Abstract
Objectives
To evaluate the in vitro activities of ceftolozane/tazobactam and imipenem/relebactam against clinical isolates of Gram-negative bacilli collected in four central and northern European countries (Belgium, Norway, Sweden, Switzerland) during 2017–21.
Methods
Participating clinical laboratories each collected up to 250 consecutive Gram-negative isolates per year from patients with bloodstream, intraabdominal, lower respiratory tract or urinary tract infections. MICs were determined by CLSI broth microdilution and interpreted using 2022 EUCAST breakpoints. β-Lactamase genes were identified in select β-lactam-non-susceptible isolate subsets.
Results
Ninety-five percent of all Enterobacterales (n = 4158), 95% of ESBL-positive non-carbapenem-resistant Enterobacterales (non-CRE) phenotype Escherichia coli and 85% of ESBL-positive non-CRE phenotype Klebsiella pneumoniae were ceftolozane/tazobactam susceptible. By country, 88% (Belgium), 91% (Sweden, Switzerland) and 96% (Norway) of ESBL-positive non-CRE phenotype Enterobacterales were ceftolozane/tazobactam susceptible. Greater than ninety-nine percent of non-Morganellaceae Enterobacterales and all ESBL-positive non-CRE phenotype Enterobacterales were imipenem/relebactam susceptible. Ceftolozane/tazobactam (96%) and imipenem/relebactam (95%) inhibited most Pseudomonas aeruginosa (n = 823). Both agents retained activity against ≥75% of cefepime-resistant, ceftazidime-resistant and piperacillin/tazobactam-resistant isolates; 56% and 43% of meropenem-resistant isolates were ceftolozane/tazobactam susceptible and imipenem/relebactam susceptible, respectively. By country, 94% (Belgium), 95% (Sweden) and 100% (Norway, Switzerland) of P. aeruginosa were ceftolozane/tazobactam susceptible and 93% (Sweden) to 98% (Norway, Switzerland) were imipenem/relebactam susceptible. Carbapenemase gene carriage among Enterobacterales and P. aeruginosa isolates was generally low (<1%) or completely absent with one exception: an estimated 2.7% of P. aeruginosa isolates from Belgium carried an MBL.
Conclusions
Recent clinical isolates of Enterobacterales and P. aeruginosa collected in four central and northern European countries were highly susceptible (≥95%) to ceftolozane/tazobactam and imipenem/relebactam.
Introduction
Ceftolozane/tazobactam, an antipseudomonal cephalosporin combined with a β-lactamase inhibitor, is approved by the EMA and the FDA for the treatment of complicated urinary tract infection, complicated intraabdominal infection and hospital-acquired and ventilator-associated bacterial pneumonia (HAP and VAP). Imipenem/relebactam is a combination of imipenem/cilastatin with relebactam, an inhibitor of class A and C β-lactamases. Imipenem/relebactam is approved by the EMA and the FDA for HAP and VAP, bacteraemia associated with HAP and VAP (EMA only) and infections due to aerobic Gram-negative bacilli in adults with limited treatment options (e.g. complicated urinary tract infection, complicated intraabdominal infection). Previous publications have not described country-specific in vitro susceptibility testing data for ceftolozane/tazobactam and imipenem/relebactam against clinical isolates of Gram-negative bacilli collected in central and northern Europe.1–4 We evaluated the activity of these two agents and relevant comparators against clinical isolates of Gram-negative bacilli collected by clinical laboratories in Belgium, Norway, Sweden and Switzerland as part of the Study for Monitoring Antimicrobial Resistance Trends (SMART) global surveillance programme.
Materials and methods
Bacterial isolates and antimicrobial susceptibility testing
During 2017–21, five clinical laboratories in central and northern Europe (two in Belgium and one each in Norway, Sweden and Switzerland) participated in the SMART global surveillance programme. Each laboratory collected consecutive aerobic or facultative Gram-negative isolates from intraabdominal infections (75 isolates in 2017 and 50 isolates/year during 2018–21), urinary tract infections (75 isolates in 2017 and 50 isolates/year during 2018–21), lower respiratory tract infections (100 isolates/year) and bloodstream infections (50 isolates/year during 2018–21 only). 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 MS (Bruker Daltonics, Billerica, MA, USA) and antimicrobial susceptibility testing was performed.
MICs were determined by the CLSI reference broth microdilution method5 using custom-made dehydrated broth microdilution panels manufactured by TREK Diagnostic Systems (Thermo Fisher Scientific, Oakwood Village, OH, USA) in 2017 and broth microdilution panels prepared at IHMA during 2018–21. MICs were interpreted using 2022 EUCAST breakpoints.6 EUCAST does not publish breakpoints for imipenem/relebactam against Morganellaceae (Proteus, Providencia and Morganella spp.) isolates because they are known to have intrinsic, lowered susceptibility to imipenem by a mechanism independent of β-lactamase production,7 and relebactam does not improve the activity of imipenem against Morganellaceae. Therefore, imipenem/relebactam susceptibility was analysed for non-Morganellaceae Enterobacterales (NME) only. An ESBL-positive non-carbapenem-resistant Enterobacterales (non-CRE) phenotype was defined by an isolate of Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae or Proteus mirabilis testing with a ceftriaxone MIC of ≥2 mg/L (ceftriaxone non-susceptible using CLSI and EUCAST breakpoints) and an ertapenem MIC of ≤0.5 mg/L (ertapenem susceptible using CLSI and EUCAST breakpoints).6,7
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 collected during 2017–21; NME and Serratia spp. isolates testing with ertapenem MIC values of ≥1 mg/L collected during 2017–18 only; isolates of Serratia spp. testing with imipenem MIC values of ≥4 mg/L collected during 2017–18; and Enterobacterales and P. aeruginosa isolates testing with ceftolozane/tazobactam MIC values of ≥4 mg/L and ≥8 mg/L, respectively, collected during 2017–21. Published multiplex PCR assays were used to screen for the following β-lactamase genes: ESBLs (CTX-M, GES, PER, SHV, TEM, VEB); acquired AmpC β-lactamases (ACC, ACT, CMY, DHA, FOX, MIR, MOX) and the chromosomal AmpC intrinsic to P. aeruginosa (PDC); serine carbapenemases [GES, KPC, OXA-48-like (Enterobacterales), OXA-24-like (P. aeruginosa)]; and MBLs (GIM, IMP, NDM, SPM, VIM).8,9 All detected genes encoding carbapenemases, ESBLs and PDC were amplified using gene-flanking primers and sequenced (Sanger). For P. aeruginosa collected in 2020 and 2021 only, isolates were characterized by short-read WGS (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 Per SMART protocol for Enterobacterales isolates collected in 2021, a representative sample of approximately 95% of isolates meeting the criteria for molecular characterization were characterized. Accordingly, of the 62 isolates that met the testing criteria, two randomly selected isolates were not molecularly characterized. Per SMART protocol for P. aeruginosa isolates collected in 2020 and 2021, a representative sample of approximately 75% of isolates meeting the criteria for molecular characterization were characterized (16 randomly selected isolates of 88 qualified isolates were not characterized). For each clinical laboratory, the percentage of qualified isolates collected in 2020 and 2021 that were not characterized was considered when calculating estimated carbapenemase rates.
Results
A brief summary of the demographic and clinical characteristics (patient location, length of hospital stay at the time of specimen collection, and infection source) associated with all isolates of Gram-negative bacilli collected in Belgium, Norway, Sweden and Switzerland (combined) in 2017–21 is presented in Table S1 (available as Supplementary data at JAC-AMR Online).
Ceftolozane/tazobactam inhibited 95.0% of all Enterobacterales isolates, 94.9% of ESBL-positive non-CRE phenotype E. coli isolates, 85.2% of ESBL-positive non-CRE phenotype K. pneumoniae isolates and 89.5% of all ESBL-positive non-CRE phenotype Enterobacterales (E. coli, K. pneumoniae, K. oxytoca, P. mirabilis) isolates (Tables 1 and 2). Imipenem/relebactam inhibited 99.6% of NME and 100% of ESBL-positive non-CRE phenotype E. coli, K. pneumoniae and K. oxytoca. Meropenem (99.4% susceptible) and amikacin (98.6%) also inhibited most Enterobacterales isolates, while cefepime, ceftazidime, ceftriaxone, piperacillin/tazobactam, levofloxacin and colistin (NME, 92.1% susceptible) all tested with percent susceptible values between 81% and 88%. Levofloxacin was the least active agent tested against E. coli (79.1% susceptible) and cefepime, ceftazidime, ceftriaxone, piperacillin/tazobactam and levofloxacin (80%–83% susceptible) were least active against K. pneumoniae. Less than 36% of ESBL-positive non-CRE phenotype isolates of E. coli and K. pneumoniae were levofloxacin susceptible; 75.7% of ESBL-positive non-CRE phenotype E. coli and 44.4% of ESBL-positive non-CRE phenotype K. pneumoniae were piperacillin/tazobactam susceptible.
Table 1.
Antimicrobial susceptibility of clinical isolates of Gram-negative bacilli collected in Belgium, Norway, Sweden and Switzerland (combined) during 2017–21
| % Susceptible | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Organism | n | C/T | IPM/REL | MEM | IPMa,b | ETP | FEPb | CAZb | CRO | TZPb | LVXb,c | AMK | CST |
| Enterobacterales | 4158 | 95.0 | NA | 99.4 | 99.5 | 97.9 | 87.5 | 82.0 | 81.4 | 84.9 | 84.9 | 98.6 | 85.0 |
| NME | 3833 | 94.7 | 99.6 | 99.4 | 99.1 | 97.7 | 86.7 | 81.3 | 80.6 | 83.7 | 85.0 | 98.7 | 92.1 |
| E. coli | 1842 | 98.9 | 99.9 | 99.8 | 99.8 | 99.5 | 85.6 | 84.4 | 84.6 | 89.0 | 79.1 | 98.9 | 99.7 |
| ESBL non-CREd | 276 | 94.9 | 100 | 100 | 100 | 100 | 15.9 | 9.8 | 0 | 75.7 | 35.5 | 94.9 | 99.3 |
| K. pneumoniae | 654 | 95.4 | 98.6 | 98.3 | 98.6 | 97.6 | 81.0 | 79.5 | 81.5 | 80.9 | 83.2 | 98.0 | 98.0 |
| ESBL non-CREd | 108 | 85.2 | 100 | 99.1 | 100 | 100 | 8.3 | 3.7 | 0 | 44.4 | 32.1 | 98.1 | 96.3 |
| P. aeruginosa | 823 | 95.7 | 94.5 | 81.7 | 80.0 | NA | 80.9 | 79.1 | NA | 77.0 | 84.2 | 93.6 | 99.9 |
| FEP resistant | 157 | 78.3 | 74.5 | 42.0 | 42.0 | NA | 0 | 15.3 | NA | 17.2 | 58.6 | 73.2 | 99.4 |
| CAZ resistant | 172 | 80.2 | 77.9 | 45.9 | 45.9 | NA | 22.7 | 0 | NA | 11.0 | 63.4 | 78.5 | 99.4 |
| MEM resistant | 54 | 55.6 | 42.6 | 0 | 3.7 | NA | 14.8 | 11.1 | NA | 3.7 | 24.1 | 63.0 | 98.1 |
| TZP resistant | 189 | 83.1 | 80.4 | 47.6 | 49.7 | NA | 31.2 | 19.0 | NA | 0 | 62.4 | 83.1 | 99.5 |
| % Susceptible | |||||||||||||
C/T, ceftolozane/tazobactam; IPM/REL, imipenem/relebactam; MEM, meropenem; ETP, ertapenem; FEP, cefepime; CAZ, ceftazidime; CRO, ceftriaxone; TZP, piperacillin/tazobactam; LVX, levofloxacin; AMK, amikacin; CST, colistin; NA, not applicable or MIC breakpoint not available.
The results provided for Enterobacterales combine % susceptible, increased exposure values for Morganellaceae and % susceptible values for NME.6
The results provided for P. aeruginosa are % susceptible, increased exposure values.6
Levofloxacin was only tested against Enterobacterales isolates from 2018 to 2021.
ESBL non-CRE was defined by an isolate testing with a ceftriaxone MIC of ≥2 mg/L and an ertapenem MIC of ≤0.5 mg/L.
Table 2.
Antimicrobial susceptibility of ESBL non-CRE phenotype Enterobacterales and NME, by country during 2017–21
| Organism | n | C/T | IPM/REL | MEM | IPMa | FEP | CAZ | TZP | LVXb | AMK | CST |
|---|---|---|---|---|---|---|---|---|---|---|---|
| ESBL non-CRE Enterobacteralesc,d | |||||||||||
| Belgium | 271 | 88.2 | NA | 99.6 | 99.6 | 15.5 | 8.5 | 60.5 | 34.8 | 93.0 | 95.9 |
| Norway | 25 | 96.0 | NA | 100 | 100 | 40.0 | 8.0 | 56.0 | 52.0 | 100 | 100 |
| Sweden | 77 | 90.9 | NA | 100 | 100 | 18.2 | 19.5 | 62.3 | 41.3 | 97.4 | 100 |
| Switzerland | 55 | 90.9 | NA | 100 | 100 | 16.4 | 16.4 | 74.5 | 38.2 | 92.7 | 98.2 |
| Central/northern Europe | 428 | 89.5 | NA | 99.8 | 99.8 | 17.5 | 11.4 | 62.4 | 37.8 | 94.2 | 97.2 |
| ESBL non-CRE NMEc,e | |||||||||||
| Belgium | 265 | 88.7 | 100 | 99.6 | 100 | 14.3 | 8.3 | 59.6 | 34.2 | 93.2 | 98.1 |
| Norway | 25 | 96.0 | 100 | 100 | 100 | 40.0 | 8.0 | 56.0 | 52.0 | 100 | 100 |
| Sweden | 77 | 90.9 | 100 | 100 | 100 | 18.2 | 19.5 | 62.3 | 41.3 | 97.4 | 100 |
| Switzerland | 55 | 90.9 | 100 | 100 | 100 | 16.4 | 16.4 | 74.5 | 38.2 | 92.7 | 98.2 |
| Central/northern Europe | 422 | 89.8 | 100 | 99.8 | 100 | 16.8 | 11.4 | 61.8 | 37.4 | 94.3 | 98.6 |
C/T, ceftolozane/tazobactam; IPM/REL, imipenem/relebactam; MEM, meropenem; FEP, cefepime; CAZ, ceftazidime; TZP, piperacillin/tazobactam; LVX, levofloxacin; AMK, amikacin; CST, colistin; NA, not applicable or MIC breakpoint not available.
The results provided for ESBL non-CRE Enterobacterales combine % susceptible, increased exposure values for Morganellaceae and % susceptible values for NME.6
Levofloxacin against Enterobacterales only available for 2018–21.
ESBL non-CRE was defined by an isolate testing with a ceftriaxone MIC of ≥2 mg/L and an ertapenem MIC of ≤0.5 mg/L.
E. coli, K. pneumoniae, K. oxytoca and P. mirabilis.
E. coli, K. pneumoniae and K. oxytoca.
By country, ceftolozane/tazobactam susceptibility for all Enterobacterales isolates was 93.6% for Belgium, 94.7% for Switzerland and 97.4% for both Norway and Sweden, while imipenem/relebactam susceptibility for NME was 99.2% for Belgium, 99.9% for Sweden and 100% for both Norway and Switzerland (Table 3). In subset analysis, ceftolozane/tazobactam susceptibility for ESBL-positive non-CRE phenotype Enterobacterales (i.e. E. coli, K. pneumoniae, K. oxytoca and P. mirabilis) ranged from 88.2% (Belgium, n = 271) to 96.0% (Norway, n = 25) while imipenem/relebactam percent susceptible values for ESBL non-CRE NME (i.e. E. coli, K. pneumoniae and K. oxytoca) were 100% for isolates from all four countries (Table 2).
Table 3.
Antimicrobial susceptibility and estimated carbapenemase rates among clinical isolates of Enterobacterales, NME and P. aeruginosa, by country during 2017–21
| % Susceptible | Estimated % carrying carbapenemasea | ||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Organism | n | C/T | IPM/REL | MEM | IPMb,c | ETP | FEPc | CAZc | CRO | TZPc | LVXc,d | AMK | CST | MBL | KPC | OXA-48-like | GES |
| Enterobacterales | |||||||||||||||||
| Belgium | 2039 | 93.6 | NA | 99.1 | 98.5 | 97.0 | 83.3 | 76.7 | 76.7 | 80.5 | 80.9 | 97.9 | 83.8 | 0.5 | 0 | 0.9 | 0 |
| Norway | 495 | 97.4 | NA | 99.8 | 99.6 | 98.4 | 94.9 | 90.5 | 90.3 | 92.3 | 91.7 | 99.6 | 90.1 | 0 | 0 | 0 | 0 |
| Sweden | 778 | 97.4 | NA | 100 | 99.7 | 99.2 | 88.9 | 86.8 | 84.7 | 89.2 | 84.2 | 99.2 | 87.0 | 0.1 | 0 | 0 | 0 |
| Switzerland | 846 | 94.7 | NA | 99.6 | 99.5 | 98.5 | 92.2 | 85.5 | 84.5 | 87.1 | 89.1 | 99.3 | 83.1 | 0 | 0.1 | 0 | 0 |
| NME | |||||||||||||||||
| Belgium | 1865 | 93.2 | 99.2 | 99.0 | 98.6 | 96.7 | 82.1 | 75.8 | 75.4 | 78.9 | 81.2 | 98.0 | 91.5 | 0.5 | 0 | 1.0 | 0 |
| Norway | 474 | 97.3 | 100 | 99.8 | 99.6 | 98.3 | 94.7 | 90.3 | 90.3 | 92.0 | 91.6 | 99.8 | 94.1 | 0 | 0 | 0 | 0 |
| Sweden | 716 | 97.2 | 99.9 | 100 | 99.7 | 99.2 | 88.3 | 86.2 | 84.1 | 88.4 | 83.8 | 99.2 | 94.6 | 0.1 | 0 | 0 | 0 |
| Switzerland | 778 | 94.2 | 100 | 99.6 | 99.6 | 98.3 | 91.5 | 84.7 | 83.8 | 86.0 | 89.5 | 99.2 | 90.1 | 0 | 0.1 | 0 | 0 |
| P. aeruginosa | |||||||||||||||||
| Belgium | 360 | 94.2 | 93.9 | 81.4 | 80.8 | NA | 79.2 | 77.5 | NA | 75.6 | 83.1 | 92.8 | 100 | 2.7 | 0 | 0 | 0 |
| Norway | 42 | 100 | 97.6 | 81.0 | 83.3 | NA | 85.7 | 78.6 | NA | 78.6 | 85.7 | 100 | 100 | 0 | 0 | 0 | 0 |
| Sweden | 280 | 95.0 | 93.2 | 80.0 | 75.7 | NA | 79.3 | 77.9 | NA | 76.8 | 79.3 | 90.7 | 99.6 | 0 | 0 | 0 | 0 |
| Switzerland | 141 | 100 | 97.9 | 85.8 | 85.1 | NA | 87.2 | 85.8 | NA | 80.9 | 96.5 | 99.3 | 100 | 0 | 0 | 0 | 0 |
C/T, ceftolozane/tazobactam; IPM/REL, imipenem/relebactam; MEM, meropenem; ETP, ertapenem; FEP, cefepime; CAZ, ceftazidime; CRO, ceftriaxone; TZP, piperacillin/tazobactam; LVX, levofloxacin; AMK, amikacin; CST, colistin; NA, not applicable or MIC breakpoint not available.
No isolates carried both an MBL and another carbapenemase.
The results provided for Enterobacterales combine % susceptible, increased exposure values for Morganellaceae and % susceptible values for NME.6
The results provided for P. aeruginosa are % susceptible, increased exposure values.6
Levofloxacin was only tested against Enterobacterales isolates from 2018 to 2021.
Ceftolozane/tazobactam (95.7% susceptible) and imipenem/relebactam (94.5%) both inhibited ∼95% of all P. aeruginosa isolates (n = 823) and retained activity against 78%–83% (ceftolozane/tazobactam) and 75%–80% (imipenem/relebactam) of cefepime-resistant, ceftazidime-resistant and piperacillin/tazobactam-resistant isolates; 56% and 43% of meropenem-resistant isolates were ceftolozane/tazobactam and imipenem/relebactam susceptible, respectively (Table 1). Ceftolozane/tazobactam inhibited 51.1% (23/45) of imipenem/relebactam-resistant (MIC >2 mg/L) P. aeruginosa and imipenem/relebactam inhibited 37.1% (13/35) of ceftolozane/tazobactam-resistant (MIC >4 mg/L) P. aeruginosa. Colistin (99.9% susceptible) was the agent with the highest percent susceptible value for P. aeruginosa, while only 77%–82% of isolates were susceptible to meropenem, cefepime, ceftazidime and piperacillin/tazobactam. Levofloxacin (24.1% susceptible), amikacin (63.0%) and colistin (98.1%) were all least active against meropenem-resistant P. aeruginosa compared with other β-lactam-resistant isolate subsets.
By country, ceftolozane/tazobactam susceptibility for all P. aeruginosa isolates was 94.2% for Belgium, 95.0% for Sweden and 100% for both Norway and Switzerland, while percent susceptible values for imipenem/relebactam were 93.2% for Sweden, 93.9% for Belgium, 97.6% for Norway and 97.9% for Switzerland (Table 3).
In considering the colistin and amikacin data, it is important to note that given the limitations associated with colistin and aminoglycoside use in treating Gram-negative infections, EUCAST only publishes bracketed colistin, amikacin (systemic infections) and gentamicin (systemic infections) susceptible and resistant MIC breakpoints with a warning against the use of any of these agents without additional therapeutic measures.6,12 Similarly, CLSI does not publish a susceptible MIC breakpoint for colistin for any Gram-negative pathogen.7
Carbapenemase gene carriage among isolates of Enterobacterales and P. aeruginosa from the four central and northern European countries studied was low (1% or less) or completely absent in all countries with one exception: an estimated 2.7% of P. aeruginosa isolates from Belgium were MBL positive (Table 3). Carbapenemase genes were not identified in P. aeruginosa isolates from other countries. MBLs among Enterobacterales were only identified in Belgium (0.5% of isolates) and Sweden (0.1%). KPCs were only identified in Enterobacterales isolates from Switzerland (0.1%) and OXA-48-like enzymes only in isolates from Belgium (0.9%). GES carbapenemase genes were not identified in any isolate.
Discussion
Carbapenem-resistant and ESBL-producing Enterobacterales rates are lower in northern, central and western European countries than in southern and eastern Europe.2,13–15 Meropenem-resistant Enterobacterales were rarely identified (<1%) in the current study of clinical isolates from central and northern Europe; 15% of E. coli and 17% of K. pneumoniae had an ESBL, non-CRE phenotype (Table 1). Approximately 18% of P. aeruginosa in the current study were meropenem non-susceptible (Table 3), accounting for 14% of isolates from Switzerland, 19% of isolates from Belgium and Norway, and 20% of isolates from Sweden. Our observations agree with previous studies that reported carbapenem-resistant P. aeruginosa rates to be lower in northern, central and western European countries than in southern and eastern Europe (≥30%).2,13
Ceftolozane/tazobactam inhibited 95% of Enterobacterales, including 95% of ESBL-positive non-CRE phenotype E. coli and 85% of ESBL-positive non-CRE phenotype K. pneumoniae, confirming data in earlier publications.16 Ceftolozane/tazobactam maintained activity against most ESBL-positive Enterobacterales that do not possess carbapenemases and is more active in vitro than piperacillin/tazobactam.1,16 Imipenem/relebactam inhibited >99% of NME (an estimated 0.3% of NME isolates carried an MBL and 0.5% an OXA-48-like enzyme) and 100% of ESBL-positive non-CRE phenotype E. coli and K. pneumoniae, again confirming earlier publications.16,17
Ceftolozane/tazobactam and imipenem/relebactam both inhibited ∼95% of all P. aeruginosa isolates but were less active against isolates with β-lactam-resistant phenotypes. Imipenem/relebactam generally retains in vitro activity against isolates without MBL carbapenemases although limited numbers of P. aeruginosa isolates without these mechanisms have tested imipenem/relebactam non-susceptible.16–18 Geographical differences in β-lactamase prevalence and other resistance mechanisms do affect the in vitro activities of all currently available β-lactams and β-lactam/β-lactamase inhibitor combinations, including ceftolozane/tazobactam and imipenem/relebactam.3,4 In the current study, we observed low numbers of MBLs, KPC, OXA-48-like and GES carbapenemases in both Enterobacterales and P. aeruginosa (Table 3). Therefore, mechanisms of carbapenem resistance other than β-lactamases (e.g. OprD mutations in combination with AmpC hyperproduction)19 must have predominated in the isolates of P. aeruginosa collected from the four central and northern European countries we studied.
The data presented in this study are limited by the small annual sample size (250 Gram-negative isolates per medical centre per year) and the small number of participating medical centres. The data generated from isolates submitted by participating medical centres within central and northern Europe should not be extrapolated to represent all isolates or geographical areas within these regions.
In conclusion, recent (2017–21) clinical isolates of Enterobacterales and P. aeruginosa collected in four central and northern European countries were highly susceptible (≥95%) to ceftolozane/tazobactam and imipenem/relebactam. Based on these in vitro data, ceftolozane/tazobactam and imipenem/relebactam may be important treatment options for patients in central and northern Europe with infections caused by Gram-negative pathogens, including ESBL-positive non-CRE phenotype Enterobacterales and many β-lactam-resistant phenotypes of P. aeruginosa.
Supplementary Material
Acknowledgements
We thank all SMART global surveillance programme participants for their contributions to the programme.
Contributor Information
James A Karlowsky, IHMA, Schaumburg, IL 60173, USA; Department of Medical Microbiology and Infectious Diseases, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
Sibylle H Lob, IHMA, Schaumburg, IL 60173, USA.
Stephen P Hawser, IHMA, Monthey, Switzerland.
Nimmi Kothari, IHMA, Monthey, Switzerland.
Fakhar Siddiqui, Merck & Co., Inc., Rahway, NJ, USA.
Irina Alekseeva, MSD, Dubai, United Arab Emirates.
C Andrew DeRyke, Merck & Co., Inc., Rahway, NJ, USA.
Katherine Young, Merck & Co., Inc., Rahway, NJ, USA.
Mary R Motyl, Merck & Co., Inc., Rahway, NJ, USA.
Daniel F Sahm, IHMA, Schaumburg, IL 60173, USA.
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
S.H.L., S.P.H., N.K. and D.F.S. work for IHMA, which receives funding from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA for the SMART surveillance programme. J.A.K. is a consultant to IHMA. F.S., I.A., C.A.D., 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 J.A.K. 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
Table S1 is available as Supplementary data at JAC-AMR Online.
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