ABSTRACT
We evaluated the activity of meropenem-vaborbactam against contemporary nonfastidious Gram-negative clinical isolates, including Enterobacteriaceae isolates with resistance phenotypes and carbapenemase genotypes. Meropenem-vaborbactam (inhibitor at 8 μg/ml) and comparators were susceptibility tested by reference broth microdilution methods against 14,304 Gram-negative clinical isolates collected worldwide during 2014. Carbapenemase-encoding genes were screened by PCR and sequencing. Meropenem-vaborbactam (MIC50/90, ≤0.015/0.06 μg/ml) inhibited 99.1 and 99.3% of the 10,426 Enterobacteriaceae isolates tested at ≤1 and ≤2 μg/ml, respectively. Meropenem inhibited 97.3 and 97.7% of these isolates at the same concentrations. Against Enterobacteriaceae isolates displaying carbapenem-resistant Enterobacteriaceae (CRE) (n = 265), multidrug-resistant (MDR) (n = 1,210), and extensively drug-resistant (XDR) (n = 161) phenotypes, meropenem-vaborbactam displayed MIC50/90 values of 0.5/32, 0.03/1, and 0.5/32 μg/ml, respectively, whereas meropenem activities were 16/>32, 0.06/32, and 0.5/32 μg/ml, respectively. Among all geographic regions, the highest meropenem-vaborbactam activities were observed for CRE and MDR isolates from the United States (MIC50/90, 0.03/1 and 0.03/0.12 μg/ml, respectively). Meropenem-vaborbactam was very active against 135 KPC producers, and all isolates were inhibited by concentrations of ≤8 μg/ml (133 isolates by concentrations of ≤2 μg/ml). This combination had limited activity against isolates producing metallo-β-lactamases (including 25 NDM-1 and 16 VIM producers) and/or oxacillinases (27 OXA-48/OXA-163 producers) that were detected mainly in Asia-Pacific and some European countries. The activity of meropenem-vaborbactam was similar to that of meropenem alone against Pseudomonas aeruginosa, Acinetobacter spp., and Stenotrophomonas maltophilia. Meropenem-vaborbactam was active against contemporary Enterobacteriaceae isolates collected worldwide, and this combination demonstrated enhanced activity compared to those of meropenem and most comparator agents against CRE isolates and KPC producers, the latter of which are often MDR.
KEYWORDS: meropenem-vaborbactam, CRE, KPC producers
INTRODUCTION
Serious infections caused by Gram-negative bacilli are increasingly reported worldwide, and these organisms contribute to infection mortality rates that range from 30 to 70% (1). Bacterial species within this group are among the pathogens that are most difficult to treat, due to either intrinsic or acquired resistance mechanisms. Among Gram-negative species, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp. have been identified as organisms that should be monitored due to limited treatment options and patient management challenges for infections caused by these pathogens (2).
Pseudomonas aeruginosa and Acinetobacter spp. are intrinsically less susceptible to many antimicrobial agents (3). Additionally, these organisms can acquire or develop resistance at high frequencies through mutations and acquisition of foreign DNA (4). Enterobacteriaceae species are usually more susceptible, but the rise of K. pneumoniae and other organisms displaying multidrug-, extensively drug-, and pandrug-resistant (MDR, XDR, and PDR, respectively) phenotypes are threatening the current treatment protocols for serious infections caused by these species (2, 3, 5).
Carbapenems were often considered the last resource for treating serious infections caused by MDR organisms or isolates producing β-lactamases, but these agents are now often hydrolyzed by carbapenemases, which include KPC serine carbapenemases, OXA-48, and class B metallo-β-lactamases (MBLs) that have become disseminated worldwide. Isolates producing KPC enzymes have been detected in all but two states in the United States according to the Centers for Disease Control and Prevention (CDC) (http://www.cdc.gov/hai/organisms/cre/TrackingCRE.html), and isolates producing these enzymes have high prevalences in the New York City area (6) and Texas (7). KPC-producing isolates have also been reported in Germany, Poland, Belgium, Hungary, Croatia, and the United Kingdom. The corresponding genes are considered endemic in Greece and Italy (http://ecdc.europa.eu/en/publications/Publications/antimicrobial-resistance-carbapenemase-producing-bacteria-europe.pdf), and these enzymes are also very prevalent in other countries, such as Israel, China, and Brazil (5). KPC enzymes hydrolyze virtually all β-lactams, and isolates producing these enzymes are often MDR, and in some instances can be XDR or PDR (resistant to all available classes of antimicrobial agents).
Vaborbactam (formerly named RPX7009) is a cyclic boronic acid β-lactamase inhibitor that has activity against Ambler class A (including KPC) and C enzymes (8). This inhibitor has been combined with meropenem, and vaborbactam enhances the activity of this carbapenem against KPC-producing isolates compared to that of the β-lactam tested alone (9, 10).
In this study, we evaluated the activities of meropenem-vaborbactam and comparator antimicrobial agents against 14,304 nonfastidious Gram-negative bacillus clinical isolates collected in 82 hospitals worldwide during 2014. We also analyzed Enterobacteriaceae isolates according to their resistance phenotypes and carbapenemase genotypes.
RESULTS
Overall activity of meropenem-vaborbactam against isolates.
Among 14,304 Gram-negative nonfastidious clinical isolates collected worldwide, 897 isolates were from the Asia-Pacific region (6.3% overall), 7,033 from Europe (49.2%), 716 from Latin America (5.0%), and 5,658 from the United States (39.6%). These isolates were collected from the following specimen sources: bloodstream infections (3,299 [23.1%]), pneumonia in hospitalized patients (4,174 [29.2%]), skin and skin structure infections (2,880 [20.1%]), urinary tract infections (2,603 [18.2%]), intra-abdominal infections (1,086 [7.6%]), and other, less prevalent or undetermined clinical specimen types (262 [1.8%]). This collection comprised all Gram-negative isolates collected in 82 hospitals as part of the SENTRY Antimicrobial Surveillance Program.
Overall, meropenem-vaborbactam (vaborbactam at 8 μg/ml; MIC50 and MIC90, ≤0.015 and 0.06 μg/ml, respectively) (Table 1) inhibited 99.3% of all Enterobacteriaceae isolates at ≤2 μg/ml and 99.1% of the isolates at ≤1 μg/ml (EUCAST and CLSI susceptibility breakpoints, respectively, for meropenem tested alone [used for comparison purposes only]) (Table 1). Using a tentative breakpoint of 8 μg/ml, based on the proposed dosing scheme and modeled attainment for meropenem-vaborbactam (11), this combination inhibited 99.6% of the Enterobacteriaceae isolates (Table 1). Meropenem alone (MIC50 and MIC90, 0.03 and 0.06 μg/ml) inhibited 97.7 and 97.3% of the isolates at the current EUCAST and CLSI susceptibility breakpoints of ≤2 and ≤1 μg/ml, respectively (Table 2). Susceptibility rates for the comparator antimicrobial agents tested against Enterobacteriaceae isolates ranged from 79.7 to 99.5% and from 78.2 to 96.2% by applying the CLSI and EUCAST breakpoints, respectively (Table 2). The lowest susceptibility rates were noted for levofloxacin and the highest for tigecycline by applying the U.S. FDA breakpoint (Table 2).
TABLE 1.
Antimicrobial activity of meropenem-vaborbactam (inhibitor at fixed concentration of 8 μg/ml) against clinical isolates belonging to common Gram-negative species collected worldwide during 2014
| Group or organism name | No. of isolates tested | No. of isolates (cumulative %) at meropenem-vaborbactam MIC (μg/ml) of: |
MIC50 (μg/ml) | MIC90 (μg/ml) | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ≤0.015 | 0.03 | 0.06 | 0.12 | 0.25 | 0.5 | 1 | 2 | 4 | 8 | 16 | 32 | >32 | ||||
| Enterobacteriaceae | 10,426 | 6,171 (59.2) | 2,828 (86.3) | 947 (95.4) | 190 (97.2) | 80 (98.0) | 66 (98.6) | 47 (99.1) | 19 (99.3) | 24 (99.5) | 12 (99.6) | 8 (99.7) | 14 (99.8) | 20 (100.0) | ≤0.015 | 0.06 |
| Escherichia coli | 4,238 | 3,916 (92.4) | 274 (98.9) | 32 (99.6) | 2 (99.7) | 4 (99.8) | 3 (99.8) | 4 (99.9) | 1 (>99.9) | 1 (>99.9) | 0 (>99.9) | 0 (>99.9) | 1 (100.0) | ≤0.015 | ≤0.015 | |
| Klebsiella pneumoniae | 2,010 | 819 (40.7) | 928 (86.9) | 32 (88.5) | 41 (90.5) | 50 (93.0) | 47 (95.4) | 28 (96.8) | 9 (97.2) | 12 (97.8) | 6 (98.1) | 7 (98.5) | 12 (99.1) | 19 (100.0) | 0.03 | 0.12 |
| Klebsiella oxytoca | 429 | 210 (49.0) | 214 (98.8) | 1 (99.1) | 0 (99.1) | 0 (99.1) | 1 (99.3) | 1 (99.5) | 0 (99.5) | 0 (99.5) | 1 (99.8) | 1 (100.0) | 0.03 | 0.03 | ||
| Enterobacter cloacae species complex | 950 | 626 (65.9) | 281 (95.5) | 13 (96.8) | 9 (97.8) | 4 (98.2) | 4 (98.6) | 4 (99.1) | 2 (99.3) | 6 (99.9) | 1 (100.0) | ≤0.015 | 0.03 | |||
| Enterobacter aerogenes | 355 | 145 (40.8) | 195 (95.8) | 7 (97.7) | 1 (98.0) | 2 (98.6) | 2 (99.2) | 2 (99.7) | 1 (100.0) | 0.03 | 0.03 | |||||
| Citrobacter freundii species complex | 276 | 199 (72.1) | 65 (95.7) | 3 (96.7) | 2 (97.5) | 0 (97.5) | 1 (97.8) | 0 (97.8) | 3 (98.9) | 1 (99.3) | 2 (100.0) | ≤0.015 | 0.03 | |||
| Citrobacter koseri | 194 | 174 (89.7) | 20 (100.0) | ≤0.015 | 0.03 | |||||||||||
| Proteus mirabilis | 525 | 4 (0.8) | 148 (29.0) | 269 (80.2) | 85 (96.4) | 9 (98.1) | 6 (99.2) | 4 (100.0) | 0.06 | 0.12 | ||||||
| Indole-positive Proteeae spp. | 585 | 2 (0.3) | 176 (30.4) | 358 (91.6) | 37 (97.9) | 8 (99.3) | 0 (99.3) | 2 (99.7) | 1 (99.8) | 0 (99.8) | 0 (99.8) | 0 (99.8) | 0 (99.8) | 1 (100.0) | 0.06 | 0.06 |
| Serratia marcescens | 666 | 6 (0.9) | 435 (66.2) | 199 (96.1) | 12 (97.9) | 3 (98.3) | 2 (98.6) | 1 (98.8) | 1 (98.9) | 4 (99.5) | 2 (99.8) | 0 (99.8) | 1 (100.0) | 0.03 | 0.06 | |
| Pseudomonas aeruginosa | 2,604 | 41 (1.6) | 78 (4.6) | 245 (14.0) | 442 (31.0) | 424 (47.2) | 438 (64.1) | 234 (73.0) | 159 (79.1) | 185 (86.3) | 138 (91.6) | 125 (96.4) | 52 (98.3) | 43 (100.0) | 0.5 | 8 |
| Acinetobacter spp. | 708 | 6 (0.8) | 16 (3.1) | 64 (12.1) | 65 (21.3) | 57 (29.4) | 37 (34.6) | 12 (36.3) | 9 (37.6) | 15 (39.7) | 47 (46.3) | 124 (63.8) | 256 (100.0) | 32 | >32 | |
| Stenotrophomonas maltophilia | 353 | 1 (0.3) | 2 (0.8) | 1 (1.1) | 2 (1.7) | 3 (2.5) | 1 (2.8) | 0 (2.8) | 0 (2.8) | 2 (3.4) | 1 (3.7) | 15 (7.9) | 40 (19.3) | 285 (100.0) | >32 | >32 |
TABLE 2.
Activities of meropenem-vaborbactam (inhibitor at fixed concentration of 8 μg/ml) and comparator antimicrobial agents against Gram-negative isolates collected during 2014
| Bacterial group (n) and antimicrobial agent | MIC50 (μg/ml) | MIC90 (μg/ml) | MIC range (μg/ml) | Susceptibility using CLSI breakpointa |
Susceptibility using EUCAST breakpointa |
||||
|---|---|---|---|---|---|---|---|---|---|
| % S | % I | % R | % S | % I | % R | ||||
| Enterobacteriaceae (10,426) | |||||||||
| Meropenem-vaborbactam | ≤0.015 | 0.06 | ≤0.015–>32 | ||||||
| Meropenem | 0.03 | 0.06 | ≤0.015–>32 | 97.3 | 0.3 | 2.3 | 97.7 | 0.8 | 1.5 |
| Aztreonam | ≤0.12 | >16 | ≤0.12–>16 | 81.6 | 1.9 | 16.5 | 78.9 | 2.7 | 18.4 |
| Cefepime | ≤0.5 | 16 | ≤0.5–>16 | 85.2 | 3.3b | 11.5 | 83.2 | 3.6 | 13.2 |
| Ceftazidime | 0.25 | >16 | ≤0.12–>16 | 83.1 | 2.7 | 14.3 | 79.2 | 3.9 | 16.9 |
| Piperacillin-tazobactam | 2 | 32 | ≤0.5–>64 | 88.1 | 4.6 | 7.3 | 84.2 | 3.8 | 11.9 |
| Amikacin | 2 | 4 | ≤0.25–>32 | 98.1 | 1.1 | 0.8 | 96.7 | 1.4 | 1.9 |
| Colistin | ≤0.5 | >8 | ≤0.5–>8 | 79.4 | 20.6 | ||||
| Levofloxacin | ≤0.12 | >4 | ≤0.12–>4 | 79.7 | 1.9 | 18.4 | 78.2 | 1.5 | 20.3 |
| Tigecyclinec | 0.12 | 0.5 | ≤0.015–4 | 99.5 | 0.5 | 0.0 | 96.2 | 3.2 | 0.5 |
| CRE (265) | |||||||||
| Meropenem-vaborbactam | 0.5 | 32 | ≤0.015–>32 | ||||||
| Meropenem | 16 | >32 | 0.25–>32 | 1.9 | 6.0 | 92.1 | 7.9 | 32.1 | 60.0 |
| Aztreonam | >16 | >16 | ≤0.12–>16 | 9.1 | 1.5 | 89.4 | 7.2 | 1.9 | 90.9 |
| Cefepime | >16 | >16 | ≤0.5–>16 | 7.2 | 5.3b | 87.5 | 5.7 | 5.3 | 89.1 |
| Ceftazidime | >16 | >16 | 0.25–>16 | 6.4 | 1.5 | 92.1 | 5.7 | 0.8 | 93.6 |
| Piperacillin-tazobactam | >64 | >64 | 1–>64 | 3.0 | 2.3 | 94.7 | 2.6 | 0.4 | 97.0 |
| Amikacin | 16 | >32 | 0.5–>32 | 56.2 | 29.8 | 14.0 | 40.8 | 15.5 | 43.8 |
| Colistin | ≤0.5 | >8 | ≤0.5–>8 | 70.3 | 29.7 | ||||
| Levofloxacin | >4 | >4 | ≤0.12–>4 | 18.9 | 1.9 | 79.2 | 15.9 | 3.0 | 81.1 |
| Tigecyclinec | 0.25 | 1 | 0.06–4 | 99.2 | 0.8 | 0.0 | 92.5 | 6.8 | 0.8 |
| KPC producers (135) | |||||||||
| Meropenem-vaborbactam | 0.12 | 0.5 | ≤0.015–8 | ||||||
| Meropenem | >32 | >32 | 1–>32 | 0.7 | 4.4 | 94.8 | 5.2 | 15.6 | 79.3 |
| Aztreonam | >16 | >16 | 2–>16 | 0.7 | 0.7 | 98.5 | 0.0 | 0.7 | 99.3 |
| Cefepime | >16 | >16 | ≤0.5–>16 | 1.5 | 3.0b | 95.6 | 1.5 | 0.7 | 97.8 |
| Ceftazidime | >16 | >16 | 0.25–>16 | 1.5 | 0.7 | 97.8 | 0.7 | 0.7 | 98.5 |
| Piperacillin-tazobactam | >64 | >64 | 2–>64 | 0.7 | 0.7 | 98.5 | 0.7 | 0.0 | 99.3 |
| Amikacin | 32 | >32 | 0.5–>32 | 39.3 | 48.9 | 11.9 | 26.7 | 12.6 | 60.7 |
| Colistin | ≤0.5 | >8 | ≤0.5–>8 | 72.4 | 27.6 | ||||
| Levofloxacin | >4 | >4 | ≤0.12–>4 | 10.4 | 1.5 | 88.1 | 7.5 | 3.0 | 89.6 |
| Tigecyclinec | 0.25 | 1 | 0.06–2 | 100.0 | 0.0 | 0.0b | 96.3 | 3.7 | 0.0 |
| Non-KPC-producing CRE (129) | |||||||||
| Meropenem-vaborbactam | 4 | >32 | ≤0.015–>32 | ||||||
| Meropenem | 8 | >32 | 0.25–>32 | 3.1 | 7.0 | 89.9 | 10.1 | 49.6 | 40.3 |
| Aztreonam | >16 | >16 | ≤0.12–>16 | 17.8 | 2.3 | 79.8 | 14.7 | 3.1 | 82.2 |
| Cefepime | >16 | >16 | ≤0.5–>16 | 13.2 | 7.8b | 79.1 | 10.1 | 10.1 | 79.8 |
| Ceftazidime | >16 | >16 | 0.25–>16 | 11.6 | 2.3 | 86.0 | 10.9 | 0.8 | 88.4 |
| Piperacillin-tazobactam | >64 | >64 | 1–>64 | 5.4 | 3.9 | 90.7 | 4.7 | 0.8 | 94.6 |
| Amikacin | 8 | >32 | 0.5–>32 | 73.6 | 10.1 | 16.3 | 55.0 | 18.6 | 26.4 |
| Colistin | 1 | >8 | ≤0.5–>8 | 68.0 | 32.0 | ||||
| Levofloxacin | >4 | >4 | ≤0.12–>4 | 27.9 | 2.3 | 69.8 | 24.8 | 3.1 | 72.1 |
| Tigecyclinec | 0.25 | 2 | 0.06–4 | 98.4 | 1.6 | 0.0b | 88.4 | 10.1 | 1.6 |
| Carbapenemase-negative isolates (63) | |||||||||
| Meropenem-vaborbactam | 1 | 4 | ≤0.015–32 | ||||||
| Meropenem | 4 | 16 | 0.25–>32 | 3.2 | 4.8 | 92.1 | 7.9 | 74.6 | 17.5 |
| Aztreonam | >16 | >16 | ≤0.12–>16 | 6.3 | 3.2 | 90.5 | 6.3 | 0.0 | 93.7 |
| Cefepime | >16 | >16 | ≤0.5–>16 | 12.7 | 6.3b | 81.0 | 9.5 | 7.9 | 82.5 |
| Ceftazidime | >16 | >16 | 0.25–>16 | 7.9 | 0.0 | 92.1 | 7.9 | 0.0 | 92.1 |
| Piperacillin-tazobactam | >64 | >64 | 1–>64 | 9.5 | 6.3 | 84.1 | 7.9 | 1.6 | 90.5 |
| Amikacin | 8 | 32 | 1–>32 | 77.8 | 14.3 | 7.9 | 58.7 | 19.0 | 22.2 |
| Colistin | 1 | >8 | ≤0.5–>8 | 67.7 | 32.3 | ||||
| Levofloxacin | >4 | >4 | ≤0.12–>4 | 25.4 | 0.0 | 74.6 | 23.8 | 1.6 | 74.6 |
| Tigecyclinec | 0.25 | 1 | 0.06–2 | 100.0 | 0.0 | 0.0 | 93.7 | 6.3 | 0.0 |
| MDR isolates (1,210) | |||||||||
| Meropenem-vaborbactam | 0.03 | 1 | ≤0.015–>32 | ||||||
| Meropenem | 0.06 | 32 | ≤0.015–>32 | 77.7 | 2.5 | 19.8 | 80.2 | 6.8 | 13.1 |
| Aztreonam | >16 | >16 | ≤0.12–>16 | 17.8 | 3.0 | 79.3 | 11.7 | 6.1 | 82.2 |
| Cefepime | >16 | >16 | ≤0.5–>16 | 21.6 | 9.7b | 68.7 | 17.0 | 8.7 | 74.4 |
| Ceftazidime | >16 | >16 | ≤0.12–>16 | 18.3 | 8.9 | 72.8 | 11.7 | 6.5 | 81.7 |
| Piperacillin-tazobactam | 64 | >64 | ≤0.5–>64 | 36.6 | 20.6 | 42.8 | 28.7 | 7.9 | 63.4 |
| Amikacin | 4 | 32 | ≤0.25–>32 | 84.2 | 8.5 | 7.3 | 75.5 | 8.7 | 15.8 |
| Colistin | ≤0.5 | >8 | ≤0.5–>8 | 73.7 | 26.3 | ||||
| Levofloxacin | >4 | >4 | ≤0.12–>4 | 14.6 | 7.5 | 77.9 | 12.1 | 2.5 | 85.4 |
| Tigecyclinec | 0.25 | 1 | 0.03–4 | 97.9 | 2.1 | 0.0 | 90.6 | 7.3 | 2.1 |
| XDR isolates (161) | |||||||||
| Meropenem-vaborbactam | 0.5 | 32 | ≤0.015–>32 | ||||||
| Meropenem | 16 | >32 | ≤0.015–>32 | 13.0 | 6.8 | 80.1 | 19.9 | 28.6 | 51.6 |
| Aztreonam | >16 | >16 | ≤0.12–>16 | 7.5 | 1.2 | 91.3 | 5.6 | 1.9 | 92.5 |
| Cefepime | >16 | >16 | ≤0.5–>16 | 4.3 | 3.7b | 91.9 | 3.1 | 3.7 | 93.2 |
| Ceftazidime | >16 | >16 | 0.25–>16 | 4.3 | 1.9 | 93.8 | 3.1 | 1.2 | 95.7 |
| Ceftriaxone | >8 | >8 | 2–>8 | 0.0 | 1.2 | 98.8 | 0.0 | 1.2 | 98.8 |
| Piperacillin-tazobactam | >64 | >64 | ≤0.5–>64 | 2.5 | 5.6 | 91.9 | 2.5 | 0.0 | 97.5 |
| Amikacin | 16 | >32 | 0.5–>32 | 58.4 | 20.5 | 21.1 | 42.2 | 16.1 | 41.6 |
| Colistin | 4 | >8 | ≤0.5–>8 | 45.3 | 54.7 | ||||
| Levofloxacin | >4 | >4 | 0.25–>4 | 0.6 | 5.0 | 94.4 | 0.6 | 0.0 | 99.4 |
| Tigecyclinec | 0.5 | 2 | 0.06–4 | 96.3 | 3.7 | 0.0 | 88.2 | 8.1 | 3.7 |
| P. aeruginosa (2,604) | |||||||||
| Meropenem-vaborbactam | 0.5 | 8 | ≤0.015–>32 | ||||||
| Meropenem | 0.5 | 8 | ≤0.015–>32 | 78.4 | 7.0 | 14.6 | 78.4 | 12.9 | 8.7 |
| Aztreonam | 8 | >16 | ≤0.12–>16 | 59.6 | 14.8 | 25.6 | 4.6 | 69.7 | 25.6 |
| Cefepime | 2 | 16 | ≤0.5–>16 | 83.7 | 9.1 | 7.2 | 83.7 | 16.3 | |
| Ceftazidime | 2 | >16 | ≤0.12–>16 | 79.0 | 5.6 | 15.4 | 79.0 | 21.0 | |
| Piperacillin-tazobactam | 4 | >64 | ≤0.5–>64 | 79.2 | 10.3 | 10.5 | 79.2 | 20.8 | |
| Amikacin | 2 | 16 | ≤0.25–>32 | 94.0 | 2.2 | 3.8 | 89.6 | 4.5 | 6.0 |
| Colistin | 2 | 2 | ≤0.5–4 | 98.3 | 1.7 | 0.0 | 100.0 | 0.0 | |
| Levofloxacin | 0.5 | >4 | ≤0.12–>4 | 73.4 | 5.9 | 20.7 | 65.3 | 8.1 | 26.6 |
| Tigecyclinec | 4 | 8 | 0.06–>16 | ||||||
Meropenem-vaborbactam (MIC50 and MIC90, ≤0.015 and ≤0.015 μg/ml) (Table 1) inhibited all but one Escherichia coli isolate (n = 4,238) at ≤4 μg/ml, and ≥99.9% of the isolates were inhibited by this carbapenem–β-lactamase inhibitor combination at ≤2 or ≤1 μg/ml. Selected comparator agents displayed good activity against E. coli isolates, and meropenem (99.8% susceptible [CLSI interpretation]), amikacin (99.6% susceptible [CLSI]), imipenem (99.7% susceptible [CLSI]), colistin (99.5% susceptible [EUCAST]), and tigecycline (100.0% susceptible [U.S. FDA]) inhibited >90% of the isolates at current breakpoints (data not shown). A total of 96.8 and 97.2% of the K. pneumoniae isolates (n = 2,010) were inhibited by meropenem-vaborbactam (MIC50 and MIC90, 0.03 and 0.12 μg/ml) at ≤1 and ≤2 μg/ml, respectively, and 98.1% of the isolates tested were inhibited by this combination at ≤8 μg/ml. Meropenem (MIC50 and MIC90, 0.03 and 4 μg/ml [data not shown]) inhibited 89.0, 89.9, and 92.6% of these isolates at the same concentrations. Other comparator agents inhibiting >90.0% of isolates at current breakpoints were limited to amikacin (92.6% susceptible [CLSI criteria]), tigecycline (99.9% susceptible [U.S. FDA]), imipenem (90.3% susceptible [EUCAST]), and colistin (94.2% susceptible [EUCAST]) (data not shown).
The activity of meropenem-vaborbactam (MIC90 range, 0.03 to 0.12 μg/ml) (Table 1) was elevated against other Enterobacteriaceae species, and this combination inhibited 99.5% of Klebsiella oxytoca isolates (n = 429), 99.3% of Enterobacter cloacae isolates (n = 950), 98.9% of Citrobacter freundii isolates (n = 276), 99.8% of the indole-positive Proteeae sp. isolates (n = 585), and 98.9% of Serratia marcescens isolates (n = 666) at ≤2 μg/ml. Meropenem-vaborbactam inhibited 99.8 to 100% of the isolates belonging to these species at ≤8 μg/ml (Table 1). All Enterobacter aerogenes (n = 355), Citrobacter koseri (n = 194), and Proteus mirabilis (n = 525) isolates were inhibited by meropenem-vaborbactam at ≤2 μg/ml (Table 1).
The activity of meropenem-vaborbactam was similar to that of meropenem alone (MIC50 and MIC90, 0.5 and 8 μg/ml, respectively, for both) (Tables 1 and 2) for 2,604 P. aeruginosa isolates tested. The presence of vaborbactam slightly enhanced the activity of meropenem: 78.4% of isolates were inhibited by meropenem alone at ≤2 μg/ml (CLSI/EUCAST susceptibility breakpoint), and 79.1% were inhibited by meropenem-vaborbactam at the same concentration (Tables 1 and 2). Additionally, this combination inhibited 91.6% of the P. aeruginosa isolates tested at ≤8 μg/ml.
As observed with meropenem alone (MIC50 and MIC90, >8 and >8 μg/ml for both groups [data not shown]), meropenem-vaborbactam had limited activity against Acinetobacter spp. (MIC50 and MIC90, 32 and >32 μg/ml) and Stenotrophomonas maltophilia (MIC50 and MIC90, >32 and >32 μg/ml) (Table 1). These isolates were also resistant to other β-lactams tested (data not shown).
Meropenem-vaborbactam testing against CRE.
A total of 265 carbapenem-resistant Enterobacteriaceae (CRE) isolates were observed in hospitals worldwide during 2014, including 167 in Europe (3.2% of isolates from this region), 65 (1.6%) in the United States, 24 (4.8%) in Latin America, and 9 (1.5%) in Asia-Pacific countries. These isolates were mostly K. pneumoniae (211/265 isolates [79.6%]), but there were also isolates of Enterobacter cloacae (18 isolates), Serratia marcescens (10), E. coli (9), Citrobacter freundii (7), Enterobacter aerogenes (3), K. oxytoca (4), Enterobacter kobei (1), Hafnia alvei (1), and Providencia stuartii (1).
Meropenem alone displayed very limited activity against CRE isolates (MIC50 and MIC90, 16 and >32 μg/ml), and only 1.9 and 7.9% of these isolates were categorized as susceptible to this carbapenem by applying the CLSI and EUCAST criteria, respectively (Table 3). Meropenem-vaborbactam (MIC50 and MIC90, 0.5 and 32 μg/ml) inhibited 65.3 and 70.9% of the CRE isolates at ≤1 and ≤2 μg/ml, respectively, and 84.2% of these isolates were inhibited at ≤8 μg/ml (Table 3). This combination was very active against U.S. (MIC50 and MIC90, 0.03 and 1 μg/ml) and Latin American (MIC50 and MIC90, 0.12 and 4 μg/ml) CRE isolates, but limited activity was noted against isolates from the Asia-Pacific region (MIC50, 32 μg/ml) (Table 3).
TABLE 3.
Antimicrobial activity of meropenem with or without vaborbactam (at a fixed concentration of 8 μg/ml) against groups of clinical Enterobacteriaceae isolates with different resistance phenotypes and genotypes, collected worldwide during 2014
| Organism group (no. of isolates tested) and antimicrobial agent | No. of isolates (cumulative %) from all regions at meropenem-vaborbactam MIC (μg/ml) of: |
MIC50/90 (μg/ml) by region, with no. (%) of isolates for each organism groupa |
||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ≤0.015 | 0.03 | 0.06 | 0.12 | 0.25 | 0.5 | 1 | 2 | 4 | 8 | 16 | 32 | >32 | Overall | Asia-Pacific | Europe | Latin America | United States | |
| CRE (265) | 265 (2.5) | 9 (1.5) | 167 (3.2) | 24 (4.8) | 65 (1.6) | |||||||||||||
| Meropenem-vaborbactam | 36 (13.6) | 20 (21.1) | 7 (23.8) | 21 (31.7) | 29 (42.6) | 34 (55.5) | 26 (65.3) | 15 (70.9) | 23 (79.6) | 12 (84.2) | 8 (87.2) | 14 (92.5) | 20 (100.0) | 0.5/32 | 32/NA | 1/32 | 0.12/4 | 0.03/1 |
| Meropenem | 1 (0.4) | 1 (0.8) | 3 (1.9) | 16 (7.9) | 48 (26.0) | 37 (40.0) | 34 (52.8) | 29 (63.8) | 96 (100.0) | 16/>32 | >32/NA | 16/>32 | 32/>32 | 16/>32 | ||||
| Carbapenem-resistant K. pneumoniae (211) | 211 (10.5) | 9 (4.5) | 132 (13.8) | 24 (15.4) | 46 (6.6) | |||||||||||||
| Meropenem-vaborbactam | 29 (13.7) | 17 (21.8) | 6 (24.6) | 20 (34.1) | 28 (47.4) | 27 (60.2) | 21 (70.1) | 8 (73.9) | 11 (79.1) | 6 (82.0) | 7 (85.3) | 12 (91.0) | 19 (100.0) | 0.5/32 | 32/NA | 0.5/>32 | 0.12/4 | 0.03/1 |
| Meropenem | 8 (3.8) | 28 (17.1) | 27 (29.9) | 28 (43.1) | 26 (55.5) | 94 (100.0) | 32/>32 | >32/NA | 32/>32 | 32/>32 | 16/>32 | |||||||
| KPC producers (135) | 135 (1.3) | 0 (0) | 63 (1.2) | 21 (4.2) | 51 (1.2) | |||||||||||||
| Meropenem-vaborbactam | 35 (25.9) | 19 (40.0) | 7 (45.2) | 19 (59.3) | 24 (77.0) | 19 (91.1) | 7 (96.3) | 3 (98.5) | 1 (99.3) | 1 (100.0) | 0.12/0.5 | NA | 0.25/0.5 | 0.12/2 | 0.03/0.5 | |||
| Meropenem | 1 (0.7) | 6 (5.2) | 11 (13.3) | 10 (20.7) | 21 (36.3) | 16 (48.1) | 70 (100.0) | >32/>32 | NA | >32/>32 | >32/>32 | 16/>32 | ||||||
| OXA-48-like-producers (25) | 25 (0.2) | 0 (0) | 23 (0.4) | 1 (0.2) | 1 (<0.1) | |||||||||||||
| Meropenem-vaborbactam | 2 (8.0) | 0 (8.0) | 0 (8.0) | 3 (20.0) | 5 (40.0) | 5 (60.0) | 5 (80.0) | 5 (100.0) | 16/>32 | NA | 16/>32 | 8b | 0.5b | |||||
| Meropenem | 1 (4.0) | 0 (4.0) | 1 (8.0) | 2 (16.0) | 5 (36.0) | 5 (56.0) | 6 (80.0) | 5 (100.0) | 16/>32 | NA | 16/>32 | 8b | 2b | |||||
| MBL producers (41) | 41 (0.4) | 7 (1.2) | 32 (0.6) | 1 (0.2) | 1 (<0.1) | |||||||||||||
| Meropenem-vaborbactam | 2 (4.9) | 4 (14.6) | 5 (26.8) | 5 (39.0) | 2 (43.9) | 8 (63.4) | 15 (100.0) | 32/>32 | 32/NA | 32/>32 | 4b | >32b | ||||||
| Meropenem | 1 (2.4) | 5 (14.6) | 6 (29.3) | 4 (39.0) | 2 (43.9) | 5 (56.1) | 18 (100.0) | 32/>32 | >32/NA | 16/>32 | 2b | >32b | ||||||
| Carbapenemase-negative isolates (63) | 63 (0.6) | 2 (0.3) | 48 (0.9) | 1 (0.2) | 12 (0.3) | |||||||||||||
| Meropenem-vaborbactam | 1 (1.6) | 1 (3.2) | 0 (3.2) | 2 (6.3) | 5 (14.3) | 13 (34.9) | 17 (61.9) | 7 (73.0) | 14 (95.2) | 1 (96.8) | 1 (98.4) | 1 (100.0) | 1/4 | 16/NA | 1/4 | 1b | 0.5/4 | |
| Meropenem | 1 (1.6) | 0 (1.6) | 1 (3.2) | 3 (7.9) | 29 (54.0) | 18 (82.5) | 6 (92.1) | 2 (95.2) | 3 (100.0) | 4/16 | 8/NA | 4/16 | 8b | 4/32 | ||||
| MDR isolates (1,210) | 1,210 (11.6) | 65 (11.1) | 714 (13.7) | 116 (23.4) | 315 (7.6) | |||||||||||||
| Meropenem-vaborbactam | 499 (41.2) | 295 (65.6) | 106 (74.4) | 65 (79.8) | 59 (84.6) | 54 (89.1) | 40 (92.4) | 16 (93.7) | 22 (95.5) | 12 (96.5) | 8 (97.2) | 14 (98.3) | 20 (100.0) | 0.03/1 | ≤0.015/16 | 0.03/1 | 0.03/0.5 | 0.03/0.12 |
| Meropenem | 214 (17.7) | 312 (43.5) | 229 (62.4) | 83 (69.3) | 30 (71.7) | 35 (74.6) | 37 (77.7) | 30 (80.2) | 46 (84.0) | 36 (86.9) | 34 (89.8) | 28 (92.1) | 96 (100.0) | 0.06/32 | 0.03/32 | 0.06/32 | 0.03/>32 | 0.06/16 |
| XDR isolates (161) | 161 (1.5) | 9 (1.5) | 94 (1.8) | 22 (4.4) | 36 (0.9) | |||||||||||||
| Meropenem-vaborbactam | 19 (11.8) | 18 (23.0) | 9 (28.6) | 10 (34.8) | 15 (44.1) | 17 (54.7) | 23 (68.9) | 9 (74.5) | 6 (78.3) | 6 (82.0) | 5 (85.1) | 10 (91.3) | 14 (100.0) | 0.5/32 | 32/NA | 1/>32 | 0.12/2 | 0.03/0.5 |
| Meropenem | 1 (0.6) | 4 (3.1) | 5 (6.2) | 6 (9.9) | 2 (11.2) | 2 (12.4) | 1 (13.0) | 11 (19.9) | 24 (34.8) | 22 (48.4) | 18 (59.6) | 15 (68.9) | 50 (100.0) | 16/>32 | >32/NA | 8/>32 | 32/>32 | 16/>32 |
Percentages of carbapenem-resistant K. pneumoniae were calculated using the number of K. pneumoniae isolates. The remaining percentages were calculated using the total number of Enterobacteriaceae isolates. NA, not applicable.
The value displayed is the actual MIC for the isolate.
CRE isolates were highly resistant to comparator agents, and the highest susceptibility rates were observed for amikacin (56.2 and 40.8% susceptible by CLSI and EUCAST criteria, respectively), colistin (70.3% susceptible by EUCAST criteria), and tigecycline (99.2 and 92.5% susceptible by U.S. FDA and EUCAST criteria) (Table 2). Meropenem-vaborbactam was the most active β-lactam agent tested against these isolates (Table 2).
Meropenem-vaborbactam testing against MDR and XDR Enterobacteriaceae.
Meropenem-vaborbactam (MIC50 and MIC90, 0.03 and 1 μg/ml) was very active against 1,210 Enterobacteriaceae isolates displaying an MDR phenotype (11.6% of all Enterobacteriaceae isolates), and the activity of this combination was higher than those of meropenem (MIC50/90, 0.06/32 μg/ml) and other comparators (Table 2). Meropenem-vaborbactam inhibited 68.9 and 74.5% of the 161 XDR isolates (1.5% of all Enterobacteriaceae isolates) at ≤1 and ≤2 μg/ml, respectively, whereas meropenem inhibited only 13.0 and 19.9% of these isolates at the same MIC values. Additionally, meropenem-vaborbactam inhibited 82.0% of the XDR Enterobacteriaceae isolates at ≤8 μg/ml (Table 3). The activity of meropenem-vaborbactam was elevated against XDR isolates from U.S. (MIC50 and MIC90, 0.03 and 0.5 μg/ml) and Latin American (MIC50 and MIC90, 0.12 and 2 μg/ml) hospitals, the latter of which displayed the highest XDR rate among the four continents (4.4% versus 0.9 to 1.8% for the others) (Table 3).
Only one Enterobacteriaceae isolate displayed a PDR phenotype (<0.1%), and this isolate had elevated MIC values for meropenem alone and meropenem-vaborbactam (MIC, >32 μg/ml). This isolate was a VIM-1-producing Providencia stuartii isolate recovered from the peritoneal fluid of a patient hospitalized in Greece.
Meropenem-vaborbactam testing against carbapenemase-producing Enterobacteriaceae.
A total of 264 CRE isolates were screened for the presence of genes encoding carbapenemases, and 201 (75.8%) isolates carried these resistance genes. One isolate could not be recovered for further testing. A total of 135 (50.9% of the CRE isolates; 1.3% of the overall population) isolates carried blaKPC genes, including 60 blaKPC-2, 74 blaKPC-3, and 1 blaKPC-4 gene (Table 4). KPC-producing isolates were detected in five European countries (63/166 CRE isolates), namely, Greece (16/21 CRE isolates), Italy (37/38 CRE isolates), Israel (4/4 CRE isolates), Poland (5/55 CRE isolates), and the United Kingdom (1/2 CRE isolates). These isolates were also found in the United States (51/65 CRE isolates), Brazil (15/15 CRE isolates), and Argentina (6/7 CRE isolates).
TABLE 4.
Activity of meropenem with or without vaborbactam (at a fixed concentration of 8 μg/ml) against isolates carrying carbapenemases
| Region (no. of isolates carrying carbapenemases) | Carbapenemase group (no. of isolates) | Meropenem-vaborbactam |
Meropenem (μg/ml) |
Carbapenemase(s) detected (no. of isolates) | Organism(s) (no. of isolates) | Country or countries (no. of isolates) | ||
|---|---|---|---|---|---|---|---|---|
| MIC50 (μg/ml)a | MIC90 (μg/ml)b | MIC50 (μg/ml)a | MIC90 (μg/ml)b | |||||
| All regions (202) | KPC (135) | 0.12 | 0.5 | >32 | >32 | KPC-2 (60), KPC-3 (74), KPC-4 (1) | Citrobacter freundii (1), Escherichia coli (5), Enterobacter cloacae species complex (3), Klebsiella oxytoca (2), K. pneumoniae (123), Serratia marcescens (1) | Argentina (6), Brazil (15), Greece (16), Israel (4), Italy (37), Poland (5), United Kingdom (1), U.S. (51) |
| OXA-48-like (25, plus 2 carrying blaVIM-1 that were not included in the MIC data) | 16 | >32 | 16 | >32 | OXA-48 (26 [2 carrying blaVIM-1]), OXA-163 (1) | Citrobacter freundii (1), Escherichia coli (1), Enterobacter cloacae species complex (2), Klebsiella oxytoca (1), K. pneumoniae (17), Serratia marcescens (5) | Argentina (1), Germany (1), Ireland (1), Romania (1), Russia (9), Sweden (1), Turkey (11), Ukraine (1), U.S. (1) | |
| MBL (41) | 32 | >32 | 32 | >32 | NDM-1 (25), VIM-1 (11), VIM-2 (1), VIM-4 (4) | Citrobacter freundii (5), Enterobacter cloacae species complex (7), Klebsiella oxytoca (2), K. pneumoniae (25), Providencia stuartii (1), Serratia marcescens (1) | Greece (5), Malaysia (5), Mexico (1), Poland (13), Portugal (1), Romania (2), Russia (3), Spain (1), Thailand (2), Turkey (5), Ukraine (2), U.S. (1) | |
| U.S. (53) | KPC (51) | 0.03 | 0.5 | 16 | >32 | KPC-2 (19), KPC-3 (31), KPC-4 (1) | Citrobacter freundii (1), Escherichia coli (5), Enterobacter cloacae (1), Klebsiella oxytoca (2), K. pneumoniae (41), Serratia marcescens (1) | U.S. (51) |
| OXA-48-like (1) | 0.5 | NA | 2 | NA | OXA-48 (1) | Enterobacter cloacae species complex (1) | U.S. (1) | |
| MBL (1) | >32 | NA | >32 | NA | NDM-1 (1) | K. pneumoniae (1) | U.S. (1) | |
| Europe (118) | KPC (63) | 0.25 | 0.5 | >32 | >32 | KPC-2 (21), KPC-3 (42) | Enterobacter cloacae species complex (2), Klebsiella pneumoniae (61) | Greece (16), Israel (4), Italy (37), Poland (5), United Kingdom (1) |
| OXA-48-like (23, plus 2 carrying blaVIM-1 that were not included in the MIC data) | 16 | >32 | 16 | >32 | OXA-48 (25 [2 carrying blaVIM-1]) | Citrobacter freundii species complex (1), Escherichia coli (1), Enterobacter cloacae species complex (1), Klebsiella oxytoca (1), K. pneumoniae (16), Serratia marcescens (5) | Germany (1), Ireland (1), Romania (1), Russia (9), Sweden (1), Turkey (11), Ukraine (1) | |
| MBL (32) | 32 | >32 | 16 | >32 | NDM-1 (16), VIM-1 (11), VIM-2 (1), VIM-4 (4) | Citrobacter freundii species complex (5), Enterobacter cloacae species complex (7), Klebsiella oxytoca (2), K. pneumoniae (16), Providencia stuartii (1), Serratia marcescens (1) | Greece (5), Poland (13), Portugal (1), Romania (2), Russia (3), Spain (1), Turkey (5), Ukraine (2) | |
| Latin America (23) | KPC (21) | 0.12 | 2 | >32 | >32 | KPC-2 (20), KPC-3 (1) | K. pneumoniae (21) | Argentina (6), Brazil (15) |
| OXA-48-like (1) | 8 | NA | 8 | NA | OXA-163 (1) | K. pneumoniae (1) | Argentina (1) | |
| MBL (1) | 4 | NA | 2 | NA | NDM-1 (1) | K. pneumoniae (1) | Mexico (1) | |
| Asia-Pacific (7) | MBL (7) | 32 | NA | >32 | NA | NDM-1 (7) | K. pneumoniae (7) | Malaysia (5), Thailand (2) |
If only 1 isolate was detected, the MIC value is displayed.
NA, not available for groups with <10 isolates.
Genes encoding MBLs were detected among 41 isolates (15.5% of CRE isolates; 0.4% of the overall collection), with the gene encoding NDM-1 being the most common (25 isolates), followed by blaVIM-1 (11 isolates), blaVIM-4 (4 isolates), and blaVIM-2 (1 isolate). MBL-producing isolates belonged to the follow bacterial species: C. freundii (5 isolates), E. cloacae (7 isolates), K. oxytoca (2 isolates), K. pneumoniae (25 isolates), P. stuartii (1 isolate), and S. marcescens (1 isolate). These isolates were collected in hospitals located in Europe (32 isolates), Asia Pacific (7 isolates), Latin America (1 isolate), and the United States (1 isolate). NDM-1 was detected among isolates from Malaysia (5 isolates), Thailand (2 isolates), Poland (7 isolates), Romania (2 isolates), Russia (3 isolates), Turkey (2 isolates), Ukraine (2 isolates), Mexico (1 isolate), and the United States (1 isolate).
OXA-48-like genes were detected among 27 isolates (10.2% of CRE isolates; 0.3% of the overall collection), 2 of which also carried VIM-1. OXA-48 genes were detected mainly in K. pneumoniae isolates (17/27 isolates) and were isolated primarily from European countries (25/27 isolates [1 each from Germany, Ireland, Romania, Ukraine, and Sweden, 11 from Turkey, and 9 from Russia]). The two remaining isolates were observed in Argentina (OXA-163; K. pneumoniae) and the United States (E. cloacae isolate from Rochester, NY).
Meropenem-vaborbactam (MIC50 and MIC90, 0.12 and 0.5 μg/ml) exhibited good activity against KPC-producing isolates. All other β-lactam agents displayed limited activity against KPC-producing isolates, and the most active non-β-lactam agents against these isolates were tigecycline (100.0 and 96.3% susceptible by applying U.S. FDA and EUCAST breakpoints, respectively) and colistin (72.4% susceptible by using EUCAST breakpoints) (Table 2).
All but two KPC-producing isolates were inhibited by meropenem-vaborbactam at ≤2 μg/ml. The other two isolates displayed MIC values of 4 and 8 μg/ml, were K. pneumoniae isolates from Brazil and Italy, and displayed resistant MIC values for meropenem (>32 μg/ml for both), imipenem (>8 μg/ml for both), doripenem (>4 μg/ml for both), levofloxacin (>4 μg/ml for both), and gentamicin (≥8 μg/ml). The isolate from Brazil was colistin resistant (MIC, >8 μg/ml [EUCAST breakpoint]) but was susceptible to amikacin (MIC, 8 μg/ml), whereas the isolate from Italy was susceptible to colistin (MIC, 0.5 μg/ml) and resistant to amikacin (MIC, >32 μg/ml). Both isolates displayed low tigecycline MIC results (0.5 and 1 μg/ml). These isolates were recovered from wound and blood specimens from 62- and 56-year-old male patients hospitalized in renal and hematology wards, respectively.
The activity of meropenem-vaborbactam against isolates harboring blaOXA-48-like genes (MIC50/90, 16/>32 μg/ml) and/or MBL-encoding genes (MIC50/90, 32/>32 μg/ml) was similar to that of meropenem (Table 4).
A total of 63 isolates yielded negative results for the carbapenemase-encoding genes tested, including less frequent genes. These isolates were mainly K. pneumoniae isolates from Europe (48/63 isolates [76.2%]) (Table 3). Meropenem-vaborbactam (MIC50/90, 1/4 μg/ml) was 4-fold more active than meropenem alone (MIC50/90, 4/16 μg/ml) against these isolates (Table 3), which were also resistant to most comparator agents tested (Table 2).
DISCUSSION
In this study, we evaluated the activities of meropenem-vaborbactam and comparator antimicrobial agents against a large collection of clinical isolates including 10,426 Enterobacteriaceae isolates. These isolates represent all nonfastidious Gram-negative organisms collected during 2014 as part of a large surveillance network collecting consecutive isolates per infection type; thus, rates for different phenotypes and genotypes are likely representative of the overall prevalences.
Among Enterobacteriaceae isolates, the worldwide rates for CRE, MDR, and XDR isolates were 2.5, 11.6, and 1.5%, respectively. Although variations were observed in the geographic regions analyzed, these isolates were detected in all four regions, highlighting the importance of developing therapeutic options that are efficacious against these difficult-to-treat organisms.
KPC is still the most common carbapenemase (1.3% of the overall population; 50.9% of CRE isolates) detected worldwide, and in certain surveyed countries, such as the United States, Brazil, Italy, and Argentina, KPC producers are the dominant population among CRE isolates. Vaborbactam is a potent KPC inhibitor, and in previous studies, the combination of this inhibitor with various carbapenems reduced the MIC values 16- to >64-fold for tested KPC-producing isolates (8). When vaborbactam was tested in combination with biapenem against 300 Enterobacteriaceae isolates, this combination was very active against KPC-producing isolates, but the activity of this combination was variable against isolates with a combination of extended-spectrum β-lactamase (ESBL) or derepressed AmpC genes and intrinsic resistance mechanisms or against isolates producing Ambler class B or D enzymes (10). Against KPC-producing K. pneumoniae, E. cloacae, P. aeruginosa, and Acinetobacter sp. isolates from New York City, meropenem-vaborbactam enhanced the activity of carbapenems; however, decreased expression of ompK36 reduced the effect of the β-lactamase inhibitor 8- to 16-fold compared to that against isolates producing the same β-lactamases (9).
In this study, 133 of the 135 KPC-producing isolates detected were inhibited by meropenem-vaborbactam at ≤2 μg/ml, and all isolates were inhibited by this combination at ≤8 μg/ml. These isolates are the main target for this combination, and simulated human exposures of meropenem-vaborbactam against CRE isolates by use of a hollow-fiber model demonstrated that a regimen of 2 g meropenem-2 g vaborbactam every 8 h by 3-h infusion was highly efficacious against isolates producing KPC with meropenem-vaborbactam MIC values of up to 8 μg/ml (11). Additionally, a phase 3 clinical trial for complicated urinary tract infection isolates was recently completed to support this dosing regimen, and another is ongoing for the treatment of CRE (https://clinicaltrials.gov/ct2/results?term=vaborbactam&Search=Search).
Meropenem-vaborbactam was active against contemporary Enterobacteriaceae isolates collected worldwide, and this combination displayed good activity against CRE, MDR, and XDR Enterobacteriaceae isolates with MIC50 and MIC90 values that were lower than those for comparator agents (except tigecycline). Additionally, and as reported by Lapuebla et al. (9), the activity of this combination was similar to that of meropenem alone against other Gram-negative nonfastidious species. As with other β-lactamase inhibitors that are clinically available or in late development stages (18), vaborbactam does not inhibit MBL-producing isolates, and the meropenem-vaborbactam combination displays limited activity against isolates producing class D oxacillinases associated with resistance to carbapenems. Isolates producing MBLs and OXA-48-like enzymes were detected mainly in Asia-Pacific and some European countries, but the worldwide spread of these resistance determinants is a matter of great concern, and the development of treatment options for these organisms is warranted.
MATERIALS AND METHODS
Bacterial isolates.
A total of 14,304 Gram-negative bacterial clinical isolates were collected consecutively during 2014 in 82 hospitals, located in 31 countries and grouped into four regions: United States (29 hospitals), Europe (35 hospitals), Latin America (8 hospitals), and Asia-Pacific (10 hospitals). Isolates were collected consecutively according to standardized protocols, and only clinically significant isolates were included in the study (1 per patient episode). Species identification was confirmed when necessary by matrix-assisted laser desorption ionization–time of flight mass spectrometry, using a Bruker Daltonics MALDI Biotyper (Billerica, Massachusetts, USA) following the manufacturer's instructions.
Antimicrobial susceptibility testing.
All isolates were susceptibility tested using the reference broth microdilution method as described by the Clinical and Laboratory Standards Institute (CLSI) (12), using validated panels produced by ThermoFisher Scientific (formerly TREK, Cleveland, OH). Meropenem was combined with vaborbactam at a fixed concentration of 8 μg/ml. Categorical interpretations for all comparator agents were those found in CLSI document M100-S26 (13), at the EUCAST website (14), or in U.S. Food and Drug Administration (FDA) package inserts. Quality control (QC) was performed using Escherichia coli ATCC 25922 and ATCC 35218, K. pneumoniae ATCC 700603 and BAA-1705, and P. aeruginosa ATCC 27853 as reference strains. All QC MIC results were within acceptable ranges as published in CLSI documents (13).
Definitions.
Carbapenem-resistant Enterobacteriaceae (CRE) isolates were defined as any isolates exhibiting imipenem (Proteus mirabilis and indole-positive Proteeae were not included due to their intrinsically elevated MIC values) and/or meropenem MIC values of ≥4 μg/ml.
MDR and XDR Enterobacteriaceae isolates were classified as such per recently recommended guidelines (15) and as adapted by Farrell et al. (16), using the following antimicrobial class representative agents and CLSI interpretive criteria for Enterobacteriaceae: ceftriaxone (≥2 μg/ml), meropenem (≥2 μg/ml), piperacillin-tazobactam (≥32 μg/ml-4 μg/ml), levofloxacin (≥4 μg/ml), gentamicin (≥8 μg/ml), tigecycline (≥4 μg/ml), and colistin (≥4 μg/ml). Classifications were based on the following recommended parameters: MDR if nonsusceptible to at least one agent in ≥3 antimicrobial classes and XDR if nonsusceptible to at least one agent in all but ≤2 antimicrobial classes. PDR isolates were resistant to all antimicrobial classes tested.
Carbapenemase screening.
All CRE isolates were screened by PCR followed by DNA sequencing of blaKPC, blaIMP, blaVIM, blaNDM, blaOXA-48, blaGES (blaGES-2, -4, -5, -6, and -8), blaNMC-A, blaSME, and blaIMI amplicons as previously described (17). Isolates yielding negative results for these genes were tested for less common carbapenemases, including FRI-1, BKC-1, GIM-1/-2, SIM-1, SPM-1, KHM-1, AIM-1, BIC-1, and DIM-1.
ACKNOWLEDGMENTS
We are grateful to L. M. Deshpande and A. P. Davis for performing the carbapenemase screening testing and to L. N. Duncan for his careful review of the manuscript.
This study was performed by JMI Laboratories and supported by Rempex Pharmaceuticals Inc., a wholly owned subsidiary of The Medicines Company, which included funding for services related to preparing the manuscript.
JMI Laboratories was contracted to perform services in 2016 for Achaogen, Actelion, Allecra Therapeutics, Allergan, AmpliPhi Biosciences, API, Astellas Pharma, AstraZeneca, Basilea Pharmaceutica, Bayer AG, BD, Biomodels, Cardeas Pharma Corp., CEM-102 Pharma, Cempra, Cidara Therapeutics, Inc., CorMedix, CSA Biotech, Cutanea Life Sciences, Inc., Debiopharm Group, Dipexium Pharmaceuticals, Inc., Duke, Entasis Therapeutics, Inc., Fortress Biotech, Fox Chase Chemical Diversity Center, Inc., Geom Therapeutics, Inc., GSK, Laboratory Specialists, Inc., Medpace, Melinta Therapeutics, Inc., Merck & Co., Micromyx, MicuRx Pharmaceuticals, Inc., Motif Bio, N8 Medical, Inc., Nabriva Therapeutics, Inc., Nexcida Therapeutics, Inc., Novartis, Paratek Pharmaceuticals, Inc., Pfizer, Polyphor, Rempex, Scynexis, Shionogi, Spero Therapeutics, Symbal Therapeutics, Synlogic, TenNor Therapeutics, TGV Therapeutics, The Medicines Company, Theravance Biopharma, ThermoFisher Scientific, VenatoRx Pharmaceuticals, Inc., Wockhardt, and Zavante Therapeutics, Inc. There are no speakers' bureaus or stock options to declare.
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