 | 8.9 | ||
| Piperacillin-tazobactam | 32 | >64 | ≤2 to >64 | 47.1 | 26.1 | 26.8 | |
Breakpoints for imipenem-relebactam have not been defined. For the purpose of comparison, MICs were interpreted using CLSI imipenem MIC breakpoints for Enterobacteriaceae (susceptible, ≤1 μg/ml; intermediate, 2 μg/ml; resistant, ≥4 μg/ml) (24).
For cefepime, the intermediate category is replaced by the “susceptible-dose dependent” category (24).
CLSI breakpoints for colistin have not been defined against Enterobacteriaceae, and MICs were interpreted using EUCAST breakpoints (26).
FIG 2.
Prevalence of imipenem-nonsusceptible (IMI-NS), cefepime-nonsusceptible (FEP-NS), ceftazidime-nonsusceptible (CAZ-NS), piperacillin-tazobactam-nonsusceptible (P/T-NS), and MDR (multidrug-resistant) phenotypes among non-Proteeae Enterobacteriaceae and P. aeruginosa isolates. 95% CI, 95% confidence interval.
TABLE 3.
In vitro activity of imipenem-relebactam against the most common MDR phenotypes of non-Proteeae Enterobacteriaceae
| Phenotypea | n (% of all MDR isolates) | Imipenem-relebactam |
|
|---|---|---|---|
| MIC90 (μg/ml) | % susceptible | ||
| All non-Proteeae Enterobacteriaceae | 3,143 | 0.25 | 99.1 |
| All MDR | 452b | 0.5 | 98.2 |
| ATM, CAZ, FEP, CIP | 137 (30.3) | 0.25 | 100 |
| ATM, CAZ, P/T | 69 (15.3) | 0.25 | 100 |
| ATM, CAZ, FEP, CIP, P/T | 57 (12.6) | 0.25 | 100 |
| ATM, CAZ, FEP, P/T | 31 (6.9) | 0.25 | 100 |
| ATM, FEP, CIP | 28 (6.2) | 0.25 | 100 |
| ATM, CAZ, FEP | 21 (4.6) | 0.5 | 100 |
| ATM, CAZ, FEP, CIP, IMI, P/T | 18 (4.0) | 4 | 88.9 |
| ATM, CAZ, FEP, IMI, P/T | 10 (2.2) | 0.25 | 100 |
Sentinel agents used for the definition of MDR included amikacin, aztreonam (ATM), cefepime (FEP), ceftazidime (CAZ), ciprofloxacin (CIP), colistin, imipenem (IMI), and piperacillin-tazobactam (P/T). The MDR phenotypes listed accounted for 82.1% (371/452) of all MDR phenotypes identified; amikacin or colistin resistance was not observed among the most common MDR phenotypes identified. Agents shown in the table tested as nonsusceptible; the other sentinel agents tested as susceptible. Agents tested but not included in the list of sentinel agents may have tested as susceptible or nonsusceptible.
MDR isolates accounted for 14.4% (452/3,143) of all isolates of non-Proteeae Enterobacteriaceae.
Among all P. aeruginosa isolates tested, 94.4% (846/896) and 74.7% (669/896) of isolates were susceptible to imipenem-relebactam and imipenem, respectively (Table 4). Of the comparator agents, only the activities of amikacin and colistin approximated or exceeded that of imipenem-relebactam. Among imipenem-nonsusceptible P. aeruginosa isolates, 78.0% (177/227) of isolates were rendered susceptible by the addition of relebactam. The MIC90 for imipenem-relebactam was 4-fold lower than that for imipenem alone. Among cefepime-nonsusceptible, ceftazidime-nonsusceptible, piperacillin-tazobactam-nonsusceptible, and MDR subsets, imipenem-relebactam susceptibility was ≥82.1%.
TABLE 4.
In vitro activity of imipenem-relebactam and comparative antimicrobial agents against P. aeruginosa
| Phenotypea (n) | Antimicrobial agent | MIC determination (μg/ml) |
MIC interpretation |
||||
|---|---|---|---|---|---|---|---|
| MIC50 | MIC90 | MIC range | % susceptible | % intermediate | % resistant | ||
| All (896) | Imipenem-relebactama | 0.5 | 2 | ≤0.06 to >32 | 94.4 | 2.8 | 2.8 |
| Imipenem | 1 | 16 | ≤0.5 to >32 | 74.7 | 5.1 | 20.2 | |
| Amikacin | ≤4 | 8 | ≤4 to >32 | 95.2 | 2.0 | 2.8 | |
| Aztreonam | 8 | >16 | ≤1 to >16 | 63.1 | 12.8 | 24.1 | |
| Cefepime | 4 | 32 | ≤1 to >32 | 73.8 | 13.4 | 12.8 | |
| Ceftazidime | 4 | >32 | ≤1 to >32 | 77.1 | 5.4 | 17.5 | |
| Ciprofloxacin | ≤0.25 | >2 | ≤0.25 to >2 | 72.9 | 5.4 | 21.8 | |
| Colistin | ≤1 | ≤1 | ≤1 to >4 | 99.7 | 0.3 | ||
| Piperacillin-tazobactam | 8 | >64 | ≤2 to >64 | 71.2 | 12.4 | 16.4 | |
| Imipenem nonsusceptible (227) | Imipenem-relebactama | 2 | 8 | 0.25 to >32 | 78.0 | 11.0 | 11.0 |
| Imipenem | 16 | 32 | 4 to >32 | 0 | 20.3 | 79.7 | |
| Amikacin | ≤4 | 32 | ≤4 to >32 | 88.1 | 5.3 | 6.6 | |
| Aztreonam | >16 | >16 | ≤1 to >16 | 33.0 | 15.9 | 51.1 | |
| Cefepime | 16 | >32 | ≤1 to >32 | 40.5 | 26.4 | 33.0 | |
| Ceftazidime | 8 | >32 | ≤1 to >32 | 50.7 | 10.6 | 38.8 | |
| Ciprofloxacin | >2 | >2 | ≤0.25 to >2 | 42.7 | 7.1 | 50.2 | |
| Colistin | ≤1 | ≤1 | ≤1 to >4 | 99.1 | 0.9 | ||
| Piperacillin-tazobactam | 32 | >64 | ≤2 to >64 | 41.0 | 22.0 | 37.0 | |
| Cefepime nonsusceptible (235) | Imipenem-relebactama | 1 | 4 | ≤0.06 to >32 | 82.1 | 8.5 | 9.4 |
| Imipenem | 8 | 32 | ≤0.5 to >32 | 42.6 | 6.4 | 51.1 | |
| Amikacin | ≤4 | 32 | ≤4 to >32 | 86.4 | 6.0 | 7.7 | |
| Aztreonam | >16 | >16 | ≤1 to >16 | 14.5 | 14.5 | 71.1 | |
| Cefepime | 16 | >32 | 16 to >32 | 0 | 51.1 | 48.9 | |
| Ceftazidime | 32 | >32 | 2 to >32 | 24.7 | 11.1 | 64.3 | |
| Ciprofloxacin | 2 | >2 | ≤0.25 to >2 | 47.7 | 8.5 | 43.8 | |
| Colistin | ≤1 | ≤1 | ≤1 to >4 | 99.6 | 0.4 | ||
| Piperacillin-tazobactam | >64 | >64 | ≤2 to >64 | 16.6 | 23.4 | 60.0 | |
| Ceftazidime nonsusceptible (205) | Imipenem-relebactama | 1 | 4 | ≤0.06 to >32 | 82.4 | 8.3 | 9.3 |
| Imipenem | 4 | 32 | ≤0.5 to >32 | 45.4 | 5.4 | 49.3 | |
| Amikacin | ≤4 | 32 | ≤4 to >32 | 87.3 | 4.9 | 7.8 | |
| Aztreonam | >16 | >16 | ≤1 to >16 | 9.8 | 14.2 | 76.1 | |
| Cefepime | 16 | >32 | 2 to >32 | 13.7 | 38.1 | 48.3 | |
| Ceftazidime | 32 | >32 | 16 to >32 | 0 | 23.4 | 76.6 | |
| Ciprofloxacin | 2 | >2 | ≤0.25 to >2 | 48.8 | 7.3 | 43.9 | |
| Colistin | ≤1 | ≤1 | ≤1 to >4 | 99.5 | 0.5 | ||
| Piperacillin-tazobactam | >64 | >64 | ≤2 to >64 | 6.3 | 25.4 | 68.3 | |
| Piperacillin-tazobactam nonsusceptible (258) | Imipenem-relebactama | 1 | 4 | ≤0.06 to >32 | 83.7 | 7.8 | 8.5 |
| Imipenem | 4 | 32 | ≤0.5 to >32 | 48.1 | 5.4 | 46.5 | |
| Amikacin | ≤4 | 16 | ≤4 to >32 | 90.3 | 2.7 | 7.0 | |
| Aztreonam | >16 | >16 | ≤1 to >16 | 10.1 | 16.7 | 73.3 | |
| Cefepime | 16 | >32 | ≤1 to >32 | 24.0 | 35.3 | 40.7 | |
| Ceftazidime | 32 | >32 | 2 to >32 | 25.6 | 15.1 | 59.3 | |
| Ciprofloxacin | 1 | >2 | ≤0.25 to >2 | 50.4 | 6.6 | 43.0 | |
| Colistin | ≤1 | ≤1 | ≤1 to >4 | 99.6 | 0.4 | ||
| Piperacillin-tazobactam | >64 | >64 | 32 to >64 | 0 | 43.0 | 57.0 | |
| MDR (264) | Imipenem-relebactama | 1 | 4 | ≤0.06 to >32 | 82.2 | 8.7 | 9.1 |
| Imipenem | 8 | 32 | ≤0.5 to >32 | 40.2 | 6.1 | 53.8 | |
| Amikacin | ≤4 | 32 | ≤4 to >32 | 87.5 | 5.3 | 7.2 | |
| Aztreonam | >16 | >16 | ≤1 to >16 | 8.7 | 20.5 | 70.8 | |
| Cefepime | 16 | >32 | 2 to >32 | 19.7 | 39.0 | 41.3 | |
| Ceftazidime | 32 | >32 | 2 to >32 | 24.6 | 16.3 | 59.1 | |
| Ciprofloxacin | 2 | >2 | ≤0.25 to >2 | 42.4 | 8.3 | 49.2 | |
| Colistin | ≤1 | ≤1 | ≤1 to >4 | 98.9 | 1.1 | ||
| Piperacillin-tazobactam | >64 | >64 | ≤2 to >64 | 12.1 | 32.6 | 55.3 | |
Breakpoints for imipenem-relebactam have not been defined. For the purpose of comparison, MICs were interpreted using CLSI imipenem MIC breakpoints for P. aeruginosa (susceptible, ≤2 μg/ml; intermediate, 4 μg/ml; resistant, ≥8 μg/ml) (24).
Figure 2 shows that the prevalences of imipenem-nonsusceptible (25.3%), cefepime-nonsusceptible (26.2%), ceftazidime-nonsusceptible (22.9%), piperacillin-tazobactam-nonsusceptible (28.8%), and MDR (29.5%) phenotypes were relatively similar (maximum difference, 6.6%) among P. aeruginosa isolates. These rates were approximately 2 to 3 times higher than those among non-Proteeae Enterobacteriaceae, except for the imipenem-nonsusceptible phenotype, which was approximately 6 times (25.3% versus 4.1%) more common among P. aeruginosa isolates.
Imipenem-relebactam inhibited 82.2% of all isolates of P. aeruginosa with an MDR phenotype (Table 5). Imipenem-relebactam inhibited all isolates of three of the seven most common MDR phenotypes but <90% of the other four most common MDR phenotypes. The most common MDR phenotypes with susceptibility to imipenem-relebactam of <90% were all nonsusceptible to imipenem, while phenotypes with 100% susceptibility to imipenem-relebactam were all susceptible to imipenem. All seven of the most common MDR phenotypes were nonsusceptible to aztreonam and piperacillin-tazobactam, and six of seven were nonsusceptible to ceftazidime.
TABLE 5.
In vitro activity of imipenem-relebactam against the most common MDR phenotypes of P. aeruginosaa
| Phenotypea | n (% of all MDR) | Imipenem-relebactam |
|
|---|---|---|---|
| MIC90 (μg/ml) | % susceptible | ||
| All P. aeruginosa | 896 | 2 | 94.4 |
| All MDR | 264b | 4 | 82.2 |
| ATM, CAZ, CIP, FEP, IMI, P/T | 57 (21.6) | 8 | 64.9 |
| ATM, CAZ, FEP, P/T | 53 (20.1) | 0.5 | 100 |
| ATM, CAZ, FEP, IMI, P/T | 24 (9.1) | 4 | 87.5 |
| AMK, ATM, CAZ, CIP, FEP, IMI, P/T | 13 (4.9) | 32 | 53.8 |
| ATM, CIP, FEP, IMI, P/T | 12 (4.5) | 8 | 58.3 |
| ATM, CAZ, P/T | 12 (4.5) | 0.5 | 100 |
| ATM, CAZ, CIP, FEP, P/T | 10 (3.8) | 0.5 | 100 |
Sentinel agents used for the definition of MDR included amikacin (AMK), aztreonam (ATM), cefepime (FEP), ceftazidime (CAZ), ciprofloxacin (CIP), colistin, imipenem (IMI), and piperacillin-tazobactam (P/T). The MDR phenotypes listed accounted for 68.7% (181/264) of all MDR phenotypes identified; colistin resistance was not observed among the most common MDR phenotypes identified. Agents shown in the table tested as nonsusceptible; the other sentinel agents tested as susceptible. Agents tested but not included in the list of sentinel agents may have tested as susceptible or nonsusceptible.
MDR isolates accounted for 29.5% (264/896) of all isolates of P. aeruginosa.
DISCUSSION
The current study determined that 99.1% of isolates of non-Proteeae Enterobacteriaceae and 94.4% of isolates of P. aeruginosa submitted to the SMART global surveillance program in 2016 from 21 hospital laboratories in the United States were susceptible to imipenem-relebactam. Imipenem-relebactam demonstrated potent in vitro activity against cefepime-, ceftazidime-, and piperacillin-nonsusceptible as well as MDR subsets of non-Proteeae Enterobacteriaceae (>98% susceptible to imipenem-relebactam) and of P. aeruginosa (>82% susceptible to imipenem-relebactam). Relebactam restored imipenem susceptibility to 78.5% of imipenem-nonsusceptible non-Proteeae Enterobacteriaceae and to 78.0% of imipenem-nonsusceptible P. aeruginosa isolates. The results of the current study are comparable to a previous 2015 study of Gram-negative bacilli from the United States, which was restricted to patients with lower respiratory tract infections. The 2015 study reported similar but slightly lower rates of susceptibility to imipenem-relebactam of 97.2% (829/853) for isolates of non-Proteeae Enterobacteriaceae and 93.1% (557/598) for isolates of P. aeruginosa (using CLSI MIC interpretative criteria for imipenem); relebactam restored imipenem susceptibility to 66.7% (48/72) and 78.5% (150/191) of isolates of imipenem-nonsusceptible non-Proteeae Enterobacteriaceae and P. aeruginosa, respectively (10).
A limited number of previous studies have also reported that relebactam restored the in vitro activity of imipenem against Gram-negative pathogens nonsusceptible to carbapenems by mechanisms other than metallo-β-lactamases (8, 9, 11, 12). The greatest impact of the addition of relebactam to imipenem has been reported for isolates of K. pneumoniae that harbor KPC-type carbapenemases and ESBLs, as well as for isolates of carbapenem-resistant P. aeruginosa that lack OprD and express AmpC β-lactamase (9, 12). Lob et al. also showed that imipenem-relebactam inhibited all (n = 21) KPC-producing K. pneumoniae and Enterobacter spp. collected in the United States in 2015 as part of the SMART program (11). Relebactam increased imipenem susceptibility from 8 to 88% in 100 isolates of carbapenem-resistant Enterobacteriaceae (8). Relebactam restored imipenem activity against CRE isolates regardless of KPC or ESBL type (8). The addition of relebactam at a fixed concentration of 4 μg/ml to imipenem has also been shown to lower imipenem MICs for 14 isolates of KPC-producing K. pneumoniae that also expressed ramA or acrB or were without frameshift mutations in ompK35 or demonstrated reduced or elevated expression of ompK36 (12). Livermore et al. indicated that both imipenem and relebactam were poor substrates for efflux in P. aeruginosa and speculated that relebactam potentiates the activity of imipenem against P. aeruginosa by inhibiting the imipenem-hydrolyzing AmpC ubiquitous in that species (9).
The 2015 U.S. study showed that 63.8% (83/130) and 85.4% (111/130) of S. marcescens isolates were susceptible to imipenem and imipenem-relebactam, respectively (10), consistent with the results of the current study. Lob et al. determined that imipenem nonsusceptibility in 91.5% (43/47) of imipenem-nonsusceptible S. marcescens isolates was not attributable to any of the screened acquired β-lactamases (10). Although the chromosomally encoded Ambler class A Serratia marcescens enzyme (SME) carbapenemase was not included in the testing algorithm, the antimicrobial susceptibility patterns of these isolates were not consistent with the susceptibilities displayed by the majority of SME producers (14–16). In the current study, the low susceptibility of S. marcescens to imipenem was increased by >25% to 89.7% by the addition of relebactam (Table 1). The findings that 96.9% of isolates of S. marcescens were susceptible to ertapenem and that susceptibility to imipenem increased by >25% when combined with relebactam suggest that the observed nonsusceptibility to imipenem for S. marcescens may be due, in part, to an undetected imipenem-hydrolyzing β-lactamase but that additional mechanisms conferring imipenem nonsusceptibility must also be present in some isolates. The resistance mechanisms among Serratia spp. are currently under further investigation.
In the literature, there is a lack of antimicrobial susceptibility data related to the activity of imipenem-relebactam against isolates resistant to commonly tested β-lactams and against MDR isolates. The current study found susceptibility rates of ∼98% and ∼82%, respectively, for NPE and P. aeruginosa isolates that were nonsusceptible to cephalosporins, nonsusceptible to piperacillin-tazobactam, or MDR. Surveillance reports indicate that the prevalence of MDR infections caused by Enterobacteriaceae and P. aeruginosa among hospitalized patients is increasing in the United States and elsewhere (3, 4). The identification of MDR bacterial pathogens is commonly an actionable result for hospital infection prevention and control programs. Definitions of MDR vary (17, 18), but MDR pathogens are widely appreciated to be associated with significant morbidity and mortality, longer hospitalizations, and increased costs compared with infections caused by susceptible organisms (19–22). Pan-drug-resistant isolates of K. pneumoniae producing carbapenemases and P. aeruginosa have been reported (23). Sader and coworkers recently published a study of 94 U.S. hospital laboratories from 2013 to 2016 and reported the prevalence of carbapenem-resistant isolates (resistant to imipenem, meropenem, or doripenem) of Enterobacteriaceae to be 1.4% (2), similar to but slightly lower than our finding (2.0 to 2.4% carbapenem-resistant non-Proteeae Enterobacteriaceae), and an MDR rate of 8.1% (2,953/36,380) (2), approximately one-half the rate of MDR identified in the current study (14.4%; 452/3,143). The difference in MDR rates may be attributable to different definitions of MDR used in the two studies as well as to isolates tested from different infection sources. The same investigators also reported 18.7% of P. aeruginosa as carbapenem nonsusceptible and 19.9% (1,562/7,868) of isolates as MDR (2), lower than the 25.3% and 29.5% (264/896) of isolates identified as carbapenem-nonsusceptible and MDR, respectively, in the current study. These differences may again reflect the different definitions of MDR and the different infection sources used in the two studies.
A review of the data for imipenem-nonsusceptible isolates of Enterobacteriaceae (Table 2) and P. aeruginosa (Table 4) in the current study identified an unexpected finding. Of the 130 isolates of imipenem-nonsusceptible Enterobacteriaceae, percent susceptibilities to ertapenem, cephalosporins, piperacillin-tazobactam, and aztreonam all exceeded 60%. This observation appears to be largely the result of the application of CLSI MIC interpretative breakpoints for imipenem (susceptible, 1 μg/ml) (24) against a collection of isolates of Enterobacteriaceae where the upper limit of the wild-type population for some species of Enterobacteriaceae in the collection (specifically Serratia spp.) is 1 doubling-dilution above the CLSI susceptible breakpoint for imipenem (i.e., 2 μg/ml); imipenem MICs of 2 μg/ml account for >10% of wild-type isolates of Serratia spp. (25). The unexpectedly low percent susceptibility of S. marcescens isolates to imipenem in the current study (64.0% susceptible; 130/203 isolates) was due primarily to 47 isolates (23.2% of isolates of S. marcescens) with imipenem MICs of 2 μg/ml (data not shown); similarly, there were 13 isolates of S. marcescens (6.4% of isolates) with imipenem-relebactam MICs of 2 μg/ml (data not shown). If the imipenem MIC data in the current study were interpreted using EUCAST MIC breakpoints, 87.2% (177/203) of isolates of S. marcescens would be imipenem susceptible (MIC, ≤2 μg/ml), only 3.4% (7/203) of isolates would be imipenem resistant, 96.1% (195/203) of isolates of S. marcescens would be imipenem-relebactam susceptible (MIC, ≤2 μg/ml), and none of the isolates would be imipenem-relebactam resistant (26). Similarly, the upper limit of the wild-type population of P. aeruginosa is 1 doubling-dilution above the CLSI susceptible breakpoint for imipenem (i.e., 4 μg/ml) (25). If the imipenem MIC data in the current study were interpreted using EUCAST MIC breakpoints for P. aeruginosa, 79.8% (715/896) of isolates of P. aeruginosa would be imipenem susceptible (MIC, ≤4 μg/ml), 14.0% (125/896) of isolates would be imipenem resistant (MIC, >8 μg/ml), 97.2% (871/896) of isolates of P. aeruginosa would be imipenem-relebactam susceptible (MIC, ≤4 μg/ml), and 1.3% (12/896) of isolates would be imipenem-relebactam resistant (MIC, >8 μg/ml) (data not shown) (26).
We conclude that non-Proteeae Enterobacteriaceae and P. aeruginosa submitted to the SMART global surveillance program in 2016 from 21 hospital laboratories in the United States demonstrated reduced in vitro susceptibility to advanced-generation cephalosporins (cefepime, ceftazidime, and ceftriaxone), piperacillin-tazobactam, and fluoroquinolones (ciprofloxacin) and that relebactam demonstrated a strong propensity to restore the in vitro activity of imipenem against carbapenem-nonsusceptible and MDR isolates of non-Proteeae Enterobacteriaceae and P. aeruginosa. Imipenem-relebactam also demonstrated potent in vitro activity against cefepime-, ceftazidime-, and piperacillin-nonsusceptible isolates of non-Proteeae Enterobacteriaceae and P. aeruginosa. Further development of imipenem-relebactam, which is currently in phase 3 development for the treatment of imipenem-resistant Gram-negative infections, including hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (see https://clinicaltrials.gov/ct2/results?term=MK-7655&Search=Search), appears warranted. Imipenem-relebactam would provide an additional option for treating patients with infections caused by antimicrobial-resistant non-Proteeae Enterobacteriaceae and P. aeruginosa beyond therapy with polymyxins, aminoglycosides, and tigecycline, which are associated with increasing resistance and significant morbidity (polymyxins and aminoglycosides), as well as intrinsic resistance of P. aeruginosa (tigecycline).
MATERIALS AND METHODS
Bacterial isolates.
In 2016, 21 hospital laboratories in 15 U.S. states (California, Colorado, Florida, Georgia, Illinois, Indiana, Iowa, Kentucky, Michigan, New York, North Carolina, Ohio, Pennsylvania, Washington, and Wisconsin) participated in the SMART global surveillance program. Each hospital laboratory was asked to collect and transport consecutive aerobic and/or facultative Gram-negative pathogens cultured from lower respiratory tract (n = 100), intra-abdominal (n = 100), or urinary tract (n = 50) specimens of unique patients to International Health Management Associates, Inc. (IHMA; Schaumburg, IL), which acted as the central testing laboratory for the SMART global surveillance program. In total, the 21 participating hospital laboratories submitted 4,678 isolates of Gram-negative bacilli from lower respiratory tract (n = 1,954), intra-abdominal (n = 1,633), urinary tract (n = 1,050), and unspecified (n = 41) specimens. Of the 4,678 isolates, 3,419 were Enterobacteriaceae (3,143 non-Proteeae Enterobacteriaceae and 276 Proteeae), 896 were P. aeruginosa, and 363 were other Gram-negative bacilli. All isolates received by IHMA were reidentified using matrix-assisted laser desorption ionization–time of flight (MALDI-TOF) mass spectrometry (Bruker Daltonics, Billerica, MA, USA).
Antimicrobial susceptibility testing.
Antimicrobial susceptibility testing was performed at IHMA using the Clinical and Laboratory Standards Institute (CLSI) reference broth microdilution method (24, 27) with custom-made dehydrated Trek Diagnostic Systems panels (Thermo Scientific, Independence, OH). Species within the tribe Proteeae were excluded from testing because they are intrinsically resistant to imipenem, by a mechanism independent of carbapenemase production (24, 28), and imipenem-relebactam is not anticipated to possess clinically useful activity against Proteeae. Non-Enterobacteriaceae Gram-negative bacilli other than P. aeruginosa were also excluded from testing because of their intrinsic resistance to imipenem (Stenotrophomonas maltophilia [n = 145] and Burkholderia spp. [n = 20]) (24), limited susceptibility to imipenem (Acinetobacter baumannii [n = 72]) (12, 29), or low numbers of isolates (126 isolates from 32 species). The concentration ranges for each of the antimicrobial agents tested in this study were as indicated: imipenem-relebactam, 0.06 to 32 μg/ml; imipenem, 0.5 to 32 μg/ml; ertapenem, 0.06 to 4 μg/ml; amikacin, 4 to 32 μg/ml; aztreonam, 1 to 16 μg/ml; cefepime, 1 to 32 μg/ml; ceftazidime, 1 to 32 μg/ml; ceftriaxone, 1 to 32 μg/ml; ciprofloxacin, 0.25 to 2 μg/ml; colistin, 1 to 4 μg/ml; and piperacillin-tazobactam, 2 to 64 μg/ml. Relebactam was tested at a fixed concentration of 4 μg/ml in combination with 2-fold dilutions of imipenem. MICs were interpreted as susceptible, intermediate, or resistant using CLSI breakpoints (24). For comparative purposes, MICs for imipenem-relebactam were interpreted using CLSI imipenem MIC breakpoints for Enterobacteriaceae (susceptible, 1 μg/ml; intermediate, 2 μg/ml; resistant, 4 μg/ml) and P. aeruginosa (susceptible, 2 μg/ml; intermediate, 4 μg/ml; resistant, 8 μg/ml). European Committee on Antimicrobial Susceptibility Testing (EUCAST) MIC breakpoints for colistin tested against Enterobacteriaceae were used (susceptible, ≤2 μg/ml; resistant, ≥4 μg/ml) (26) because CLSI or FDA colistin breakpoints have not been defined for Enterobacteriaceae. Escherichia coli ATCC 25922, E. coli ATCC 35218, and P. aeruginosa ATCC 27853 were used as quality control strains for testing (24).
For both Enterobacteriaceae and P. aeruginosa, MDR was defined as nonsusceptibility (intermediate or resistant) to any three or more of the following eight sentinel agents: amikacin, aztreonam, cefepime, ceftazidime, ciprofloxacin, colistin, imipenem, and piperacillin-tazobactam.
ACKNOWLEDGMENTS
We thank all SMART participants for their contributions to the program.
Funding for this research was provided by Merck & Co., Inc., Kenilworth, NJ, which also included compensation for services in relation to preparing the manuscript.
J.A.K. is a consultant to International Health Management Associates, Inc. (IHMA, Inc.), and an employee of the University of Manitoba and Diagnostic Services Manitoba. S.H.L., K.M.K., and D.F.S. work for IHMA, Inc., which receives funding from Merck & Co., Inc., for the SMART surveillance program. K.Y. and M.R.M. are employees of Merck & Co., Inc., and own stock and options in the company. J.A.K. and the IHMA authors do not have personal financial interests in the sponsor of this paper (Merck & Co., Inc.).
REFERENCES
- 1.Centers for Disease Control and Prevention. 2013. Antibiotic resistance threats in the United States, 2013. Centers for Disease Control and Prevention, Atlanta, GA: https://www.cdc.gov/drugresistance/threat-report-2013/index.html. [Google Scholar]
- 2.Sader HS, Castanheira M, Shortridge D, Mendes RE, Flamm RK. 2017. Antimicrobial activity of ceftazidime-avibactam tested against multidrug-resistant Enterobacteriaceae and Pseudomonas aeruginosa isolates from U.S. medical centers, 2013 to 2016. Antimicrob Agents Chemother 61:e01045-. doi: 10.1128/AAC.01045-17. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Weiner LM, Webb AK, Limbago B, Dudeck MA, Patel J, Srinivasan A, Kallen A, 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]
- 4.Sievert DM, Ricks P, Edwards JR, Schneider A, Patel J, Srinivasan A, Kallen A, Limbago B, Fridkin S, National Healthcare Safety Network (NHSN) Team, Participating NHSN Facilities . 2013. 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, 2009–2010. Infect Control Hosp Epidemiol 34:1–14. doi: 10.1086/668770. [DOI] [PubMed] [Google Scholar]
- 5.Wright H, Bonomo RA, Paterson DL. 2017. New agents for the treatment of infections with Gram-negative bacteria: restoring the miracle or false dawn? Clin Microbiol Infect 23:704–712. doi: 10.1016/j.cmi.2017.09.001. [DOI] [PubMed] [Google Scholar]
- 6.Olsen I. 2015. New promising β-lactamase inhibitors for clinical use. Eur J Clin Microbiol Infect Dis 34:1303–1308. doi: 10.1007/s10096-015-2375-0. [DOI] [PubMed] [Google Scholar]
- 7.Livermore DM, Jamrozy D, Mushtaq S, Nichols WW, Young K, Woodford N. 2017. AmpC β-lactamase induction by avibactam and relebactam. J Antimicrob Chemother 72:3342–3348. doi: 10.1093/jac/dkx298. [DOI] [PubMed] [Google Scholar]
- 8.Haidar G, Clancy CJ, Chen L, Samanta P, Shields RK, Kreiswirth BN, Nguyen MH. 2017. Identifying spectra of activity and therapeutic niches for ceftazidime-avibactam and imipenem-relebactam against carbapenem-resistant Enterobacteriaceae. Antimicrob Agents Chemother 61:e00642-. doi: 10.1128/AAC.00642-17. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Livermore DM, Warner M, Mushtaq S. 2013. Activity of MK-7655 combined with imipenem against Enterobacteriaceae and Pseudomonas aeruginosa. J Antimicrob Chemother 68:2286–2290. doi: 10.1093/jac/dkt178. [DOI] [PubMed] [Google Scholar]
- 10.Lob SH, Hackel MA, Kazmierczak KM, Hoban DJ, Young K, Motyl MR, Karlowsky JA, Sahm DF. 2017. In vitro activity of imipenem-relebactam against Gram-negative bacilli isolated from patients with lower respiratory tract infections in the United States in 2015—results from the SMART global surveillance program. Diagn Microbiol Infect Dis 88:171–176. doi: 10.1016/j.diagmicrobio.2017.02.018. [DOI] [PubMed] [Google Scholar]
- 11.Lob SH, Hackel MA, Kazmierczak KM, Young K, Motyl MR, Karlowsky JA, Sahm DF. 2017. In vitro activity of imipenem-relebactam against Gram-negative ESKAPE pathogens isolated by clinical laboratories in the United States in 2015 (results from the SMART global surveillance program). Antimicrob Agents Chemother 61:e02209-. doi: 10.1128/AAC.02209-16. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Lapuebla A, Abdallah M, Olafisoye O, Cortes C, Urban C, Landman D, Quale J. 2015. Activity of imipenem with relebactam against Gram-negative pathogens from New York City. Antimicrob Agents Chemother 59:5029–5031. doi: 10.1128/AAC.00830-15. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Morrissey I, Hackel M, Badal R, Bouchillon S, Hawser S, Biedenbach D. 2013. A review of ten years of the Study for Monitoring Antimicrobial Resistance Trends (SMART) from 2002 to 2011. Pharmaceuticals (Basel) 6:1335–1346. doi: 10.3390/ph6111335. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Bush K, Pannell M, Lock JL, Queenan AM, Jorgensen JH, Lee RM, Lewis JS, Jarrett D. 2013. Detection systems for carbapenemase gene identification should include the SME serine carbapenemase. Int J Antimicrob Agents 41:1–4. doi: 10.1016/j.ijantimicag.2012.08.008. [DOI] [PubMed] [Google Scholar]
- 15.Hopkins KL, Findlay J, Meunier D, Cummins M, Curtis S, Kustos I, Mustafa N, Perry C, Pike R, Woodford N. 2017. Serratia marcescens producing SME carbapenemases: an emerging resistance problem in the UK? J Antimicrob Chemother 72:1535–1537. doi: 10.1093/jac/dkx103. [DOI] [PubMed] [Google Scholar]
- 16.Mataseje LF, Boyd DA, Delport J, Hoang L, Imperial M, Lefebvre B, Kuhn M, Van Caeseele P, Willey BM, Mulvey MR. 2014. Serratia marcescens harbouring SME-type class A carbapenemases in Canada and the presence of blaSME on a novel genomic island, SmarGI1-1. J Antimicrob Chemother 69:1825–1829. doi: 10.1093/jac/dku040. [DOI] [PubMed] [Google Scholar]
- 17.Magiorakos A-P, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CG, Harbarth S, Hindler JF, Kahlmeter G, Olsson-Liljequist B, Paterson DL, Rice LB, Stelling J, Struelens MJ, Vatopoulos A, Weber JT, Monnet JL. 2012. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistant. Clin Microbiol Infect 18:268–281. doi: 10.1111/j.1469-0691.2011.03570.x. [DOI] [PubMed] [Google Scholar]
- 18.German GJ, Jamieson FB, Gilmour M, Almohri H, Bullard J, Domingo MC, Fuller J, Girouard G, Haldane D, Hoang L, Levett PN, Longtin J, Melano R, Needle R, Patel SN, Rebbapragada A, Reyes RC, Mulvey MR. 2016. Interim recommendations for the reporting of extensively drug resistant and pan-drug resistant isolates of Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter spp. and Stenotrophomonas maltophilia. Can Commun Dis Rep 42:91–97. doi: 10.14745/ccdr.v42i04a04. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Thaden JT, Li Y, Ruffin F, Maskarinec SA, Hill-Rorie JM, Wanda LC, Reed SD, Fowler VG Jr. 2017. Increased costs associated with bloodstream infections caused by multidrug-resistant Gram-negative bacteria are due primarily to patients with hospital-acquired infections. Antimicrob Agents Chemother 61:e01709-16. doi: 10.1128/AAC.01709-16. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Zarkotou O, Pournaras S, Tselioti P, Dragoumanos V, Pitiriga V, Ranellou K, Prekates A, Themeli-Digalaki K, Tsakris A. 2011. Predictors of mortality in patients with bloodstream infections caused by KPC-producing Klebsiella pneumoniae and impact of appropriate antimicrobial treatment. Clin Microbiol Infect 17:1798–1803. doi: 10.1111/j.1469-0691.2011.03514.x. [DOI] [PubMed] [Google Scholar]
- 21.Patel TW, Nagel JL. 2015. Clinical outcomes of Enterobacteriaceae infections stratified by carbapenem MICs. J Clin Microbiol 53:201–205. doi: 10.1128/JCM.03057-14. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Pogue JM, Kaye KS, Cohen DA, Marchaim D. 2015. Appropriate antimicrobial therapy in the era of multidrug-resistant human pathogens. Clin Microbiol Infect 21:302–312. doi: 10.1016/j.cmi.2014.12.025. [DOI] [PubMed] [Google Scholar]
- 23.Schwaber MJ, Carmeli Y. 2007. Mortality and delay in effective therapy associated with extended-spectrum beta-lactamase production in Enterobacteriaceae bacteraemia: a systematic review and meta-analysis. J Antimicrob Chemother 60:913–920. doi: 10.1093/jac/dkm318. [DOI] [PubMed] [Google Scholar]
- 24.Clinical and Laboratory Standards Institute. 2017. Performance standards for antimicrobial susceptibility testing. M100, 27th ed Clinical and Laboratory Standards Institute, Wayne, PA. [Google Scholar]
- 25.EUCAST. 2018. MIC and zone diameter distributions and ECOFFs. Accessed 1 April 2018. http://www.eucast.org/mic_distributions_and_ecoffs/.
- 26.EUCAST. 2017. EUCAST breakpoint tables for interpretation of MICs and zone diameters. Version 7.1 http://www.eucast.org/clinical_breakpoints/.
- 27.Clinical and Laboratory Standards Institute. 2015. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically: 10th ed: approved standard M07-A10. Clinical and Laboratory Standards Institute, Wayne, PA. [Google Scholar]
- 28.Neuwirth C, Siébor E, Duez JM, Péchinot A, Kazmierczak A. 1995. Imipenem resistance in clinical isolates of Proteus mirabilis associated with alterations in penicillin-binding proteins. J Antimicrob Chemother 36:335–342. doi: 10.1093/jac/36.2.335. [DOI] [PubMed] [Google Scholar]
- 29.Lob SH, Hoban DJ, Sahm DF, Badal RE. 2016. Regional differences and trends in antimicrobial susceptibility of Acinetobacter baumannii. Int J Antimicrob Agents 47:317–323. doi: 10.1016/j.ijantimicag.2016.01.015. [DOI] [PubMed] [Google Scholar]