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Background: Zidebactam is a β-lactam enhancer antibiotic with a dual mechanism of action involving binding to Gram-negative PBP2 and β-lactamase inhibition. Cefepime combined with zidebactam (WCK 5222) is under clinical development for treatment of Gram-negative infections.

Objectives: To evaluate the in vitro activities of cefepime and zidebactam separately and combined at 1:1 and 2:1 ratios when tested against Gram-negative organisms producing the most clinically relevant β-lactamase types.

Methods: β-Lactamase-producing (193) and WT (71) isolates were tested for susceptibility by broth microdilution method against cefepime/zidebactam, cefepime and zidebactam.

Results: Cefepime/zidebactam (1:1) was very active against Enterobacteriaceae producing CTX-M-15 (21; MIC50/90 0.25/1 mg/L), SHV (20; MIC50/90 0.12/0.25 mg/L), other ESBLs (20, including GES-18, OXA-1/30 and OXY-, PER-, TEM- and VEB-like; MIC50/90 0.25/1 mg/L), plasmidic AmpC (10; MIC50/90 ≤0.06/≤0.06 mg/L), derepressed AmpC (23; MIC50/90 0.12/0.5 mg/L), KPC (35; MIC50/90 0.25/1 mg/L) and metallo-β-lactamases (MBLs; 20 including VIM, IMP and NDM; MIC50/90 0.5/8 mg/L). Cefepime/zidebactam (1:1) was also active against Pseudomonas aeruginosa with overexpression of AmpC (21; MIC50/90 4/8 mg/L) and MBLs [12 (VIM and IMP); MIC50/90 4/8 mg/L]. Zidebactam alone exhibited potent in vitro activity against some Enterobacteriaceae and P. aeruginosa, including β-lactamase-producing strains. Cefepime/zidebactam MIC values were lower than those of each agent tested alone for many β-lactamase-producing strains, indicating synergy. Cefepime/zidebactam showed moderate activity against OXA-23/24/58-producing Acinetobacter baumannii [MIC50/90 32 mg/L (1:1)].

Conclusions: Cefepime/zidebactam showed potent activities against Enterobacteriaceae and P. aeruginosa producing various clinically relevant β-lactamases, including ESBLs, KPCs, AmpC and MBLs for which limited treatment options are currently available.

Introduction

β-Lactam antibiotics represent the most used class of antibacterial agents. These agents are generally well tolerated and effective, but their activity has been threatened by the rapid emergence and dissemination of β-lactamases.1 Zidebactam (molecular formula C13H21N5O7S; Figure 1) is a non-β-lactam agent with a dual mechanism of action involving selective and high-affinity Gram-negative PBP2 binding and β-lactamase inhibition.2 Owing to its PBP2 binding feature, standalone zidebactam demonstrates antibacterial activity against various Enterobacteriaceae and Pseudomonas.3
Chemical structure of zidebactam.
Figure 1.

Chemical structure of zidebactam.

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Cefepime has a broad spectrum of activity against aerobic Gram-positive and -negative bacteria, including Pseudomonas aeruginosa,4–6 and its clinical indications in the current US FDA product package insert include the treatment of moderate to severe pneumonia, complicated and uncomplicated urinary tract infections, complicated intra-abdominal infections and uncomplicated skin and skin-structure infections, as well as empirical therapy for febrile neutropenic patients.7–9 Therefore, zidebactam combined with cefepime (WCK 5222) is under clinical development for treatment of Gram-negative infections (NCT02707107 and NCT02674347; www.clinicaltrials.gov).

Because zidebactam has potent in vitro antimicrobial activity against many Gram-negative species, the cefepime/zidebactam combination should be tested at a fixed ratio instead of a fixed concentration of zidebactam, which is generally used for β-lactamase inhibitor combinations when the β-lactamase inhibitor has limited antibacterial activity. We evaluated the in vitro activities of these two compounds separately and combined at 1:1 and 2:1 ratios when tested against a well-characterized collection of contemporary clinical isolates of β-lactamase-producing Gram-negative organisms.

Materials and methods

Organism collection

A total of 264 contemporary clinical isolates, including 193 strains producing the most clinically relevant β-lactamases, were evaluated. The isolates were collected worldwide through the SENTRY Antimicrobial Surveillance Program and screened for β-lactamase-encoding genes using the microarray-based assay Check-MDR CT101 kit (Check-Points, Wageningen, The Netherlands). The assay was performed according to the manufacturer’s instructions. This kit has the capability to detect CTX-M groups 1, 2, 8 + 25 and 9, TEM WT and ESBL, SHV WT and ESBL, ACC, ACT/MIR, CMYII, DHA, FOX, KPC and NDM-1. The most common mutations that expand the spectrum of TEM and SHV enzymes are detected by this assay and these mutations include 104K, 164S/C/H or 123S for TEM and 138S, 238A and 240K for SHV. Validation of the assay against US isolates was previously performed.10 The isolates included in the collection are shown in Table 1.

Table 1.
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Isolates included in the study

A. Enterobacteriaceae (200 isolates)
 1. WT (cefepime susceptible) isolates (51 total)
  (a) Escherichia coli (10 isolates)
  (b) Klebsiella spp. (11 isolates)
  (c) Enterobacter spp. (10 isolates)
  (d) indole-positive Proteeae (10 isolates)
  (e) Serratia marcescens (10 isolates)
 2. ESBL-producing isolates (61 isolates)
  (a) CTX-M-15 producing (21 isolates; 9 E. coli and 12 Klebsiella pneumoniae)
  (b) SHV producing (20 isolates; 1 E. coli and 19 K. pneumoniae)
  (c) producing other less common ESBL types or combinations [20 isolates; including Citrobacter freundii (2), E. coli (5), Enterobacter cloacae (1), Klebsiella oxytoca (4), K. pneumoniae (3), Proteus mirabilis (3) and Providencia spp. (2)]; the ESBLs produced by these isolates included GES-18 (1 isolate), OXA-1/30 (3), OXY-like (4), PER-like (4), TEM-like (6) and VEB-like (2)
 3. AmpC-producing isolates (33 isolates)
  (a) plasmidic AmpC (10 isolates; 7 E. coli and 3 K. pneumoniae)
  (b) derepressed AmpC [23 isolates; including C. freundii (5), Citrobacter koseri (1), Enterobacter aerogenes (4), E. cloacae (7) and S. marcescens (6)]
 4. KPC-producing isolates [35 isolates; including K. pneumoniae (24), C. freundii (2), E. coli (3), E. aerogenes (2), E. cloacae (1), P. mirabilis (1) and S. marcescens (2)]
 5. MBL-producing isolates (20 isolates)
  (a) IMP producing [4 isolates; E. cloacae (1), K. oxytoca (1), K. pneumoniae (1) and S. marcescens (1)]
  (b) NDM producing [8 isolates; E. coli (3), E. cloacae (1), K. pneumoniae (2), P. mirabilis (1) and S. marcescens (1)]
  (c) VIM producing [8 isolates; C. freundii (1), E. cloacae (4), K. pneumoniae (2) and P. mirabilis (1)]
B. Pseudomonas aeruginosa (43 isolates)
 1. Cefepime susceptible (MIC ≤8 mg/L; 10 isolates)
 2. Isolates with overexpression of AmpC and/or efflux pump(s) (21 isolates)
 3. MBL producing [12 isolates; including IMP-13 (1), IMP-15 (1), VIM-1 (1), VIM-2 (6), VIM-4 (2) and VIM-7 (1)]
C. Acinetobacter baumannii (21 isolates)
 1. Imipenem susceptible (10 isolates)
 2. OXA producing (11 isolates)
A. Enterobacteriaceae (200 isolates)
 1. WT (cefepime susceptible) isolates (51 total)
  (a) Escherichia coli (10 isolates)
  (b) Klebsiella spp. (11 isolates)
  (c) Enterobacter spp. (10 isolates)
  (d) indole-positive Proteeae (10 isolates)
  (e) Serratia marcescens (10 isolates)
 2. ESBL-producing isolates (61 isolates)
  (a) CTX-M-15 producing (21 isolates; 9 E. coli and 12 Klebsiella pneumoniae)
  (b) SHV producing (20 isolates; 1 E. coli and 19 K. pneumoniae)
  (c) producing other less common ESBL types or combinations [20 isolates; including Citrobacter freundii (2), E. coli (5), Enterobacter cloacae (1), Klebsiella oxytoca (4), K. pneumoniae (3), Proteus mirabilis (3) and Providencia spp. (2)]; the ESBLs produced by these isolates included GES-18 (1 isolate), OXA-1/30 (3), OXY-like (4), PER-like (4), TEM-like (6) and VEB-like (2)
 3. AmpC-producing isolates (33 isolates)
  (a) plasmidic AmpC (10 isolates; 7 E. coli and 3 K. pneumoniae)
  (b) derepressed AmpC [23 isolates; including C. freundii (5), Citrobacter koseri (1), Enterobacter aerogenes (4), E. cloacae (7) and S. marcescens (6)]
 4. KPC-producing isolates [35 isolates; including K. pneumoniae (24), C. freundii (2), E. coli (3), E. aerogenes (2), E. cloacae (1), P. mirabilis (1) and S. marcescens (2)]
 5. MBL-producing isolates (20 isolates)
  (a) IMP producing [4 isolates; E. cloacae (1), K. oxytoca (1), K. pneumoniae (1) and S. marcescens (1)]
  (b) NDM producing [8 isolates; E. coli (3), E. cloacae (1), K. pneumoniae (2), P. mirabilis (1) and S. marcescens (1)]
  (c) VIM producing [8 isolates; C. freundii (1), E. cloacae (4), K. pneumoniae (2) and P. mirabilis (1)]
B. Pseudomonas aeruginosa (43 isolates)
 1. Cefepime susceptible (MIC ≤8 mg/L; 10 isolates)
 2. Isolates with overexpression of AmpC and/or efflux pump(s) (21 isolates)
 3. MBL producing [12 isolates; including IMP-13 (1), IMP-15 (1), VIM-1 (1), VIM-2 (6), VIM-4 (2) and VIM-7 (1)]
C. Acinetobacter baumannii (21 isolates)
 1. Imipenem susceptible (10 isolates)
 2. OXA producing (11 isolates)
Table 1.
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Isolates included in the study

A. Enterobacteriaceae (200 isolates)
 1. WT (cefepime susceptible) isolates (51 total)
  (a) Escherichia coli (10 isolates)
  (b) Klebsiella spp. (11 isolates)
  (c) Enterobacter spp. (10 isolates)
  (d) indole-positive Proteeae (10 isolates)
  (e) Serratia marcescens (10 isolates)
 2. ESBL-producing isolates (61 isolates)
  (a) CTX-M-15 producing (21 isolates; 9 E. coli and 12 Klebsiella pneumoniae)
  (b) SHV producing (20 isolates; 1 E. coli and 19 K. pneumoniae)
  (c) producing other less common ESBL types or combinations [20 isolates; including Citrobacter freundii (2), E. coli (5), Enterobacter cloacae (1), Klebsiella oxytoca (4), K. pneumoniae (3), Proteus mirabilis (3) and Providencia spp. (2)]; the ESBLs produced by these isolates included GES-18 (1 isolate), OXA-1/30 (3), OXY-like (4), PER-like (4), TEM-like (6) and VEB-like (2)
 3. AmpC-producing isolates (33 isolates)
  (a) plasmidic AmpC (10 isolates; 7 E. coli and 3 K. pneumoniae)
  (b) derepressed AmpC [23 isolates; including C. freundii (5), Citrobacter koseri (1), Enterobacter aerogenes (4), E. cloacae (7) and S. marcescens (6)]
 4. KPC-producing isolates [35 isolates; including K. pneumoniae (24), C. freundii (2), E. coli (3), E. aerogenes (2), E. cloacae (1), P. mirabilis (1) and S. marcescens (2)]
 5. MBL-producing isolates (20 isolates)
  (a) IMP producing [4 isolates; E. cloacae (1), K. oxytoca (1), K. pneumoniae (1) and S. marcescens (1)]
  (b) NDM producing [8 isolates; E. coli (3), E. cloacae (1), K. pneumoniae (2), P. mirabilis (1) and S. marcescens (1)]
  (c) VIM producing [8 isolates; C. freundii (1), E. cloacae (4), K. pneumoniae (2) and P. mirabilis (1)]
B. Pseudomonas aeruginosa (43 isolates)
 1. Cefepime susceptible (MIC ≤8 mg/L; 10 isolates)
 2. Isolates with overexpression of AmpC and/or efflux pump(s) (21 isolates)
 3. MBL producing [12 isolates; including IMP-13 (1), IMP-15 (1), VIM-1 (1), VIM-2 (6), VIM-4 (2) and VIM-7 (1)]
C. Acinetobacter baumannii (21 isolates)
 1. Imipenem susceptible (10 isolates)
 2. OXA producing (11 isolates)
A. Enterobacteriaceae (200 isolates)
 1. WT (cefepime susceptible) isolates (51 total)
  (a) Escherichia coli (10 isolates)
  (b) Klebsiella spp. (11 isolates)
  (c) Enterobacter spp. (10 isolates)
  (d) indole-positive Proteeae (10 isolates)
  (e) Serratia marcescens (10 isolates)
 2. ESBL-producing isolates (61 isolates)
  (a) CTX-M-15 producing (21 isolates; 9 E. coli and 12 Klebsiella pneumoniae)
  (b) SHV producing (20 isolates; 1 E. coli and 19 K. pneumoniae)
  (c) producing other less common ESBL types or combinations [20 isolates; including Citrobacter freundii (2), E. coli (5), Enterobacter cloacae (1), Klebsiella oxytoca (4), K. pneumoniae (3), Proteus mirabilis (3) and Providencia spp. (2)]; the ESBLs produced by these isolates included GES-18 (1 isolate), OXA-1/30 (3), OXY-like (4), PER-like (4), TEM-like (6) and VEB-like (2)
 3. AmpC-producing isolates (33 isolates)
  (a) plasmidic AmpC (10 isolates; 7 E. coli and 3 K. pneumoniae)
  (b) derepressed AmpC [23 isolates; including C. freundii (5), Citrobacter koseri (1), Enterobacter aerogenes (4), E. cloacae (7) and S. marcescens (6)]
 4. KPC-producing isolates [35 isolates; including K. pneumoniae (24), C. freundii (2), E. coli (3), E. aerogenes (2), E. cloacae (1), P. mirabilis (1) and S. marcescens (2)]
 5. MBL-producing isolates (20 isolates)
  (a) IMP producing [4 isolates; E. cloacae (1), K. oxytoca (1), K. pneumoniae (1) and S. marcescens (1)]
  (b) NDM producing [8 isolates; E. coli (3), E. cloacae (1), K. pneumoniae (2), P. mirabilis (1) and S. marcescens (1)]
  (c) VIM producing [8 isolates; C. freundii (1), E. cloacae (4), K. pneumoniae (2) and P. mirabilis (1)]
B. Pseudomonas aeruginosa (43 isolates)
 1. Cefepime susceptible (MIC ≤8 mg/L; 10 isolates)
 2. Isolates with overexpression of AmpC and/or efflux pump(s) (21 isolates)
 3. MBL producing [12 isolates; including IMP-13 (1), IMP-15 (1), VIM-1 (1), VIM-2 (6), VIM-4 (2) and VIM-7 (1)]
C. Acinetobacter baumannii (21 isolates)
 1. Imipenem susceptible (10 isolates)
 2. OXA producing (11 isolates)

Susceptibility testing

MIC values were determined using CLSI broth microdilution methodology as described in CLSI document M07-A10.11 The combination of cefepime/zidebactam (WCK 5222; two ratio concentrations, 1:1 and 2:1) and both compounds alone were tested in 96-well, frozen-form panels produced by JMI Laboratories (North Liberty, IA, USA). Zidebactam and cefepime powders were provided by Wockhardt Bio AG (Switzerland) and the comparator agents were provided by the respective manufacturer or acquired from Sigma–Aldrich. Quality control (QC) isolates were tested in each test batch and the inoculum density was monitored by colony counts. QC ranges and interpretive criteria for the comparator compounds were as published in CLSI M100-S26.12 Wockhardt Bio AG provided available target MIC information for cefepime/zidebactam and zidebactam alone tested against the listed QC organisms. The tested QC strains included the following: Escherichiacoli ATCC 25922, ATCC 35218 and NCTC 13353, Klebsiellapneumoniae ATCC 700603 and ATCC BAA-1705 and P. aeruginosa ATCC 27853.

Results

WT (cefepime susceptible) Enterobacteriaceae

The highest cefepime MIC among WT (cefepime susceptible) Enterobacteriaceae was 1 mg/L (MIC50/90 ≤0.06/0.12 mg/L) and MICs of cefepime/zidebactam at ratios of 2:1 (MIC50/90 ≤0.06/0.12 mg/L) and 1:1 (MIC50/90 ≤0.06/≤0.06 mg/L) were similar to those of cefepime (Table 2). A significant decrease in the cefepime MIC was observed for only one isolate, an E. coli with a cefepime MIC of 1 mg/L and MICs of 2:1 and 1:1 cefepime/zidebactam of 0.12 and ≤0.06 mg/L, respectively (Table 2).

Table 2.
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Cumulative frequency distribution of cefepime, cefepime/zidebactam at 2:1 and 1:1 ratios and zidebactam MIC results when tested against WT (cefepime susceptible) Enterobacteriaceae strains

No. of isolates (cumulative %) inhibited at MIC (mg/L) of:
Organism group/ antimicrobial agentn≤0.060.120.250.51248163264128>128MIC50MIC90
All strains
 cefepime5142 (82.4)5 (92.2)3 (98.0)0 (98.0)1 (100.0)————————≤0.060.12
 cefepime/zidebactam (2:1)5143 (84.3)8 (100.0)———————————≤0.060.12
 cefepime/zidebactam (1:1)5148 (94.1)3 (100.0)———————————≤0.06≤0.06
 zidebactam511 (2.0)20 (41.2)5 (51.0)1 (52.9)1 (54.9)1 (56.9)0 (56.9)0 (56.9)0 (56.9)0 (56.9)0 (56.9)0 (56.9)22 (100.0)0.25>128
E. coli
 cefepime107 (70.0)1 (80.0)1 (90.0)0 (90.0)1 (100.0)————————≤0.060.25
 cefepime/zidebactam (2:1)108 (80.0)2 (100.0)———————————≤0.060.12
 cefepime/zidebactam (1:1)1010 (100.0)————————————≤0.06≤0.06
 zidebactam101 (10.0)9 (100.0)———————————0.120.12
Klebsiella spp.
 cefepime1111 (100.0)————————————≤0.06≤0.06
 cefepime/zidebactam (2:1)1111 (100.0)————————————≤0.06≤0.06
 cefepime/zidebactam (1:1)1111 (100.0)————————————≤0.06≤0.06
 zidebactam11—3 (27.3)3 (54.5)1 (63.6)1 (72.7)1 (81.8)0 (81.8)0 (81.8)0 (81.8)0 (81.8)0 (81.8)0 (81.8)2 (100.0)0.25>128
Enterobacter spp.
 cefepime1010 (100.0)————————————≤0.06≤0.06
 cefepime/zidebactam (2:1)108 (80.0)2 (100.0)———————————≤0.060.12
 cefepime/zidebactam (1:1)1010 (100.0)————————————≤0.06≤0.06
 zidebactam10—8 (80.0)2 (100.0)——————————0.120.25
Indole-positive Proteeae
 cefepime1010 (100.0)————————————≤0.06≤0.06
 cefepime/zidebactam (2:1)1010 (100.0)————————————≤0.06≤0.06
 cefepime/zidebactam (1:1)1010 (100.0)————————————≤0.06≤0.06
 zidebactam10————————————10 (100.0)>128>128
S. marcescens
 cefepime104 (40.0)4 (80.0)2 (100.0)——————————0.120.25
 cefepime/zidebactam (2:1)106 (60.0)4 (100.0)———————————≤0.060.12
 cefepime/zidebactam (1:1)107 (70.0)3 (100.0)———————————≤0.060.12
 zidebactam10————————————10 (100.0)>128>128
No. of isolates (cumulative %) inhibited at MIC (mg/L) of:
Organism group/ antimicrobial agentn≤0.060.120.250.51248163264128>128MIC50MIC90
All strains
 cefepime5142 (82.4)5 (92.2)3 (98.0)0 (98.0)1 (100.0)————————≤0.060.12
 cefepime/zidebactam (2:1)5143 (84.3)8 (100.0)———————————≤0.060.12
 cefepime/zidebactam (1:1)5148 (94.1)3 (100.0)———————————≤0.06≤0.06
 zidebactam511 (2.0)20 (41.2)5 (51.0)1 (52.9)1 (54.9)1 (56.9)0 (56.9)0 (56.9)0 (56.9)0 (56.9)0 (56.9)0 (56.9)22 (100.0)0.25>128
E. coli
 cefepime107 (70.0)1 (80.0)1 (90.0)0 (90.0)1 (100.0)————————≤0.060.25
 cefepime/zidebactam (2:1)108 (80.0)2 (100.0)———————————≤0.060.12
 cefepime/zidebactam (1:1)1010 (100.0)————————————≤0.06≤0.06
 zidebactam101 (10.0)9 (100.0)———————————0.120.12
Klebsiella spp.
 cefepime1111 (100.0)————————————≤0.06≤0.06
 cefepime/zidebactam (2:1)1111 (100.0)————————————≤0.06≤0.06
 cefepime/zidebactam (1:1)1111 (100.0)————————————≤0.06≤0.06
 zidebactam11—3 (27.3)3 (54.5)1 (63.6)1 (72.7)1 (81.8)0 (81.8)0 (81.8)0 (81.8)0 (81.8)0 (81.8)0 (81.8)2 (100.0)0.25>128
Enterobacter spp.
 cefepime1010 (100.0)————————————≤0.06≤0.06
 cefepime/zidebactam (2:1)108 (80.0)2 (100.0)———————————≤0.060.12
 cefepime/zidebactam (1:1)1010 (100.0)————————————≤0.06≤0.06
 zidebactam10—8 (80.0)2 (100.0)——————————0.120.25
Indole-positive Proteeae
 cefepime1010 (100.0)————————————≤0.06≤0.06
 cefepime/zidebactam (2:1)1010 (100.0)————————————≤0.06≤0.06
 cefepime/zidebactam (1:1)1010 (100.0)————————————≤0.06≤0.06
 zidebactam10————————————10 (100.0)>128>128
S. marcescens
 cefepime104 (40.0)4 (80.0)2 (100.0)——————————0.120.25
 cefepime/zidebactam (2:1)106 (60.0)4 (100.0)———————————≤0.060.12
 cefepime/zidebactam (1:1)107 (70.0)3 (100.0)———————————≤0.060.12
 zidebactam10————————————10 (100.0)>128>128
Table 2.
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Cumulative frequency distribution of cefepime, cefepime/zidebactam at 2:1 and 1:1 ratios and zidebactam MIC results when tested against WT (cefepime susceptible) Enterobacteriaceae strains

No. of isolates (cumulative %) inhibited at MIC (mg/L) of:
Organism group/ antimicrobial agentn≤0.060.120.250.51248163264128>128MIC50MIC90
All strains
 cefepime5142 (82.4)5 (92.2)3 (98.0)0 (98.0)1 (100.0)————————≤0.060.12
 cefepime/zidebactam (2:1)5143 (84.3)8 (100.0)———————————≤0.060.12
 cefepime/zidebactam (1:1)5148 (94.1)3 (100.0)———————————≤0.06≤0.06
 zidebactam511 (2.0)20 (41.2)5 (51.0)1 (52.9)1 (54.9)1 (56.9)0 (56.9)0 (56.9)0 (56.9)0 (56.9)0 (56.9)0 (56.9)22 (100.0)0.25>128
E. coli
 cefepime107 (70.0)1 (80.0)1 (90.0)0 (90.0)1 (100.0)————————≤0.060.25
 cefepime/zidebactam (2:1)108 (80.0)2 (100.0)———————————≤0.060.12
 cefepime/zidebactam (1:1)1010 (100.0)————————————≤0.06≤0.06
 zidebactam101 (10.0)9 (100.0)———————————0.120.12
Klebsiella spp.
 cefepime1111 (100.0)————————————≤0.06≤0.06
 cefepime/zidebactam (2:1)1111 (100.0)————————————≤0.06≤0.06
 cefepime/zidebactam (1:1)1111 (100.0)————————————≤0.06≤0.06
 zidebactam11—3 (27.3)3 (54.5)1 (63.6)1 (72.7)1 (81.8)0 (81.8)0 (81.8)0 (81.8)0 (81.8)0 (81.8)0 (81.8)2 (100.0)0.25>128
Enterobacter spp.
 cefepime1010 (100.0)————————————≤0.06≤0.06
 cefepime/zidebactam (2:1)108 (80.0)2 (100.0)———————————≤0.060.12
 cefepime/zidebactam (1:1)1010 (100.0)————————————≤0.06≤0.06
 zidebactam10—8 (80.0)2 (100.0)——————————0.120.25
Indole-positive Proteeae
 cefepime1010 (100.0)————————————≤0.06≤0.06
 cefepime/zidebactam (2:1)1010 (100.0)————————————≤0.06≤0.06
 cefepime/zidebactam (1:1)1010 (100.0)————————————≤0.06≤0.06
 zidebactam10————————————10 (100.0)>128>128
S. marcescens
 cefepime104 (40.0)4 (80.0)2 (100.0)——————————0.120.25
 cefepime/zidebactam (2:1)106 (60.0)4 (100.0)———————————≤0.060.12
 cefepime/zidebactam (1:1)107 (70.0)3 (100.0)———————————≤0.060.12
 zidebactam10————————————10 (100.0)>128>128
No. of isolates (cumulative %) inhibited at MIC (mg/L) of:
Organism group/ antimicrobial agentn≤0.060.120.250.51248163264128>128MIC50MIC90
All strains
 cefepime5142 (82.4)5 (92.2)3 (98.0)0 (98.0)1 (100.0)————————≤0.060.12
 cefepime/zidebactam (2:1)5143 (84.3)8 (100.0)———————————≤0.060.12
 cefepime/zidebactam (1:1)5148 (94.1)3 (100.0)———————————≤0.06≤0.06
 zidebactam511 (2.0)20 (41.2)5 (51.0)1 (52.9)1 (54.9)1 (56.9)0 (56.9)0 (56.9)0 (56.9)0 (56.9)0 (56.9)0 (56.9)22 (100.0)0.25>128
E. coli
 cefepime107 (70.0)1 (80.0)1 (90.0)0 (90.0)1 (100.0)————————≤0.060.25
 cefepime/zidebactam (2:1)108 (80.0)2 (100.0)———————————≤0.060.12
 cefepime/zidebactam (1:1)1010 (100.0)————————————≤0.06≤0.06
 zidebactam101 (10.0)9 (100.0)———————————0.120.12
Klebsiella spp.
 cefepime1111 (100.0)————————————≤0.06≤0.06
 cefepime/zidebactam (2:1)1111 (100.0)————————————≤0.06≤0.06
 cefepime/zidebactam (1:1)1111 (100.0)————————————≤0.06≤0.06
 zidebactam11—3 (27.3)3 (54.5)1 (63.6)1 (72.7)1 (81.8)0 (81.8)0 (81.8)0 (81.8)0 (81.8)0 (81.8)0 (81.8)2 (100.0)0.25>128
Enterobacter spp.
 cefepime1010 (100.0)————————————≤0.06≤0.06
 cefepime/zidebactam (2:1)108 (80.0)2 (100.0)———————————≤0.060.12
 cefepime/zidebactam (1:1)1010 (100.0)————————————≤0.06≤0.06
 zidebactam10—8 (80.0)2 (100.0)——————————0.120.25
Indole-positive Proteeae
 cefepime1010 (100.0)————————————≤0.06≤0.06
 cefepime/zidebactam (2:1)1010 (100.0)————————————≤0.06≤0.06
 cefepime/zidebactam (1:1)1010 (100.0)————————————≤0.06≤0.06
 zidebactam10————————————10 (100.0)>128>128
S. marcescens
 cefepime104 (40.0)4 (80.0)2 (100.0)——————————0.120.25
 cefepime/zidebactam (2:1)106 (60.0)4 (100.0)———————————≤0.060.12
 cefepime/zidebactam (1:1)107 (70.0)3 (100.0)———————————≤0.060.12
 zidebactam10————————————10 (100.0)>128>128

Zidebactam alone exhibited variable activity (MIC50/90 0.25/>128 mg/L) when tested against WT Enterobacteriaceae. Overall, E. coli (MIC50/90 0.12/0.12 mg/L) and Enterobacter spp. (MIC50/90 0.12/0.25 mg/L) isolates exhibited low zidebactam MIC values, whereas indole-positive Proteeae (MIC50/90 >128/>128 mg/L) and Serratiamarcescens (MIC50/90 >128/>128 mg/L) showed much higher zidebactam MICs. Among WT Klebsiella spp. isolates, zidebactam MICs ranged from 0.12 to >128 mg/L (MIC50/90 0.25/>128 mg/L; Table 2).

β-Lactamase-producing Enterobacteriaceae

The MIC values of the cefepime/zidebactam combinations (2:1 and 1:1 ratios) were substantially lower than those of cefepime alone for ESBL-phenotype Enterobacteriaceae (Table 3). Among CTX-M-producing isolates, significant reductions in cefepime MICs were noticeable with E. coli (MIC50 >128, 0.5 and 0.25 mg/L for cefepime and cefepime/zidebactam at ratios of 2:1 and 1:1, respectively) and K. pneumoniae (MIC50 64, 0.5 and 0.5 mg/L for cefepime and cefepime/zidebactam at ratios of 2:1 and 1:1, respectively). Overall, 85.7% of isolates were inhibited at ≤2 mg/L zidebactam alone. Furthermore, the MICs of 1:1 cefepime/zidebactam were generally 2-fold lower than those of 2:1 cefepime/zidebactam (Table 3).

Table 3.
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Cumulative frequency distribution of cefepime, cefepime/zidebactam at 2:1 and 1:1 ratios and zidebactam MIC results when tested against β-lactamase-producing Enterobacteriaceae strains

No. of isolates (cumulative %) inhibited at MIC (mg/L) of:
Organism group/ antimicrobial agentn≤0.060.120.250.51248163264128>128MIC50MIC90
CTX-M-15-producing strainsa
 cefepime21—————————2 (9.5)4 (28.6)2 (38.1)13 (100.0)>128>128
 cefepime/zidebactam (2:1)21——3 (14.3)12 (71.4)3 (85.7)1 (90.5)1 (95.2)1 (100.0)—————0.52
 cefepime/zidebactam (1:1)21—6 (28.6)8 (66.7)4 (85.7)1 (90.5)1 (95.2)1 (100.0)——————0.251
 zidebactam21—2 (9.5)9 (52.4)4 (71.4)2 (81.0)1 (85.7)0 (85.7)0 (85.7)0 (85.7)0 (85.7)1 (90.5)0 (90.5)2 (100.0)0.2564
SHV-producing strainsb
 cefepime200 (0.0)1 (5.0)2 (15.0)1 (20.0)2 (30.0)4 (50.0)5 (75.0)3 (90.0)2 (100.0)————28
 cefepime/zidebactam (2:1)202 (10.0)6 (40.0)10 (90.0)1 (95.0)0 (95.0)1 (100.0)———————0.250.25
 cefepime/zidebactam (1:1)204 (20.0)10 (70.0)5 (95.0)0 (95.0)1 (100.0)————————0.120.25
 zidebactam200 (0.0)8 (40.0)2 (50.0)0 (50.0)0 (50.0)0 (50.0)0 (50.0)0 (50.0)0 (50.0)1 (55.0)0 (55.0)0 (55.0)9 (100.0)0.25>128
Strains producing other ESBLsc
 cefepime20——1 (5.0)2 (15.0)2 (25.0)4 (45.0)2 (55.0)3 (70.0)2 (80.0)1 (85.0)1 (90.0)2 (100.0)—464
 cefepime/zidebactam (2:1)20—3 (15.0)9 (60.0)3 (75.0)4 (95.0)1 (100.0)———————0.251
 cefepime/zidebactam (1:1)201 (5.0)8 (45.0)6 (75.0)2 (85.0)3 (100.0)————————0.251
 zidebactam20—3 (15.0)1 (20.0)2 (30.0)2 (40.0)0 (40.0)1 (45.0)0 (45.0)0 (45.0)0 (45.0)1 (50.0)1 (55.0)9 (100.0)64>128
Plasmidic AmpC-producing strainsd
 cefepime100 (0.0)1 (10.0)5 (60.0)4 (100.0)—————————0.250.5
 cefepime/zidebactam (2:1)106 (60.0)3 (90.0)1 (100.0)——————————≤0.060.12
 cefepime/zidebactam (1:1)109 (90.0)1 (100.0)———————————≤0.06≤0.06
 zidebactam101 (10.0)2 (30.0)5 (80.0)0 (80.0)0 (80.0)0 (80.0)0 (80.0)0 (80.0)1 (90.0)1 (100.0)———0.2516
Derepressed AmpC-producing strainse
 cefepime231 (4.3)2 (13.0)0 (13.0)5 (34.8)4 (52.2)0 (52.2)3 (65.2)5 (87.0)1 (91.3)2 (100.0)———116
 cefepime/zidebactam (2:1)233 (13.0)5 (34.8)6 (60.9)6 (87.0)2 (95.7)1 (100.0)———————0.251
 cefepime/zidebactam (1:1)236 (26.1)9 (65.2)4 (82.6)2 (91.3)2 (100.0)————————0.120.5
 zidebactam23—5 (21.7)3 (34.8)3 (47.8)0 (47.8)2 (56.5)0 (56.5)0 (56.5)1 (60.9)0 (60.9)0 (60.9)0 (60.9)9 (100.0)2>128
KPC-producing strainsf
 cefepime35—————2 (5.7)5 (20.0)2 (25.7)5 (40.0)5 (54.3)3 (62.9)3 (71.4)10 (100.0)32>128
 cefepime/zidebactam (2:1)35——8 (22.9)14 (62.9)7 (82.9)5 (97.1)1 (100.0)——————0.52
 cefepime/zidebactam (1:1)35—7 (20.0)12 (54.3)11 (85.7)4 (97.1)1 (100.0)———————0.251
 zidebactam35—1 (2.9)7 (22.9)3 (31.4)5 (45.7)1 (48.6)1 (51.4)0 (51.4)3 (60.0)1 (62.9)1 (65.7)1 (68.6)11 (100.0)4>128
MBL-producing strainsg
 cefepime20———————1 (5.0)0 (5.0)2 (15.0)2 (25.0)1 (30.0)14 (100.0)>128>128
 cefepime/zidebactam (2:1)20——2 (10.0)5 (35.0)6 (65.0)2 (75.0)0 (75.0)2 (85.0)1 (90.0)2 (100.0)———116
 cefepime/zidebactam (1:1)20—1 (5.0)6 (35.0)3 (50.0)1 (55.0)4 (75.0)1 (80.0)2 (90.0)1 (95.0)1 (100.0)———0.58
 zidebactam20—1 (5.0)4 (25.0)5 (50.0)1 (55.0)0 (55.0)1 (60.0)0 (60.0)0 (60.0)0 (60.0)0 (60.0)0 (60.0)8 (100.0)0.5>128
No. of isolates (cumulative %) inhibited at MIC (mg/L) of:
Organism group/ antimicrobial agentn≤0.060.120.250.51248163264128>128MIC50MIC90
CTX-M-15-producing strainsa
 cefepime21—————————2 (9.5)4 (28.6)2 (38.1)13 (100.0)>128>128
 cefepime/zidebactam (2:1)21——3 (14.3)12 (71.4)3 (85.7)1 (90.5)1 (95.2)1 (100.0)—————0.52
 cefepime/zidebactam (1:1)21—6 (28.6)8 (66.7)4 (85.7)1 (90.5)1 (95.2)1 (100.0)——————0.251
 zidebactam21—2 (9.5)9 (52.4)4 (71.4)2 (81.0)1 (85.7)0 (85.7)0 (85.7)0 (85.7)0 (85.7)1 (90.5)0 (90.5)2 (100.0)0.2564
SHV-producing strainsb
 cefepime200 (0.0)1 (5.0)2 (15.0)1 (20.0)2 (30.0)4 (50.0)5 (75.0)3 (90.0)2 (100.0)————28
 cefepime/zidebactam (2:1)202 (10.0)6 (40.0)10 (90.0)1 (95.0)0 (95.0)1 (100.0)———————0.250.25
 cefepime/zidebactam (1:1)204 (20.0)10 (70.0)5 (95.0)0 (95.0)1 (100.0)————————0.120.25
 zidebactam200 (0.0)8 (40.0)2 (50.0)0 (50.0)0 (50.0)0 (50.0)0 (50.0)0 (50.0)0 (50.0)1 (55.0)0 (55.0)0 (55.0)9 (100.0)0.25>128
Strains producing other ESBLsc
 cefepime20——1 (5.0)2 (15.0)2 (25.0)4 (45.0)2 (55.0)3 (70.0)2 (80.0)1 (85.0)1 (90.0)2 (100.0)—464
 cefepime/zidebactam (2:1)20—3 (15.0)9 (60.0)3 (75.0)4 (95.0)1 (100.0)———————0.251
 cefepime/zidebactam (1:1)201 (5.0)8 (45.0)6 (75.0)2 (85.0)3 (100.0)————————0.251
 zidebactam20—3 (15.0)1 (20.0)2 (30.0)2 (40.0)0 (40.0)1 (45.0)0 (45.0)0 (45.0)0 (45.0)1 (50.0)1 (55.0)9 (100.0)64>128
Plasmidic AmpC-producing strainsd
 cefepime100 (0.0)1 (10.0)5 (60.0)4 (100.0)—————————0.250.5
 cefepime/zidebactam (2:1)106 (60.0)3 (90.0)1 (100.0)——————————≤0.060.12
 cefepime/zidebactam (1:1)109 (90.0)1 (100.0)———————————≤0.06≤0.06
 zidebactam101 (10.0)2 (30.0)5 (80.0)0 (80.0)0 (80.0)0 (80.0)0 (80.0)0 (80.0)1 (90.0)1 (100.0)———0.2516
Derepressed AmpC-producing strainse
 cefepime231 (4.3)2 (13.0)0 (13.0)5 (34.8)4 (52.2)0 (52.2)3 (65.2)5 (87.0)1 (91.3)2 (100.0)———116
 cefepime/zidebactam (2:1)233 (13.0)5 (34.8)6 (60.9)6 (87.0)2 (95.7)1 (100.0)———————0.251
 cefepime/zidebactam (1:1)236 (26.1)9 (65.2)4 (82.6)2 (91.3)2 (100.0)————————0.120.5
 zidebactam23—5 (21.7)3 (34.8)3 (47.8)0 (47.8)2 (56.5)0 (56.5)0 (56.5)1 (60.9)0 (60.9)0 (60.9)0 (60.9)9 (100.0)2>128
KPC-producing strainsf
 cefepime35—————2 (5.7)5 (20.0)2 (25.7)5 (40.0)5 (54.3)3 (62.9)3 (71.4)10 (100.0)32>128
 cefepime/zidebactam (2:1)35——8 (22.9)14 (62.9)7 (82.9)5 (97.1)1 (100.0)——————0.52
 cefepime/zidebactam (1:1)35—7 (20.0)12 (54.3)11 (85.7)4 (97.1)1 (100.0)———————0.251
 zidebactam35—1 (2.9)7 (22.9)3 (31.4)5 (45.7)1 (48.6)1 (51.4)0 (51.4)3 (60.0)1 (62.9)1 (65.7)1 (68.6)11 (100.0)4>128
MBL-producing strainsg
 cefepime20———————1 (5.0)0 (5.0)2 (15.0)2 (25.0)1 (30.0)14 (100.0)>128>128
 cefepime/zidebactam (2:1)20——2 (10.0)5 (35.0)6 (65.0)2 (75.0)0 (75.0)2 (85.0)1 (90.0)2 (100.0)———116
 cefepime/zidebactam (1:1)20—1 (5.0)6 (35.0)3 (50.0)1 (55.0)4 (75.0)1 (80.0)2 (90.0)1 (95.0)1 (100.0)———0.58
 zidebactam20—1 (5.0)4 (25.0)5 (50.0)1 (55.0)0 (55.0)1 (60.0)0 (60.0)0 (60.0)0 (60.0)0 (60.0)0 (60.0)8 (100.0)0.5>128
a

Includes E. coli (9) and K. pneumoniae (12).

b

Includes E. coli (1) and K. pneumoniae (19). It does not exclude the production of other β-lactamases.

c

Includes GES-18, OXA-1/30, OXY-like, PER-like, ESBL TEM-like and VEB-like (see the Materials and methods section). The organisms are C. freundii (2), E. coli (5), E. cloacae (1), K. oxytoca (4), K. pneumoniae (3), P. mirabilis (3) and Providencia spp. (2). It does not exclude the production of other β-lactamases.

d

Includes E. coli (7) and K. pneumoniae (3). It does not exclude the production of other β-lactamases.

e

Includes C. freundii (5), C. koseri (1), E. aerogenes (4), E. cloacae (7) and S. marcescens (6). It does not exclude the production of other β-lactamases.

f

Includes K. pneumoniae (24), C. freundii (2), E. coli (3), E. aerogenes (2), E. cloacae (1), P. mirabilis (1) and S. marcescens (2).

g

Includes IMP producers [4; E. cloacae (1), K. oxytoca (1), K. pneumoniae (1) and S. marcescens (1)], NDM producers [8; E. coli (3), E. cloacae (1), K. pneumoniae (2), P. mirabilis (1) and S. marcescens (1)] and VIM producers [8; C. freundii (1), E. cloacae (4), K. pneumoniae (2) and P. mirabilis (1)].

Table 3.
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Cumulative frequency distribution of cefepime, cefepime/zidebactam at 2:1 and 1:1 ratios and zidebactam MIC results when tested against β-lactamase-producing Enterobacteriaceae strains

No. of isolates (cumulative %) inhibited at MIC (mg/L) of:
Organism group/ antimicrobial agentn≤0.060.120.250.51248163264128>128MIC50MIC90
CTX-M-15-producing strainsa
 cefepime21—————————2 (9.5)4 (28.6)2 (38.1)13 (100.0)>128>128
 cefepime/zidebactam (2:1)21——3 (14.3)12 (71.4)3 (85.7)1 (90.5)1 (95.2)1 (100.0)—————0.52
 cefepime/zidebactam (1:1)21—6 (28.6)8 (66.7)4 (85.7)1 (90.5)1 (95.2)1 (100.0)——————0.251
 zidebactam21—2 (9.5)9 (52.4)4 (71.4)2 (81.0)1 (85.7)0 (85.7)0 (85.7)0 (85.7)0 (85.7)1 (90.5)0 (90.5)2 (100.0)0.2564
SHV-producing strainsb
 cefepime200 (0.0)1 (5.0)2 (15.0)1 (20.0)2 (30.0)4 (50.0)5 (75.0)3 (90.0)2 (100.0)————28
 cefepime/zidebactam (2:1)202 (10.0)6 (40.0)10 (90.0)1 (95.0)0 (95.0)1 (100.0)———————0.250.25
 cefepime/zidebactam (1:1)204 (20.0)10 (70.0)5 (95.0)0 (95.0)1 (100.0)————————0.120.25
 zidebactam200 (0.0)8 (40.0)2 (50.0)0 (50.0)0 (50.0)0 (50.0)0 (50.0)0 (50.0)0 (50.0)1 (55.0)0 (55.0)0 (55.0)9 (100.0)0.25>128
Strains producing other ESBLsc
 cefepime20——1 (5.0)2 (15.0)2 (25.0)4 (45.0)2 (55.0)3 (70.0)2 (80.0)1 (85.0)1 (90.0)2 (100.0)—464
 cefepime/zidebactam (2:1)20—3 (15.0)9 (60.0)3 (75.0)4 (95.0)1 (100.0)———————0.251
 cefepime/zidebactam (1:1)201 (5.0)8 (45.0)6 (75.0)2 (85.0)3 (100.0)————————0.251
 zidebactam20—3 (15.0)1 (20.0)2 (30.0)2 (40.0)0 (40.0)1 (45.0)0 (45.0)0 (45.0)0 (45.0)1 (50.0)1 (55.0)9 (100.0)64>128
Plasmidic AmpC-producing strainsd
 cefepime100 (0.0)1 (10.0)5 (60.0)4 (100.0)—————————0.250.5
 cefepime/zidebactam (2:1)106 (60.0)3 (90.0)1 (100.0)——————————≤0.060.12
 cefepime/zidebactam (1:1)109 (90.0)1 (100.0)———————————≤0.06≤0.06
 zidebactam101 (10.0)2 (30.0)5 (80.0)0 (80.0)0 (80.0)0 (80.0)0 (80.0)0 (80.0)1 (90.0)1 (100.0)———0.2516
Derepressed AmpC-producing strainse
 cefepime231 (4.3)2 (13.0)0 (13.0)5 (34.8)4 (52.2)0 (52.2)3 (65.2)5 (87.0)1 (91.3)2 (100.0)———116
 cefepime/zidebactam (2:1)233 (13.0)5 (34.8)6 (60.9)6 (87.0)2 (95.7)1 (100.0)———————0.251
 cefepime/zidebactam (1:1)236 (26.1)9 (65.2)4 (82.6)2 (91.3)2 (100.0)————————0.120.5
 zidebactam23—5 (21.7)3 (34.8)3 (47.8)0 (47.8)2 (56.5)0 (56.5)0 (56.5)1 (60.9)0 (60.9)0 (60.9)0 (60.9)9 (100.0)2>128
KPC-producing strainsf
 cefepime35—————2 (5.7)5 (20.0)2 (25.7)5 (40.0)5 (54.3)3 (62.9)3 (71.4)10 (100.0)32>128
 cefepime/zidebactam (2:1)35——8 (22.9)14 (62.9)7 (82.9)5 (97.1)1 (100.0)——————0.52
 cefepime/zidebactam (1:1)35—7 (20.0)12 (54.3)11 (85.7)4 (97.1)1 (100.0)———————0.251
 zidebactam35—1 (2.9)7 (22.9)3 (31.4)5 (45.7)1 (48.6)1 (51.4)0 (51.4)3 (60.0)1 (62.9)1 (65.7)1 (68.6)11 (100.0)4>128
MBL-producing strainsg
 cefepime20———————1 (5.0)0 (5.0)2 (15.0)2 (25.0)1 (30.0)14 (100.0)>128>128
 cefepime/zidebactam (2:1)20——2 (10.0)5 (35.0)6 (65.0)2 (75.0)0 (75.0)2 (85.0)1 (90.0)2 (100.0)———116
 cefepime/zidebactam (1:1)20—1 (5.0)6 (35.0)3 (50.0)1 (55.0)4 (75.0)1 (80.0)2 (90.0)1 (95.0)1 (100.0)———0.58
 zidebactam20—1 (5.0)4 (25.0)5 (50.0)1 (55.0)0 (55.0)1 (60.0)0 (60.0)0 (60.0)0 (60.0)0 (60.0)0 (60.0)8 (100.0)0.5>128
No. of isolates (cumulative %) inhibited at MIC (mg/L) of:
Organism group/ antimicrobial agentn≤0.060.120.250.51248163264128>128MIC50MIC90
CTX-M-15-producing strainsa
 cefepime21—————————2 (9.5)4 (28.6)2 (38.1)13 (100.0)>128>128
 cefepime/zidebactam (2:1)21——3 (14.3)12 (71.4)3 (85.7)1 (90.5)1 (95.2)1 (100.0)—————0.52
 cefepime/zidebactam (1:1)21—6 (28.6)8 (66.7)4 (85.7)1 (90.5)1 (95.2)1 (100.0)——————0.251
 zidebactam21—2 (9.5)9 (52.4)4 (71.4)2 (81.0)1 (85.7)0 (85.7)0 (85.7)0 (85.7)0 (85.7)1 (90.5)0 (90.5)2 (100.0)0.2564
SHV-producing strainsb
 cefepime200 (0.0)1 (5.0)2 (15.0)1 (20.0)2 (30.0)4 (50.0)5 (75.0)3 (90.0)2 (100.0)————28
 cefepime/zidebactam (2:1)202 (10.0)6 (40.0)10 (90.0)1 (95.0)0 (95.0)1 (100.0)———————0.250.25
 cefepime/zidebactam (1:1)204 (20.0)10 (70.0)5 (95.0)0 (95.0)1 (100.0)————————0.120.25
 zidebactam200 (0.0)8 (40.0)2 (50.0)0 (50.0)0 (50.0)0 (50.0)0 (50.0)0 (50.0)0 (50.0)1 (55.0)0 (55.0)0 (55.0)9 (100.0)0.25>128
Strains producing other ESBLsc
 cefepime20——1 (5.0)2 (15.0)2 (25.0)4 (45.0)2 (55.0)3 (70.0)2 (80.0)1 (85.0)1 (90.0)2 (100.0)—464
 cefepime/zidebactam (2:1)20—3 (15.0)9 (60.0)3 (75.0)4 (95.0)1 (100.0)———————0.251
 cefepime/zidebactam (1:1)201 (5.0)8 (45.0)6 (75.0)2 (85.0)3 (100.0)————————0.251
 zidebactam20—3 (15.0)1 (20.0)2 (30.0)2 (40.0)0 (40.0)1 (45.0)0 (45.0)0 (45.0)0 (45.0)1 (50.0)1 (55.0)9 (100.0)64>128
Plasmidic AmpC-producing strainsd
 cefepime100 (0.0)1 (10.0)5 (60.0)4 (100.0)—————————0.250.5
 cefepime/zidebactam (2:1)106 (60.0)3 (90.0)1 (100.0)——————————≤0.060.12
 cefepime/zidebactam (1:1)109 (90.0)1 (100.0)———————————≤0.06≤0.06
 zidebactam101 (10.0)2 (30.0)5 (80.0)0 (80.0)0 (80.0)0 (80.0)0 (80.0)0 (80.0)1 (90.0)1 (100.0)———0.2516
Derepressed AmpC-producing strainse
 cefepime231 (4.3)2 (13.0)0 (13.0)5 (34.8)4 (52.2)0 (52.2)3 (65.2)5 (87.0)1 (91.3)2 (100.0)———116
 cefepime/zidebactam (2:1)233 (13.0)5 (34.8)6 (60.9)6 (87.0)2 (95.7)1 (100.0)———————0.251
 cefepime/zidebactam (1:1)236 (26.1)9 (65.2)4 (82.6)2 (91.3)2 (100.0)————————0.120.5
 zidebactam23—5 (21.7)3 (34.8)3 (47.8)0 (47.8)2 (56.5)0 (56.5)0 (56.5)1 (60.9)0 (60.9)0 (60.9)0 (60.9)9 (100.0)2>128
KPC-producing strainsf
 cefepime35—————2 (5.7)5 (20.0)2 (25.7)5 (40.0)5 (54.3)3 (62.9)3 (71.4)10 (100.0)32>128
 cefepime/zidebactam (2:1)35——8 (22.9)14 (62.9)7 (82.9)5 (97.1)1 (100.0)——————0.52
 cefepime/zidebactam (1:1)35—7 (20.0)12 (54.3)11 (85.7)4 (97.1)1 (100.0)———————0.251
 zidebactam35—1 (2.9)7 (22.9)3 (31.4)5 (45.7)1 (48.6)1 (51.4)0 (51.4)3 (60.0)1 (62.9)1 (65.7)1 (68.6)11 (100.0)4>128
MBL-producing strainsg
 cefepime20———————1 (5.0)0 (5.0)2 (15.0)2 (25.0)1 (30.0)14 (100.0)>128>128
 cefepime/zidebactam (2:1)20——2 (10.0)5 (35.0)6 (65.0)2 (75.0)0 (75.0)2 (85.0)1 (90.0)2 (100.0)———116
 cefepime/zidebactam (1:1)20—1 (5.0)6 (35.0)3 (50.0)1 (55.0)4 (75.0)1 (80.0)2 (90.0)1 (95.0)1 (100.0)———0.58
 zidebactam20—1 (5.0)4 (25.0)5 (50.0)1 (55.0)0 (55.0)1 (60.0)0 (60.0)0 (60.0)0 (60.0)0 (60.0)0 (60.0)8 (100.0)0.5>128
a

Includes E. coli (9) and K. pneumoniae (12).

b

Includes E. coli (1) and K. pneumoniae (19). It does not exclude the production of other β-lactamases.

c

Includes GES-18, OXA-1/30, OXY-like, PER-like, ESBL TEM-like and VEB-like (see the Materials and methods section). The organisms are C. freundii (2), E. coli (5), E. cloacae (1), K. oxytoca (4), K. pneumoniae (3), P. mirabilis (3) and Providencia spp. (2). It does not exclude the production of other β-lactamases.

d

Includes E. coli (7) and K. pneumoniae (3). It does not exclude the production of other β-lactamases.

e

Includes C. freundii (5), C. koseri (1), E. aerogenes (4), E. cloacae (7) and S. marcescens (6). It does not exclude the production of other β-lactamases.

f

Includes K. pneumoniae (24), C. freundii (2), E. coli (3), E. aerogenes (2), E. cloacae (1), P. mirabilis (1) and S. marcescens (2).

g

Includes IMP producers [4; E. cloacae (1), K. oxytoca (1), K. pneumoniae (1) and S. marcescens (1)], NDM producers [8; E. coli (3), E. cloacae (1), K. pneumoniae (2), P. mirabilis (1) and S. marcescens (1)] and VIM producers [8; C. freundii (1), E. cloacae (4), K. pneumoniae (2) and P. mirabilis (1)].

When tested against SHV-producing isolates, the MICs of the cefepime/zidebactam combinations (MIC50/90 0.12–0.25/0.25 mg/L) were 8- to 32-fold lower than those of cefepime alone (MIC50/90 2/8 mg/L). The MICs of 1:1 cefepime/zidebactam (MIC50/90 0.12/0.25 mg/L) were generally 2-fold lower than those of 2:1 cefepime/zidebactam (MIC50/90 0.25/0.25 mg/L; Table 3).

Zidebactam alone exhibited potent in vitro activity against CTX-M-producing E. coli (MIC50 0.25 mg/L and highest MIC 0.5 mg/L; nine isolates tested) and variable activity against CTX-M-producing Klebsiella spp. (MIC50/90 0.5/>128 mg/L), SHV-producing isolates (mostly K. pneumoniae; MIC50/90 0.25/128 mg/L) and Enterobacteriaceae isolates producing other β-lactamases (MIC50/90 64/>128 mg/L; Table 3).

Cefepime (MIC50/90 0.25/0.5 mg/L), cefepime/zidebactam 2:1 ratio (MIC50/90 ≤0.06/0.12 mg/L) and cefepime/zidebactam 1:1 ratio (MIC50/90 ≤0.06/≤0.06 mg/L) were very active against plasmidic AmpC-producing isolates. The MIC50 and MIC90 values of the cefepime/zidebactam combinations were at least 4-fold lower than those of cefepime alone (Table 3). When tested against derepressed AmpC-producing isolates, the MICs of the cefepime/zidebactam combinations (MIC50/90 0.12–0.25/0.5–1 mg/L) were 4- to 32-fold lower than those of cefepime alone (MIC50/90 1/16 mg/L) and the MICs of cefepime/zidebactam 1:1 ratio were usually 2-fold lower than those of cefepime/zidebactam 2:1 ratio. Zidebactam alone was active against some plasmidic AmpC-producing isolates (MIC50/90 0.25/16 mg/L) as well as some derepressed AmpC-producing isolates (MIC50/90 2/>128 mg/L) (Table 3).

Cefepime/zidebactam 2:1 (MIC50/90 0.5/2 mg/L) and cefepime/zidebactam 1:1 (MIC50/90 0.25/1 mg/L) were very active against KPC-producing isolates. The MIC50 and MIC90 values of the cefepime/zidebactam combinations were 64- to 128-fold lower than those of cefepime alone and the highest MICs were 2 and 4 mg/L for the 1:1 and 2:1 combinations, respectively. Overall, 51.4% of isolates were inhibited at a zidebactam concentration of 4 mg/L or less (MIC50/90 4/>128 mg/L (Table 3).

Cefepime/zidebactam 1:1 (MIC50/90 0.5/8 mg/L) inhibited 75.0% and 90.0% of metallo-β-lactamase (MBL)-producing Enterobacteriaceae isolates at ≤2 and ≤8 mg/L, respectively. Note that zidebactam alone (MIC50/90 0.5/>128 mg/L) inhibited 60.0% (12/20) of MBL-producing isolates at 4 mg/L, whereas the remaining 40.0% (8/20) had zidebactam MIC values of >128 mg/L. When tested against MBL-producing Enterobacteriaceae, the MIC50 and MIC90 values for cefepime/zidebactam 1:1 (MIC50/90 0.5/8 mg/L) were 2-fold lower than those of cefepime/zidebactam 2:1 (MIC50/90 1/16 mg/L; Table 3).

P. aeruginosa and Acinetobacter baumannii

The MICs of the cefepime/zidebactam combinations (MIC50/90 1/2 mg/L for both combinations) were generally 2-fold lower than those of cefepime and zidebactam alone (MIC50/90 2/4 mg/L) when tested against cefepime-susceptible P. aeruginosa isolates (Table 4). When tested against P. aeruginosa with overexpression of AmpC and/or efflux pump(s), the MICs of the cefepime/zidebactam combinations (MIC50/90 4–8/8–16 mg/L) were generally 2- to 8-fold lower than those for cefepime alone (MIC50/90 16/64 mg/L). Furthermore, the MICs of cefepime/zidebactam 1:1 were usually 2-fold lower than those of cefepime/zidebactam 2:1 (Table 4).

Table 4.
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Cumulative frequency distribution of cefepime, cefepime/zidebactam at 2:1 and 1:1 ratios and zidebactam MIC results when tested against P. aeruginosa and A. baumannii strains

No. of isolates (cumulative %) inhibited at MIC (mg/L) of:
Organism group/ antimicrobial agentn0.250.51248163264128>128MIC50MIC90
P. aeruginosa
 cefepime-susceptible strains
  cefepime10——3 (30.0)3 (60.0)3 (90.0)1 (100.0)—————24
  cefepime/zidebactam (2:1)10—1 (10.0)7 (80.0)2 (100.0)———————12
  cefepime/zidebactam (1:1)10—1 (10.0)7 (80.0)2 (100.0)———————12
  zidebactam10——1 (10.0)6 (70.0)3 (100.0)——————24
 AmpC-producing strains
  cefepime21————1 (4.8)4 (23.8)6 (52.4)7 (85.7)3 (100.0)——1664
  cefepime/zidebactam (2:1)21——1 (4.8)2 (14.3)6 (42.9)6 (71.4)5 (95.2)1 (100.0)———816
  cefepime/zidebactam (1:1)21—1 (4.8)1 (9.5)4 (28.6)7 (61.9)6 (90.5)2 (100.0)————48
  zidebactam21———2 (9.5)7 (42.9)2 (52.4)7 (85.7)1 (90.5)0 (90.5)1 (95.2)1 (100.0)832
 MBL-producing strains
  cefepime12—————1 (8.3)0 (8.3)5 (50.0)4 (83.3)1 (91.7)1 (100.0)32128
  cefepime/zidebactam (2:1)12——1 (8.3)0 (8.3)2 (25.0)6 (75.0)2 (91.7)1 (100.0)———816
  cefepime/zidebactam (1:1)12—1 (8.3)0 (8.3)2 (25.0)6 (75.0)2 (91.7)1 (100.0)—–——48
  zidebactam12—1 (8.3)0 (8.3)0 (8.3)6 (58.3)3 (83.3)2 (100.0)————416
A. baumannii
 imipenem-susceptible strains
  cefepime10——1 (10.0)2 (30.0)1 (40.0)4 (80.0)2 (100.0)————816
  cefepime/zidebactam (2:1)10——1 (10.0)0 (10.0)5 (60.0)4 (100.0)—————48
  cefepime/zidebactam (1:1)10——1 (10.0)1 (20.0)6 (80.0)2 (100.0)—————48
  zidebactam10——————————10 (100.0)>128>128
 OXA-23/24/58-producing strainsa
  cefepime11——————1 (9.1)2 (27.3)2 (45.5)2 (63.6)4 (100.0)128>128
  cefepime/zidebactam (2:1)11–—————3 (27.3)6 (81.8)2 (100.0)——3264
  cefepime/zidebactam (1:1)11—————1 (9.1)3 (36.4)6 (90.9)1 (100.0)——3232
  zidebactam11——————————11 (100.0)>128>128
No. of isolates (cumulative %) inhibited at MIC (mg/L) of:
Organism group/ antimicrobial agentn0.250.51248163264128>128MIC50MIC90
P. aeruginosa
 cefepime-susceptible strains
  cefepime10——3 (30.0)3 (60.0)3 (90.0)1 (100.0)—————24
  cefepime/zidebactam (2:1)10—1 (10.0)7 (80.0)2 (100.0)———————12
  cefepime/zidebactam (1:1)10—1 (10.0)7 (80.0)2 (100.0)———————12
  zidebactam10——1 (10.0)6 (70.0)3 (100.0)——————24
 AmpC-producing strains
  cefepime21————1 (4.8)4 (23.8)6 (52.4)7 (85.7)3 (100.0)——1664
  cefepime/zidebactam (2:1)21——1 (4.8)2 (14.3)6 (42.9)6 (71.4)5 (95.2)1 (100.0)———816
  cefepime/zidebactam (1:1)21—1 (4.8)1 (9.5)4 (28.6)7 (61.9)6 (90.5)2 (100.0)————48
  zidebactam21———2 (9.5)7 (42.9)2 (52.4)7 (85.7)1 (90.5)0 (90.5)1 (95.2)1 (100.0)832
 MBL-producing strains
  cefepime12—————1 (8.3)0 (8.3)5 (50.0)4 (83.3)1 (91.7)1 (100.0)32128
  cefepime/zidebactam (2:1)12——1 (8.3)0 (8.3)2 (25.0)6 (75.0)2 (91.7)1 (100.0)———816
  cefepime/zidebactam (1:1)12—1 (8.3)0 (8.3)2 (25.0)6 (75.0)2 (91.7)1 (100.0)—–——48
  zidebactam12—1 (8.3)0 (8.3)0 (8.3)6 (58.3)3 (83.3)2 (100.0)————416
A. baumannii
 imipenem-susceptible strains
  cefepime10——1 (10.0)2 (30.0)1 (40.0)4 (80.0)2 (100.0)————816
  cefepime/zidebactam (2:1)10——1 (10.0)0 (10.0)5 (60.0)4 (100.0)—————48
  cefepime/zidebactam (1:1)10——1 (10.0)1 (20.0)6 (80.0)2 (100.0)—————48
  zidebactam10——————————10 (100.0)>128>128
 OXA-23/24/58-producing strainsa
  cefepime11——————1 (9.1)2 (27.3)2 (45.5)2 (63.6)4 (100.0)128>128
  cefepime/zidebactam (2:1)11–—————3 (27.3)6 (81.8)2 (100.0)——3264
  cefepime/zidebactam (1:1)11—————1 (9.1)3 (36.4)6 (90.9)1 (100.0)——3232
  zidebactam11——————————11 (100.0)>128>128
a

OXA-23-producing (6), OXA-24-producing (3), OXA-58-producing (1) and OXA-23- and OXA-58-producing (1) strains.

Table 4.
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Cumulative frequency distribution of cefepime, cefepime/zidebactam at 2:1 and 1:1 ratios and zidebactam MIC results when tested against P. aeruginosa and A. baumannii strains

No. of isolates (cumulative %) inhibited at MIC (mg/L) of:
Organism group/ antimicrobial agentn0.250.51248163264128>128MIC50MIC90
P. aeruginosa
 cefepime-susceptible strains
  cefepime10——3 (30.0)3 (60.0)3 (90.0)1 (100.0)—————24
  cefepime/zidebactam (2:1)10—1 (10.0)7 (80.0)2 (100.0)———————12
  cefepime/zidebactam (1:1)10—1 (10.0)7 (80.0)2 (100.0)———————12
  zidebactam10——1 (10.0)6 (70.0)3 (100.0)——————24
 AmpC-producing strains
  cefepime21————1 (4.8)4 (23.8)6 (52.4)7 (85.7)3 (100.0)——1664
  cefepime/zidebactam (2:1)21——1 (4.8)2 (14.3)6 (42.9)6 (71.4)5 (95.2)1 (100.0)———816
  cefepime/zidebactam (1:1)21—1 (4.8)1 (9.5)4 (28.6)7 (61.9)6 (90.5)2 (100.0)————48
  zidebactam21———2 (9.5)7 (42.9)2 (52.4)7 (85.7)1 (90.5)0 (90.5)1 (95.2)1 (100.0)832
 MBL-producing strains
  cefepime12—————1 (8.3)0 (8.3)5 (50.0)4 (83.3)1 (91.7)1 (100.0)32128
  cefepime/zidebactam (2:1)12——1 (8.3)0 (8.3)2 (25.0)6 (75.0)2 (91.7)1 (100.0)———816
  cefepime/zidebactam (1:1)12—1 (8.3)0 (8.3)2 (25.0)6 (75.0)2 (91.7)1 (100.0)—–——48
  zidebactam12—1 (8.3)0 (8.3)0 (8.3)6 (58.3)3 (83.3)2 (100.0)————416
A. baumannii
 imipenem-susceptible strains
  cefepime10——1 (10.0)2 (30.0)1 (40.0)4 (80.0)2 (100.0)————816
  cefepime/zidebactam (2:1)10——1 (10.0)0 (10.0)5 (60.0)4 (100.0)—————48
  cefepime/zidebactam (1:1)10——1 (10.0)1 (20.0)6 (80.0)2 (100.0)—————48
  zidebactam10——————————10 (100.0)>128>128
 OXA-23/24/58-producing strainsa
  cefepime11——————1 (9.1)2 (27.3)2 (45.5)2 (63.6)4 (100.0)128>128
  cefepime/zidebactam (2:1)11–—————3 (27.3)6 (81.8)2 (100.0)——3264
  cefepime/zidebactam (1:1)11—————1 (9.1)3 (36.4)6 (90.9)1 (100.0)——3232
  zidebactam11——————————11 (100.0)>128>128
No. of isolates (cumulative %) inhibited at MIC (mg/L) of:
Organism group/ antimicrobial agentn0.250.51248163264128>128MIC50MIC90
P. aeruginosa
 cefepime-susceptible strains
  cefepime10——3 (30.0)3 (60.0)3 (90.0)1 (100.0)—————24
  cefepime/zidebactam (2:1)10—1 (10.0)7 (80.0)2 (100.0)———————12
  cefepime/zidebactam (1:1)10—1 (10.0)7 (80.0)2 (100.0)———————12
  zidebactam10——1 (10.0)6 (70.0)3 (100.0)——————24
 AmpC-producing strains
  cefepime21————1 (4.8)4 (23.8)6 (52.4)7 (85.7)3 (100.0)——1664
  cefepime/zidebactam (2:1)21——1 (4.8)2 (14.3)6 (42.9)6 (71.4)5 (95.2)1 (100.0)———816
  cefepime/zidebactam (1:1)21—1 (4.8)1 (9.5)4 (28.6)7 (61.9)6 (90.5)2 (100.0)————48
  zidebactam21———2 (9.5)7 (42.9)2 (52.4)7 (85.7)1 (90.5)0 (90.5)1 (95.2)1 (100.0)832
 MBL-producing strains
  cefepime12—————1 (8.3)0 (8.3)5 (50.0)4 (83.3)1 (91.7)1 (100.0)32128
  cefepime/zidebactam (2:1)12——1 (8.3)0 (8.3)2 (25.0)6 (75.0)2 (91.7)1 (100.0)———816
  cefepime/zidebactam (1:1)12—1 (8.3)0 (8.3)2 (25.0)6 (75.0)2 (91.7)1 (100.0)—–——48
  zidebactam12—1 (8.3)0 (8.3)0 (8.3)6 (58.3)3 (83.3)2 (100.0)————416
A. baumannii
 imipenem-susceptible strains
  cefepime10——1 (10.0)2 (30.0)1 (40.0)4 (80.0)2 (100.0)————816
  cefepime/zidebactam (2:1)10——1 (10.0)0 (10.0)5 (60.0)4 (100.0)—————48
  cefepime/zidebactam (1:1)10——1 (10.0)1 (20.0)6 (80.0)2 (100.0)—————48
  zidebactam10——————————10 (100.0)>128>128
 OXA-23/24/58-producing strainsa
  cefepime11——————1 (9.1)2 (27.3)2 (45.5)2 (63.6)4 (100.0)128>128
  cefepime/zidebactam (2:1)11–—————3 (27.3)6 (81.8)2 (100.0)——3264
  cefepime/zidebactam (1:1)11—————1 (9.1)3 (36.4)6 (90.9)1 (100.0)——3232
  zidebactam11——————————11 (100.0)>128>128
a

OXA-23-producing (6), OXA-24-producing (3), OXA-58-producing (1) and OXA-23- and OXA-58-producing (1) strains.

Cefepime/zidebactam 2:1 (MIC50/90 8/16 mg/L) and cefepime/zidebactam 1:1 (MIC50/90 4/8 mg/L) were very active against MBL-producing P. aeruginosa and inhibited 75.0% (9/12) and 91.7% (11/12) of isolates at ≤8 mg/L, respectively. Furthermore, the in vitro activity of zidebactam alone (MIC50/90 4/16 mg/L) was similar to those of the cefepime/zidebactam combinations (MIC50/90 4–8/8–16 mg/L) when tested against these organisms. In contrast, cefepime alone showed limited activity against MBL-producing P. aeruginosa isolates (MIC50/90 32/128 mg/L; Table 4).

The MICs of the cefepime/zidebactam combinations (MIC50/90 4/8 mg/L for both combinations) were similar or slightly lower (2-fold) than those of cefepime alone (MIC50/90 8/16 mg/L) when tested against imipenem-susceptible A.baumannii isolates. Moreover, cefepime (MIC50/90 128/>128 mg/L) and zidebactam alone (MIC50/90 >128/>128 mg/L) showed very limited activity against OXA-producing (OXA-23/24/58) A. baumannii isolates. The cefepime/zidebactam combinations were at least 2-fold more active (MIC50/90 32/32–64 mg/L) than either of the agents tested alone (Table 4). For this collection of MDR Acinetobacter, the imipenem and meropenem MIC50 values were >8 mg/L (data not shown).

Discussion

Infections caused by MDR Gram-negative bacteria represent a great challenge to infectious diseases clinicians. Most of these organisms harbour β-lactamase genes along with resistance determinants for other antimicrobial classes, resulting in multidrug resistance or pandrug resistance.13 A variety of non-β-lactam agents are being studied in attempts to address MDR Gram-negative pathogens and numerous investigational approaches have involved both established and new β-lactamase inhibitors in novel combinations.14 The search for new inhibitor classes has been prompted in part by the rapid and continuous increase in the number of β-lactamases. In the last few years, new β-lactamase families have emerged with properties that make them more resistant to clavulanic acid and the sulfone inhibitors, thus encouraging the development of new approaches involving β-lactams.1 Efforts to discover newer β-lactamase inhibitors over the last 25 years have resulted in very few compounds with an expanded inhibition spectrum and therefore no single β-lactamase inhibitor is able to offer a comprehensive coverage against all four classes of β-lactamases.1,14 Moreover, novel β-lactamase inhibitors will continue to be challenged by emergence of newer mutant enzymes.15,16 Therefore, alternative approaches independent of β-lactamase inhibition need to be explored.

WCK 5222 consists of the combination of cefepime with zidebactam. Cefepime is a well-established fourth-generation cephalosporin with broad-spectrum activity, which includes P. aeruginosa and stably derepressed AmpC-producing Enterobacteriaceae; zidebactam is a non-β-lactam agent with intrinsic in vitro activity against some Gram-negative organisms due to its high affinity for PBP2 binding and β-lactamase inhibition properties.2,4–6 We evaluated the in vitro activity of each compound separately and the combination at two ratios (1:1 and 2:1) against a selected collection of Gram-negative organisms harbouring the most clinically relevant β-lactamases. The decision to combine the compounds in a fixed ratio instead of using a fixed concentration of the inhibitor (zidebactam) was driven by the fact that zidebactam exhibits potent in vitro antimicrobial activity against many Gram-negative species, such as E. coli, Enterobacter spp. and P. aeruginosa, including β-lactamase-producing strains. The highest zidebactam MICs for WT isolates of E. coli, Enterobacter spp. and P. aeruginosa were 0.12, 0.25 and 4 mg/L, respectively (Tables 2 and 4). In contrast, other Gram-negative organisms, such as S.marcescens, indole-positive Proteeae and Acinetobacter spp., appear to be intrinsically resistant to zidebactam. The in vitro activity of zidebactam against Klebsiella spp. was inconstant, with some isolates showing low MICs and others showing off-scale high MICs. Moreover, many Klebsiella spp. isolates exhibited trailing or haze growth in all or most zidebactam wells of the MIC panel.

When tested against Enterobacteriaceae, cefepime demonstrated potent in vitro activity against WT isolates as well as most AmpC-producing isolates. Although cefepime activity was compromised against Enterobacteriaceae producing ESBL and/or carbapenemases, cefepime/zidebactam combinations (2:1 and 1:1 ratios) demonstrated potent in vitro activities against Enterobacteriaceae producing most clinically relevant β-lactamases, including KPC, MBLs, CTX-M-15, SHV and AmpC. The highest cefepime/zidebactam (1:1) MIC among KPC-producing Enterobacteriaceae was only 2 mg/L and 90.0% of MBL-producing Enterobacteriaceae isolates were inhibited at cefepime/zidebactam 1:1 MIC of ≤8 mg/L (Table 3). It is important to note that many β-lactamase-producing Enterobacteriaceae exhibited elevated MICs of cefepime and zidebactam when these were tested separately, but very low MICs of the cefepime/zidebactam combinations, emphasizing the synergy between these two compounds.

Cefepime/zidebactam combinations (2:1 and 1:1 ratios) were also very active against P. aeruginosa, including MBL- and AmpC-producing isolates (Table 4). Furthermore, cefepime/zidebactam 1:1 was slightly (2-fold) more active than cefepime/zidebactam 2:1 against β-lactamase-producing Enterobacteriaceae and P. aeruginosa. When tested against OXA-producing (OXA-23/24/58) A.baumannii isolates, cefepime and zidebactam alone showed limited activity (MIC50/90 128–>128/>128 mg/L). However, cefepime/zidebactam 1:1 (MIC50/90, 32/32 mg/L) was at least 4-fold more active than cefepime or zidebactam tested alone.

The number of β-lactamases produced by clinically relevant bacterial species has increased astronomically in the last 10–20 years and this number continues to increase rapidly.1,10 Because it is not feasible to evaluate adequate numbers of all clinically relevant β-lactamases, this study focused on the most common β-lactamases observed in the last few years, mainly in Western Europe and the USA. Thus, some β-lactamases that are relatively common in some geographical regions, such as some MBLs (e.g. NDM, VIM and SPM), the class D enzymes OXA-48 (Enterobacteriaceae) and OXA-58 (A. baumannii) and some CTX-M variants (e.g. CTX-M-3 and CTX-M-14), were tested in small number or not included in this investigation. This is certainly a limitation of this study and the activity of WCK 5222 should be further evaluated against larger collections of organisms producing selected β-lactamases in future investigations.

In summary, WCK 5222 (cefepime/zidebactam) demonstrated potent in vitro activity against Enterobacteriaceae and P. aeruginosa, including isolates producing all four classes of clinically relevant β-lactamases. These in vitro results support further clinical development of cefepime/zidebactam for treatment of serious Gram-negative infections, especially those caused by MDR organisms.

Acknowledgements

This study was presented at ASM Microbe, Boston, MA, USA, 2016 (Poster Sunday-446).

Funding

This study was supported by Wockhardt Bio AG (Switzerland).

Transparency declarations

JMI Laboratories, Inc. has also received research and educational grants in 2014–15 from Achaogen, Actavis, Actelion, Allergan, American Proficiency Institute (API), AmpliPhi, Anacor, Astellas, AstraZeneca, Basilea, Bayer, BD, Cardeas, Cellceutix, CEM-102 Pharmaceuticals, Cempra, Cerexa, Cidara, Cormedix, Cubist, Debiopharm, Dipexium, Dong Wha, Durata, Enteris, Exela, Forest Research Institute, Furiex, Genentech, GSK, Helperby, ICPD, Janssen, Lannett, Longitude, Medpace, Meiji Seika Kasha, Melinta, Merck, Motif, Nabriva, Novartis, Paratek, Pfizer, Pocared, PTC Therapeutics, Rempex, Roche, Salvat, Scynexis, Seachaid, Shionogi, Tetraphase, The Medicines Co., Theravance, ThermoFisher, VenatoRX, Vertex, Zavante and some other corporations. Some JMI employees are advisors/consultants for Allergan, Astellas, Cubist, Pfizer, Cempra and Theravance. In regards to speakers’ bureaus and stock options, the authors have none to declare.

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© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: [email protected].
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