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JAC Antimicrob Resist
JAC Antimicrob Resist
jacamr
JAC-Antimicrobial Resistance
2632-1823
Oxford University Press UK

10.1093/jacamr/dlae150
dlae150
Original Article
AcademicSubjects/MED00740
AcademicSubjects/SCI01150
Susceptibility of Gram-negative pathogens collected in Israel to ceftolozane/tazobactam, imipenem/relebactam and comparators: SMART 2018–22
https://orcid.org/0000-0001-7356-1851
Wise Mark G IHMA, Schaumburg, IL, USA

DeRyke C Andrew IHMA, Schaumburg, IL, USA

Alekseeva Irina MSD, Dubai, United Arab Emirates

Siddiqui Fakhar Merck & Co., Inc., Rahway, NJ, USA

Young Katherine Merck & Co., Inc., Rahway, NJ, USA

Motyl Mary R Merck & Co., Inc., Rahway, NJ, USA

Sahm Daniel F IHMA, Schaumburg, IL, USA

Corresponding author. E-mail: mwise@ihma.com
10 2024
17 9 2024
17 9 2024
6 5 dlae15011 7 2024
02 9 2024
© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.
2024
https://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Objectives

To assess the in vitro antimicrobial activity of ceftolozane/tazobactam, imipenem/relebactam and comparator agents against clinical isolates of Gram-negative bacilli collected in Israel from 2018 to 2022.

Methods

Six clinical laboratories each collected up to 250 consecutive Gram-negative isolates per year from patients with bloodstream, intra-abdominal, lower respiratory tract and urinary tract infections. MICs were determined by CLSI broth microdilution and interpreted with 2024 EUCAST breakpoints. Acquired β-lactamase gene carriage was investigated for most ceftolozane/tazobactam- and imipenem/relebactam-resistant isolates.

Results

Among the full collection of Enterobacterales (n = 4420), 95.1% were susceptible to ceftolozane/tazobactam, including 95.3% of putative AmpC/ESBL-positive, non-carbapenem-resistant Enterobacterales (CRE) phenotype Escherichia coli and 86.6% of AmpC/ESBL-positive, non-CRE phenotype Klebsiella pneumoniae. Overall, 99.8% of non-Morganellaceae Enterobacterales (n = 3723) were imipenem/relebactam susceptible including 98% of the MDR isolates. Most Pseudomonas aeruginosa isolates (n = 1182) were inhibited by ceftolozane/tazobactam (93.9% susceptible) and imipenem/relebactam (94.7%). Imipenem/relebactam retained activity against ≥78% of cefepime-resistant, ceftazidime-resistant, and piperacillin/tazobactam-resistant P. aeruginosa, while ceftolozane/tazobactam inhibited the greatest percentage of meropenem-resistant P. aeruginosa (67.4%) among comparator β-lactam antimicrobials. Molecular characterization showed the majority of imipenem/relebactam-resistant Enterobacterales harboured a metallo-β-lactamase, while half of the ceftolozane/tazobactam-resistant Enterobacterales carried an acquired ESBL or AmpC. Most of the imipenem/relebactam- and ceftolozane/tazobactam-resistant P. aeruginosa characterized did not possess acquired β-lactamases.

Conclusions

Recent clinical isolates of Enterobacterales and P. aeruginosa collected in Israel were highly susceptible to ceftolozane/tazobactam and imipenem/relebactam.

Merck Sharp & Dohme 10.13039/100009947
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pmcIntroduction

Ceftolozane/tazobactam and imipenem/relebactam are newer β-lactam/β-lactamase inhibitor combinations that have been approved by both the FDA and EMA for treatment of serious infections, including hospital-acquired bacterial pneumonia. Routine surveillance of these newer agents is critical in the ongoing effort to define their utility and appropriate use. Surveillance data describing in vitro susceptibility testing results for ceftolozane/tazobactam and imipenem/relebactam against clinical isolates of Gram-negative bacilli from Israel have been generally presented as a part of the Middle East region as a whole,1–3 and data specific to isolates collected in Israel are sparse. Thus, we evaluated the activity of these two agents and relevant comparators against isolates of Gram-negative bacilli collected by clinical laboratories in Israel as part of the Study for Monitoring Antimicrobial Resistance Trends (SMART) global surveillance programme.

Materials and methods

Bacterial isolates and antimicrobial susceptibility testing

From 2018 to 2022, six clinical laboratories in Israel participated in the SMART programme. Each laboratory collected consecutive, aerobic or facultative Gram-negative isolates from intra-abdominal, urinary tract, lower respiratory tract and bloodstream infections. Only one isolate per patient per species per year was accepted. All isolates were sent to a central laboratory (IHMA, Monthey, Switzerland), where species identity was confirmed using MALDI-TOF mass spectrometry (Bruker Daltonics, Billerica, MA, USA) and antimicrobial susceptibility performed following the CLSI reference broth microdilution method.4 MICs were interpreted using 2024 EUCAST breakpoints.5 EUCAST does not publish breakpoints for imipenem/relebactam against Morganellaceae family (Proteus, Providencia and Morganella spp.) because they display intrinsic, lowered susceptibility to imipenem by a mechanism independent of β-lactamase production6 and relebactam does not improve the activity of imipenem against Morganellaceae. Therefore, imipenem/relebactam susceptibility was analysed for non-Morganellaceae Enterobacterales (NME) only.

A putative AmpC/ESBL-positive non-carbapenem-resistant Enterobacterales (CRE) phenotype was defined for isolates of Escherichia coli and Klebsiella pneumoniae as those testing with a ceftazidime MIC ≥ 2 mg/L and a meropenem MIC ≤ 1 mg/L. A MDR phenotype was defined as resistance (EUCAST) to ≥3 sentinel agents [amikacin, aztreonam, cefepime, ceftazidime (Enterobacterales only), colistin, imipenem, levofloxacin and piperacillin/tazobactam]. Difficult-to-treat resistance (DTR) was defined as non-susceptibility (EUCAST) to all β-lactams (including aztreonam, ceftazidime, cefepime, imipenem, meropenem and piperacillin/tazobactam), as well as fluoroquinolones (levofloxacin).7

Screening for β-lactamase genes

Isolates meeting the following phenotypic criteria were screened for β-lactamase genes: NME isolates (excluding Serratia spp.) testing with imipenem or imipenem/relebactam MIC values of ≥2 mg/L and Pseudomonas aeruginosa isolates testing with imipenem or imipenem/relebactam MIC values of ≥4 mg/L; Enterobacterales and P. aeruginosa isolates testing with ceftolozane/tazobactam MIC values of ≥4 and ≥8 mg/L, respectively. Published multiplex PCR assays were used to screen for β-lactamase genes as described previously.8,9 For P. aeruginosa collected in 2020–22 only, isolates were characterized by short-read whole-genome sequencing (Illumina Hiseq 2 × 150-bp reads) to a targeted coverage depth of 100×10 and analysed using the CLC Genomics Workbench (Qiagen). The ResFinder database was used to detect β-lactamase genes.11 In total, 214 NME were molecularly characterized. Per SMART protocol for P. aeruginosa, a representative sample of approximately 75% of isolates meeting the criteria for molecular characterization was characterized for β-lactamase genes (54 randomly selected isolates of 293 that qualified were not characterized).

Results

A brief summary of the demographic and clinical characteristics associated with all isolates of Enterobacterales and P. aeruginosa collected in Israel in 2018–22 is provided in Table S1 (available as Supplementary data at JAC-AMR Online).

Ceftolozane/tazobactam inhibited 95.1% of all Enterobacterales isolates, including 98.4% of E. coli isolates, 91.8% of K. pneumoniae isolates, 100% of Klebsiella oxytoca isolates, 94.5% of Citrobacter spp. and 100% of Serratia spp. (Table 1). Reduced ceftolozane/tazobactam activity was observed against organisms with intrinsic AmpC-type enzymes, such as Enterobacter spp. (79.6% susceptible) and Klebsiella aerogenes (77.2% susceptible). Regarding E. coli and K. pneumoniae exhibiting the putative AmpC/ESBL-positive, non-CRE phenotype, 95.3% and 86.6% were inhibited by ceftolozane/tazobactam, respectively. 80.4% of the MDR Enterobacterales isolates were susceptible to ceftolozane/tazobactam; however, none of the 14 DTR isolates were susceptible. Imipenem/relebactam was highly active, inhibiting 99.8% of NME and 100% of AmpC/ESBL-positive, non-CRE phenotype E. coli and K. pneumoniae. Meropenem (99.3% susceptible), ceftazidime/avibactam (99.7%) and amikacin (97.7%) also inhibited very high percentages of Enterobacterales isolates, while cefepime, ceftazidime, piperacillin/tazobactam and levofloxacin were less active, inhibiting <87% of the isolates. Colistin inhibited 81.6% of all Enterobacterales, but 92.3% of the NME, as it is inactive against Morganellaceae species.12 Both imipenem/relebactam (98.0% susceptible) and ceftazidime/avibactam (98.9%) demonstrated potent activity versus Enterobacterales with an MDR phenotype, and each inhibited 11/14 (78.6%) of DTR isolates.

Table 1. Antimicrobial susceptibility of clinical isolates of Enterobacterales and P. aeruginosa collected in Israel 2018–22

		% Susceptible	
Organism group or phenotype	n	C/T	IMR	IPMa,b	MEM	CZA	CAZb	FEPb	TZPb	LVXb,c	AMK	CST	
Enterobacterales	4420	95.1	NA	97.8	99.3	99.7	70.9	73.6	86.9	68.4	97.7	81.6	
 NME	3723	94.7	99.8	99.3	99.2	99.8	69.2	73.7	85.5	71.6	98.0	92.3	
  E. coli	1883	98.4	99.9	99.8	99.8	99.8	70.6	73.7	91.3	64.8	97.9	99.4	
   ESBL non-CREd	549	95.3	100	100	100	100	0.0	14.8	77.8	29.9	94.5	98.7	
  K. pneumoniae	923	91.8	99.6	98.2	97.8	99.6	54.6	56.6	75.8	67.2	97.4	99.2	
   ESBL non-CREd	396	86.6	100	100	100	100	0.0	7.1	56.1	40.2	96.5	99.5	
  Citrobacter spp.	183	94.5	100	99.5	99.5	100	86.3	94.5	89.1	92.9	100	100	
  Enterobacter spp.	226	79.6	100	99.6	99.6	100	66.8	79.2	74.8	86.3	99.1	82.7	
  K. aerogenes	123	77.2	100	100	100	100	54.5	90.2	57.7	87.8	100	100	
  K. oxytoca	100	95.0	98.0	98.0	99.0	98.0	91.0	95.0	92.0	95.0	98.0	99.0	
  Serratia spp.	231	100	100	100	100	100	99.6	99.1	94.4	90.9	98.3	2.6	
 MDR	998	80.4	98.0	95.6	97.0	98.9	6.6	9.5	56.5	28.9	91.7	85.8	
 DTR	14	0.0	78.6	0.0	0.0	78.6	0.0	0.0	0.0	0.0	35.7	92.9	
P. aeruginosa	1182	93.9	94.7	82.4	82.3	95.2	77.2	81.7	76.4	75.9	95.6	99.5	
 FEP-resistant	216	68.1	78.2	53.2	50.0	75.0	11.6	0	12.0	37.0	81.0	99.1	
 CAZ-resistant	269	74.0	82.9	61.0	58.0	79.2	0	29.0	13.0	48.0	84.4	99.3	
 MEM-resistant	92	67.4	44.6	2.2	0	59.8	32.6	33.7	19.6	35.9	76.1	100	
 TZP-resistant	279	77.4	81.4	58.8	54.8	80.3	16.1	31.9	0	48.0	86.7	99.6	
 MDR	240	71.7	75.8	44.2	41.7	77.1	16.7	16.7	10.4	32.5	80.8	98.3	
 DTR	33	39.4	27.3	0	0	21.2	0	0	0	0	57.6	100	
AMK, amikacin; C/T, ceftolozane/tazobactam; CAZ, ceftazidime; CRE, carbapenem-resistant Enterobacterales; CST, colistin; CZA, ceftazidime/avibactam; DTR, difficult-to-treat resistant; ESBL, extended-spectrum β-lactamase; FEP, cefepime; IMR, imipenem/relebactam; IPM, imipenem; LVX, levofloxacin; MDR, multi-drug resistant; MEM, meropenem; NA, not applicable or MIC breakpoint not available; NME, non-Morganellaceae Enterobacterales; TZP, piperacillin/tazobactam.

aThe results combine % susceptible, increased exposure values for Morganellaceae and % susceptible values for non-Morganellaceae Enterobacterales.

bFor IPM, CAZ, FEP, TZP and LVX against P. aeruginosa, the results represent ‘% susceptible, increased exposure’ as defined in the EUCAST guidelines.

cLevofloxacin was only tested against Enterobacterales isolates from 2018 to 2021.

dPutative ESBL non-CRE phenotype was defined by an isolate testing with a CAZ MIC ≥ 2 mg/L and a MEM MIC ≤ 1 mg/L.

Ceftolozane/tazobactam and imipenem/relebactam were both active against the full collection of P. aeruginosa isolates (n = 1182), with 93.9% and 94.7 of the population susceptible, respectively (Table 1). Ceftolozane/tazobactam and imipenem/relebactam retained activity against 68%–77% (ceftolozane/tazobactam) and 78%–82% (imipenem/relebactam) of cefepime-resistant, ceftazidime-resistant and piperacillin/tazobactam-resistant isolates. Against meropenem-resistant isolates, 67.4% and 44.6% were ceftolozane/tazobactam and imipenem/relebactam susceptible, respectively. Both ceftolozane/tazobactam (71.7%) and imipenem/relebactam (75.8%) inhibited >70% of the MDR P. aeruginosa, but <40% of the DTR subset. Ceftazidime/avibactam, amikacin and colistin also displayed potent activity against the full collection of P. aeruginosa, each inhibiting >95% of the isolates.

Figure 1 illustrates the acquired β-lactamase carriage among imipenem/relebactam- and ceftolozane/tazobactam-resistant NME and Enterobacterales, as well as that of imipenem/relebactam- and ceftolozane/tazobactam-resistant P. aeruginosa. Five of the eight imipenem/relebactam-resistant NME carried an MBL (NDM, n = 3; VIM, n = 2), while one isolate harboured OXA-48. No acquired β-lactamases were found in the remaining two. Both of these were identified as E. coli and may harbour non-β-lactamase-based resistance mechanisms such as efflux, PBP changes and/or permeability mutations accounting for the elevated MICs. Among the 206 ceftolozane/tazobactam-resistant Enterobacterales, half were found to carry an acquired ESBL or AmpC only, while 72/206 (35.0%) were species known to possess intrinsic (chromosomal) AmpCs with no acquired β-lactamases detected. Most of the remaining isolates harboured carbapenemases: NDM, n = 5 (2.4%); VIM, n = 2 (1.0%); KPC, n = 9 (4.4%); and OXA-48-like, n = 5 (2.4%), while two isolates carried only OSBLs (i.e. original spectrum β-lactamases, i.e., TEM-1, SHV-1, etc.), and for eight isolates, no acquired β-lactamases could be detected.

Figure 1. β-Lactamase content among imipenem/relebactam and ceftolozane/tazobactam resistant NME/Enterobacterales (a) and P. aeruginosa (b) collected in Israel, 2018–22. C/T, ceftolozane/tazobactam; ESBL, extended-spectrum β-lactamase; IMR, imipenem/relebactam; MBL, metallo-β-lactamase; NME, non-Morganellaceae Enterobacterales; OSBL, original spectrum β-lactamase.

Most of the 63 P. aeruginosa resistant to imipenem/relebactam did not carry an acquired β-lactamase (61.9%), while 10 isolates did, including GES (n = 4, 6.3%), LCR-1 (n = 4, 6.3%), OXA-10, (n = 1, 1.6%) and VIM (n = 1, 1.6%). Fourteen isolates were not characterized. Similarly, no acquired β-lactamases were observed in 37.5% (27/72) of ceftolozane/tazobactam-resistant P. aeruginosa. Among those with acquired β-lactamases, GES was most common 13/72 (18.1%), six carried VEB (8.3%), three (4.2%) carried LCR-1, and one each (1.6%) carried VIM and OXA-10. Twenty-one of the C/T-R P. aeruginosa were not molecularly characterized. MIC value frequency distributions for both ceftolozane/tazobactam and imipenem/relebactam among all the molecular-characterized Enterobacterales and P. aeruginosa stratified by β-lactamase carriage in were provided in Table S2.

Discussion

Previous reports on antimicrobial resistance in Israel are limited. Often Israel is included as part of broader Middle Eastern or European data sets, making interpretation of the information specific to Israel difficult to ascertain, although, in general, resistance rates tend to be lower than other countries in the region. For example, Sader et al.13 reported that the percentages of Israeli isolates susceptible to ceftolozane/tazobactam among Enterobacterales (93.3%) and P. aeruginosa (98.2%) collected from 2012 to 2018 were higher than that of most surrounding countries. Similarly, an earlier SMART publication showed that 94.5% (n = 1126) of P. aeruginosa collected in Israel were ceftolozane/tazobactam susceptible, the second highest percentage among countries surveyed in the Middle East/Africa region.14 Data generated by the SENTRY surveillance programme in 2013–16 noted a 22.8% MDR rate among Enterobacterales collected in Israel,15 nearly identical to that reported here (22.6%), values slightly lower than the 30% found in a recent mini-review,16 with the variation likely due to differences in isolate infection sources and patient populations. The current study is unique in that it is the first to report Israel-specific imipenem/relebactam susceptibility data for both Enterobacterales and P. aeruginosa, while confirming high rates of susceptibility of P. aeruginosa to ceftolozane/tazobactam.

Ceftolozane/tazobactam inhibited 95% of Enterobacterales, including 95% of the putative AmpC/ESBL-positive non-CRE phenotype E. coli and 87% of AmpC/ESBL-positive non-CRE phenotype K. pneumoniae. The activity of ceftolozane/tazobactam against P. aeruginosa (94% susceptible) surpassed that of standard first-line empiric agents (piperacillin/tazobactam, cefepime and ceftazidime) and a commonly used carbapenem, meropenem. Amikacin and colistin each inhibited >95% of the P. aeruginosa; however, despite their excellent in vitro activity, it is important to note the practical limitations associated with these agents in treating Gram-negative infections. EUCAST only publishes bracketed colistin and amikacin (systemic infections) MIC breakpoints with a warning against the use of these agents without additional therapeutic measures. Similarly, CLSI does not publish susceptible MIC breakpoints for colistin against any Gram-negative pathogen.

Imipenem/relebactam inhibited over 99% of NME and 100% of the putative AmpC/ESBL-positive non-CRE phenotype E. coli and K. pneumoniae. Imipenem/relebactam was specifically developed to retain activity against isolates carrying KPCs and generally retains in vitro activity against those without MBL-type carbapenemases and has variable activity against organisms with OXA-48-like enzymes. Geographic differences in β-lactamase prevalence and other resistance mechanisms affect the in vitro activities of all currently available β-lactams and β-lactam/β-lactamase inhibitor combinations, including ceftolozane/tazobactam and imipenem/relebactam. In the current study, we observed low numbers of MBLs, KPC, OXA-48-like and GES carbapenemases in both Enterobacterales and P. aeruginosa (Figure 1). Therefore, mechanisms of carbapenem resistance other than β-lactamases (e.g. OprD mutations in combination with AmpC hyperproduction in P. aeruginosa) likely predominated in the isolates we studied.

In conclusion, recent clinical isolates of Enterobacterales and P. aeruginosa collected in Israel from 2018 to 2022 showed high susceptibility (≥93%) to ceftolozane/tazobactam and imipenem/relebactam. If the in vitro data described here translate into successful clinical results, ceftolozane/tazobactam and imipenem/relebactam could be vital treatment options for patients in Israel with infections caused by Gram-negative pathogens, including antimicrobial-non-susceptible and -resistant Enterobacterales and P. aeruginosa.

Supplementary Material

dlae150_Supplementary_Data

Acknowledgements

The authors thank all SMART global surveillance programme participants for their contributions to the programme.

Funding

Funding for this research, which included compensation for services related to preparing this manuscript, was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Transparency declarations

M.G.W. and D.F.S. are employees of IHMA, which receives funding from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA for the SMART surveillance program. C.A.D. is a consultant to IHMA. F.S., I.A., K.Y., and M.R.M. are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and own stock in Merck & Co., Inc., Rahway, NJ, USA. The IHMA authors and C.A.D. do not have personal financial interests in the sponsor of this manuscript (Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA). All authors provided analysis input and have read and approved the final manuscript.

Supplementary data

Tables S1 and S2 are available as Supplementary data at JAC-AMR Online.
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