Evaluating the Susceptibility of MBL Carbapenemase-Producing Enterobacteriaceae and Pseudomonas spp. to Ceftazidime/Avibactam plus aztreonam and Cefiderocol: A Synergy Study Using the gradient strip stacking method and Susceptibility profile to the novel combination by gradient Concentration Strips.
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Abstract Purpose This study investigates the in vitro effectiveness of the combination aztreonam and ceftazidime/avibactam (ATM/CZA) against metallo-β-lactamase (MBL)-producing Enterobacterales and Pseudomonas spp., using the gradient strip stacking method to evaluate synergy, and compares it with the novel aztreonam/avibactam (ATM/AVI) combination. Susceptibility to cefiderocol and other antimicrobials was studied. Methods A total of 38 non-duplicate strains were analyzed: 31 Enterobacterales and 7 Pseudomonas spp., all confirmed carbapenemase MBL producers. Results ATM/AVI showed 100% susceptibility among Enterobacterales using epsilon test method according to EUCAST breakpoints, although synergy AZT plus CZA was found in only 58% of the strains. The 100% of aztreonam-resistant strains showed synergy, compared to only 18.8% of aztreonam-susceptible strains, suggesting that the combination provides greater benefit in resistant strains. In contrast, Pseudomonas spp. strains showed minimal synergy as previous reported(14.3%) and low susceptibility (1/7 strains) to the ATM/AVI combination, highlighting the limited efficacy of this therapy against these organisms. Cefiderocol, however, demonstrated high activity: 93.5% susceptibility in Enterobacterales group and 100% in Pseudomonas spp. Conclusion The study emphasizes that gradient strips test may not reveal which aztreonam-susceptible strains would benefit from the ATM/AVI combination, therefore, synergy testing remains crucial. Ultimately, ATM/AVI is a promising option for treating infections caused by MBL-producing Enterobacterales, while cefiderocol remains a important agent against MBL-producing Pseudomonas spp.
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Evaluating the Susceptibility of MBL Carbapenemase-Producing Enterobacteriaceae and Pseudomonas spp. to Ceftazidime/Avibactam plus aztreonam and Cefiderocol: A Synergy Study Using the gradient strip stacking method and Susceptibility profile to the novel combination by gradient Concentration Strips. | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Evaluating the Susceptibility of MBL Carbapenemase-Producing Enterobacteriaceae and Pseudomonas spp. to Ceftazidime/Avibactam plus aztreonam and Cefiderocol: A Synergy Study Using the gradient strip stacking method and Susceptibility profile to the novel combination by gradient Concentration Strips. Ana Collazos Blanco, Ana Belén García Sáez, Carolina Plaza Cristobal, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6856947/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose This study investigates the in vitro effectiveness of the combination aztreonam and ceftazidime/avibactam (ATM/CZA) against metallo-β-lactamase (MBL)-producing Enterobacterales and Pseudomonas spp., using the gradient strip stacking method to evaluate synergy, and compares it with the novel aztreonam/avibactam (ATM/AVI) combination. Susceptibility to cefiderocol and other antimicrobials was studied. Methods A total of 38 non-duplicate strains were analyzed: 31 Enterobacterales and 7 Pseudomonas spp., all confirmed carbapenemase MBL producers. Results ATM/AVI showed 100% susceptibility among Enterobacterales using epsilon test method according to EUCAST breakpoints, although synergy AZT plus CZA was found in only 58% of the strains. The 100% of aztreonam-resistant strains showed synergy, compared to only 18.8% of aztreonam-susceptible strains, suggesting that the combination provides greater benefit in resistant strains. In contrast, Pseudomonas spp. strains showed minimal synergy as previous reported(14.3%) and low susceptibility (1/7 strains) to the ATM/AVI combination, highlighting the limited efficacy of this therapy against these organisms. Cefiderocol, however, demonstrated high activity: 93.5% susceptibility in Enterobacterales group and 100% in Pseudomonas spp. Conclusion The study emphasizes that gradient strips test may not reveal which aztreonam-susceptible strains would benefit from the ATM/AVI combination, therefore, synergy testing remains crucial. Ultimately, ATM/AVI is a promising option for treating infections caused by MBL-producing Enterobacterales, while cefiderocol remains a important agent against MBL-producing Pseudomonas spp. aztreonam/avibactam synergy cefiderocol carbapenemase Introduction Carbapenem-resistant Gram-negatives pose a significant threat to global public health, especially due to carbapenemases. Carbapenem-resistant Enterobacterales (CRE) and Pseudomonas spp (CR-PS) have become serious causes of recalcitrant health care-associated infections that are often resistant to common therapeutic options ( 1 ). Specifically, the metallo-β-lactamases (MBL) confer multiple resistance to β-lactam drugs and their increasing prevalence complicates the clinical and therapeutical management( 2 ). Aztreonam/avibactam (ATM/AVI) recently emerged as a promising option, which restores the monobactam effectiveness against specific β-lactamases, enhancing their antimicrobial activity with a non-β-lactam β-lactamase inhibitor ( 3 ). The combination ATM/AVI allows aztreonam to act against MBL (whose activity cannot inhibit monobactams) and avibactam to contrast the contextual presence of SHV, TEM, CTX-M, AmpC, KPC and OXA ( 4 ). Recent data documented ATM/AVI resistance mechanisms among Escherichia coli isolates due to acquired PBP mutations (PBP-3), decreased membrane permeability, efflux pump activation or β-lactamases enzymes active against aztreonam but refractory to avibactam ( 5 ). In the year 2022, the European Society of Clinical Microbiology and Infectious Diseases (ESCMID), in its guidelines, has recommended using the above combination against MBL-producing Enterobacterales ( 6 ). However, it is imperative to demonstrate AZT synergy in the presence of AVI in an in-vitro test before using the above regimen in patients. Carbapenem resistance in P. aeruginosa is most commonly mediated by noncarbapenemase mechanisms that include the overproduction of AmpC, porin loss, and drug efflux, although some isolates also produce carbapenemases ( 7 ). The European Medicines Agency (EMA) has recommended marketing authorization for Aztreonam/avibactam (Emblaveo®) in the European Union to treat multi-drug resistant Gram-negatives complicated infections. Currently, there is no practical and widely accepted antimicrobial susceptibility testing (AST) method available for use in clinical laboratories for assessing the efficacy of the ATM-CZA combination. Established testing methods to evaluate combinations like the checkerboard assay or time-kill assays are complex, labor intensive, and difficult to interpret. But some methods like the gradient strip stacking and gradient strip crossing, although more expensive, could be the test(s) of choice for a clinical lab that already has established workflows for susceptibility testing using gradient strips ( 1 ) ( 8 )( 9 ). The aim of this study was to evaluate the in vitro activity of the combination aztreonam and ceftazidime/Avibactam using the gradient strip stacking method and compare results with the aztreonam/avibactam MICs determined by epsilon test method recently commercialized. At the same time, cefiderocol susceptibility was determined to analyze the susceptibility profile of the strains studied. Material and methods Strain collection Our collection included 38 nonduplicated strains, Enterobacterales group (n = 31) and Pseudomonas spp (n = 7) with decreased susceptibility to carbapenems (at least to one among imipenem or meropenem) collected from clinical patients during routine clinical diagnostics in the Hospital Central de la Defensa Gomez Ulla (CSVE) across 2 years period (from January 1, 2023 to November 31, 2024). All strains were confirmed carbapenemase producers. Susceptibility testing and MIC determination All isolates were identified using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (Bruker Daltonik, Bremen, Germany). Antimicrobial susceptibility testing was conducted following the recommendations of the European Committee on Antimicrobial Susceptibility testing (EUCAST). Susceptibility testing was performed using the MicroScan WalkAway Plus automated system (Beckman Coulter). Quality control (QC) strains Pseudomonas aeruginosa ATCC 27853 and Escherichia coli ATCC 25922 were utilized for each experimental sitting. Carbapenemases were detected using immunochromatographic RESIST-5 O.K.N.V.I assay (Coris)( 10 ) or Xpert® Carba-R test ( 11 ). The cefiderocol susceptibility tests were performed by the disc diffusion method (Liofilchem, Roseto degli Abruzzi, Italy) on Mueller–Hinton medium plates (MH agar plates). The results were interpreted according to the breakpoints proposed by EUCAST for the cefiderocol 30 µg disk: zone diameters of ≥ 23 mm into enterobacterales group and ≥ 22 mm in Pseudomonas spp that correspond to minimum inhibitory concentration (MIC) values below the PK-PD breakpoint of S ≤ 2 mg/L ( https://www.eucast.org/clinical_breakpoints , accessed on may 2025). The aztreonam-avibactam susceptibility tests were performed by the epsilon test diffusion method (Biomerieux) on Mueller–Hinton medium plates (MH agar plates). The results were interpreted according to the breakpoints proposed by EUCAST for enterobacterales S ≤ 4 mg/L if the concentration of avibactam is fixed at 4 mg/L. The Synergy test Synergy analyses were performed using the gradient strip stacking method. The fractional inhibitory concentration (FIC) index (FICI) was calculated for the E-test by using the following formula: FICI = FIC of agent A + FIC B, where FIC A is the MIC of the combination/MIC of drug A alone, and FIC B is the MIC of the combination/MIC of drug B alone. FICI results were interpreted with the following criteria: synergy, FICI ≤ 0.5; independent interaction, FICI 0.5- ≤ 4; and antagonism, FICI > 4( 12 ). Results Antimicrobial Susceptibility and Characteristics of Carbapenemases producers Enterobacterales strains. All 31 isolates were collected from our hospital, comprising 15 (48.4%) Klebsiella pneumoniae ( K. pneumoniae) , 6 (19.4%) Escherichia coli ( E. coli) , 5 (16.1%) Enterobacter cloacae (E. cloacae), 3 (9.7%) Klebsiella oxytoca (K.oxytoca), 1 (3.2%) Citrobacter frendii (C. freundii) and 1 (3.2%) Serratia marcenses (S. marcenses) isolate. All strains demonstrated resistance to β -lactams including any carbapenems. Additionally, they exhibited partial resistance to other antimicrobial agents such as amikacin and ciprofloxacin. In contrast, tigecycline and Cefiderocol (27/31, 93.5%) maintained high susceptibility levels. The results were summarized in Table 1 . Cefiderocol resistance was confirmed by microdilution method (UMIC® Cefiderocol, Bruker). Table 1 Antimicrobial Susceptibility profile. Specie strain (n) Antimicrobial Number and % of isolates Susceptible (S) or Susceptible Increase Exposure (I) K. pneumoniae ( 15 ) Amikacin 11 (73.3) Ciprofloxacin 3 (20.0) Tigecycline 15 (100.0) Aztreonam 5 (33.3) Meropenem 10 (66.7) Ceftolozane/tazobactam 0 (0.0) Ceftazidime/avibactam 2 (13.3) Cefiderocol 15 (100.0) E.coli ( 6 ) Amikacin 4 (66.7) Ciprofloxacin 1 (16.7) Tigecycline 6 (100.0) Aztreonam 4 (66.7) Meropenem 4 (66.7) Ceftolozane /tazobactam 0 (0.0) Ceftazidime/avibactam 0 (0.0) Cefiderocol 5 (83.3) E.cloacae ( 5 ) Amikacin 4 (80.0) Ciprofloxacin 1 (20.0) Tigecycline 5 (100.0) Aztreonam 3 (60.0) Meropenem 3 (60.0) Ceftolozane /tazobactam 0 (0.0) Ceftazidime/avibactam 0 (0.0) Cefiderocol 4 (80.0) K.oxytoca ( 3 ) Amikacin 3 (100.0) Ciprofloxacin 1 (33.3) Tigecycline 3 (100.0) Aztreonam 2 (66.7) Meropenem 1 (33.3) Ceftolozane /tazobactam 0 (0.0) Ceftazidime/avibactam 0 (0.0) Cefiderocol 3 (100.0) C. freundii ( 1 ) Amikacin 1 (100.0) Ciprofloxacin 1 (100.0) Tigecycline 1 (100.0) Aztreonam 1 (100.0) Meropenem 1 (100.0) Ceftolozane /tazobactam 0 (0.0) Ceftazidime/avibactam 0 (0.0) Cefiderocol 1 (100.0) S. marscenses ( 1 ) Amikacin 1 (100.0) Ciprofloxacin 0 (0.0) Tigecycline 0 (0.0) Aztreonam 1 (100.0) Meropenem 0 (0.0) Ceftolozane /tazobactam 0 (0.0) Ceftazidime/avibactam 0 (0.0) Cefiderocol 1 (100.0) Pseudomonas spp. ( 7 ) Amikacin 7 (100.0) Ciprofloxacin 0 (0.0) Tigecycline 0 (0.0) Aztreonam 7 (100.0) Meropenem 1 (14.3) Ceftolozane /tazobactam 0 (0.0) Ceftazidime/avibactam 0 (0.0) Cefiderocol 7 (100.0) The results of the RESIST-5 O.K.N.V.I assay (Coris) and Xpert® Carba-R test revealed that 28 strains produced carbapenemase VIM type and 3 strains produced carbapenemase NDM type. Synergy study To the study of the synergistic effects of ATM in combination with CZA the gradient strip stacking method, was used against the respective strains. Among enterobacterales group 16/31 (51.6%) were susceptible (S) or Susceptible, increased exposure (I) to aztreonam and 15/31 (48.4%) were resistant to aztreonam (R > 4 mg/L) according to EUCAST breakpoints. Among the 16 susceptible strains to aztreonam, synergy effect was observed in only 3 (18.8%) strains (two E. cloacae and one K. oxytoca ). These strains were carbapenemase VIM type producers and they have aztreonam MIC between 1–4 mg/L, so they were susceptible exposure increased (I). Indifference was observed in 13 (81.2%) strains. In aztreonam resistant group, all strains demonstrated synergy effect 15/15 (100%). Most of the strains demonstrated resistance (29/31; 93.5%) to Caftazidime/Avibactam as expected because all of our strains were metallo-β-lactamases producers (MBL). The results of the synergy study are shown in the Table 2 . Table 2 Results of synergy analysis with the fixed proportion with the E-test method. Specie Carbapenemase type MIC Aztreonam (mg/L) MIC Ceftazidime/Avibactam (mg/L) IFIC Interpretation MIC Aztreonam/Avibactam (Embableo®) (mg/L) K.pneumoniae VIM 16 96 0,0017 SYNERGY 0,016 K.pneumoniae VIM 0,047 256 1,0002 INDIFERENCE 0,023 E. coli NDM 256 256 0,0059 SYNERGY 0,75 E. coli VIM 0,094 256 0,6811 INDIFERENCE 0,047 K.pneumoniae VIM 32 0,38 0,2503 SYNERGY 0,094 E. cloacae VIM 128 256 0,0027 SYNERGY 0,094 K.pneumoniae VIM 0,064 256 1,0003 INDIFERENCE 0,047 S. marscenses VIM 0,094 256 1,3302 INDIFERENCE 0,25 K.pneumoniae VIM 64 256 0,0024 SYNERGY 0,064 K.pneumoniae VIM 256 256 0,0012 SYNERGY 0,064 K. oxytoca VIM 256 256 0,0015 SYNERGY 0,19 K.pneumoniae VIM 96 256 0,0013 SYNERGY 0,047 K.pneumoniae VIM 0,19 256 1,0007 INDIFERENCE 0,094 K.pneumoniae VIM 12 256 0,0029 SYNERGY 0,016 E. cloacae VIM 2 256 0,1920 SYNERGY 0,19 K.pneumoniae VIM 0,19 256 1,0007 INDIFERENCE 0,125 K. oxytoca VIM 1,5 256 0,1674 SYNERGY 0,125 K.pneumoniae VIM 256 256 0,0017 SYNERGY 0,094 E. coli NDM 256 256 0,0098 SYNERGY 0,5 K.pneumoniae NDM 192 256 0,0010 SYNERGY 0,047 K. oxytoca VIM 0,125 256 0,7524 INDIFERENCE 0,047 E. cloacae VIM 128 256 0,0029 SYNERGY 0,094 K.pneumoniae VIM 0,064 256 1,4691 INDIFERENCE 0,047 E. coli VIM 0,38 256 0,5007 INDIFERENCE 0,064 E. cloacae VIM 0,125 256 1,0004 INDIFERENCE 0,064 C.freundii VIM 0,25 256 0,7605 INDIFERENCE 0,047 E. coli VIM 0,125 256 1,0002 INDIFERENCE 0,064 E. coli VIM 0,125 256 0,5123 INDIFERENCE 0,023 K.pneumoniae VIM 32 256 0,0063 SYNERGY 0,047 E. cloacae VIM 1,5 256 0,3353 SYNERGY 0,064 K.pneumoniae VIM 8 0,25 0,2619 SYNERGY 0,125 P.fluorescens VIM 8 32 0,9375 INDIFERENCE 6 P.aeruginosa VIM 6 96 1,375 INDIFERENCE 8 P.aeruginosa VIM 8 16 1,125 INDIFERENCE 8 P.putida VIM 12 48 0,7917 INDIFERENCE 8 P.aeruginosa IMP 12 256 0,1784 SYNERGY 2 P.monteilli VIM 16 24 0,8333 INDIFERENCE 8 P.aeruginosa VIM 6 64 0,7292 INDIFERENCE 8 We determined the susceptibility to the novel combination aztreonam/avibactam using the epsilon test method as described above. All 31 strains were susceptible to this combination according to the EUCAST breakpoints (S ≤ 4 mg/L). When comparing the main parameters of the strains that showed synergy using the fixed proportion with the E-test method, with those that did not, no significant differences were observed (Table 3 ). Table 3 Results of the novel combination Aztreonam/avibactam (EmblaveoÒ) among enterobacterales group. ETEST ® Aztreonam/Avibactam (AZA) Aztreonam S/I (16/31, 51.6%) Aztreonam R (15/31; 48.4%) Synergy (3/16, 18.8) Indifference (13/18, 81.2) Synergy (15/15; 100%) Indifference (0/15; 0%) p50 0.125 0.047 0.094 p90 0.19 0.125 0.5 Min 0.064 0.023 0.016 Max 0.19 0.25 0.75 Rage 0.126 0.227 0.734 Antimicrobial Susceptibility and Characteristics of Carbapenemase producers Pseudomonas spp strains. The results of the RESIST-5 O.K.N.V.I assay (Coris) and Xpert® Carba-R test revealed that 6/7 (85.7%) strains produced carbapenemase VIM type and 1 (14.3) carbapenemase IMP type. All strains demonstrated resistance to the principal antipseudomonic β -lactams including any carbapenems. Additionally, they exhibited partial resistance to other antimicrobial agents such as ciprofloxacin. Cefiderocol was the most susceptible agent (7/7, 100%). The results were summarized in Table 1 . All strains were susceptible increased exposure to aztreonam according to the EUCAST breakpoints (S ≤ 0.001–16 mg/L) and all of them were resistant to Ceftazidime/Avibactam (≤ 8 mg/L). Sinergy study To the study of the synergistic effects of ATM in combination with CZA the gradient strip stacking method, was used against the respective strains. Among Psudomonas spp group, in 6/7 strains (85.7%) indifference effect were observed and only in one strain (14.3%) synergy effect were observed. This strain was Pseudomonas aeruginosa IMP carbapenemase producer. We determined the susceptibility to the novel combination aztreonam/avibactam by epsilon test method as described above. 7/7 (100.0%) Strains were susceptible to this novel combination according to the EUCAST ECOFF for Pseudomonas spp (16 mg/L) however, higher MIC values were observed compared with Enterobacterales group.. The results of the synergy study are shown in the Table 2 . Discussion During the 2023–2024 study period, strains producing metallo-β-lactamase (MBL) carbapenemases, mainly of the VIM type, increased in our hospital and in other regions of Spain ( 13 )( 14 ). The growing challenge of antibiotic resistance has accelerated the development of new drugs and novel β-lactam/β-lactamase inhibitor combinations like cefiderocol and Aztreonam/Avibactam. Current guidelines recommend treating MBL-producing CRE infections with a combination of ceftazidime-avibactam and the simultaneous infusion of aztreonam or cefiderocol( 15 )( 16 ). In this study, we analyzed a well-characterized collection of 31 Enterobacterales MBL producers and 7 Pseudomonas spp MBL producers obtained from clinical samples. Cefiderocol exhibited the most potent in vitro activity against carbapenemase-producing Enterobacterales (CRE) and carbapenemase-resistant Pseudomonas spp (CR-PS), with susceptibility rates of 93.5% and 100.0% respectively, according to EUCAST breakpoints as previous reported ( 17 ). Cefiderocol activity has shown variability across different studies. In the CREDIBLE-CR and APEKS-NP trials, clinical cure of infections caused by MBL-producing Gram-negative bacteria was achieved in only 70.8% of cases (17/24). When focusing specifically on MBL producers Enterobacteriaceae , the clinical success rate was 73% (11/15 cases). However, other surveillance studies have demonstrated excellent in vitro activity of cefiderocol against carbapenem-resistant Gram-negative bacteria ( 18 )( 19 )( 20 ). A surveillance study by M. Delgado-Valverde et al. reported that cefiderocol was active against 80% of 160 carbapenem-resistant Enterobacterales (CRE) isolates. However, susceptibility was lower among NDM and VIM-producing strains, with only 86% (49/57) and 76.9%, categorized as susceptible. ( 21 ). In the SIDERO study, the overall susceptibility of cefiderocol against carbapenem-resistant Enterobacterales (Carb-NS) was 81.6%. However, when susceptibility was analyzed according to carbapenemase type, the lowest activity was observed against NDM-producing isolates, with a susceptibility rate of only 51.4% ( 17 ) so data suggest that NDM-producing Enterobacteriaceae tend to have higher MICs to cefiderocol compared to isolates producing other metalo β-lactamases. In our study, only three NDM-type carbapenemase-producing isolates were identified, and just one of them was resistant to cefiderocol. Aztreonam/avibactam (Emblaveo, Pfizer) is a novel combination consisting of a monobactam that interferes with bacterial cell wall synthesis and a non-β-lactam β-lactamase inhibitor active against class A, class C, and some class D β-lactamases. It was approved by the European Medicines Agency (EMA) in April 2024 for the treatment of multidrug-resistant (MDR) infections in patients with limited therapeutic options, including complicated intra-abdominal infections (cIAI), hospital-acquired pneumonia (HAP), and complicated urinary tract infections (cUTI). Although aztreonam is not hydrolyzed by metallo-β-lactamases, co-expression of MBLs with other Ambler class β-lactamases capable of hydrolyzing aztreonam is common. As a result, aztreonam monotherapy is often ineffective against MBL-producing strains. Several studies have evaluated the in vitro activity of aztreonam/avibactam against worldwide isolates of Enterobacterales exhibiting carbapenem non-susceptibility and/or MBL production. ( 22 )( 23 )( 24 )( 25 ). According to the 2024 EUCAST/CLSI breakpoints, a recent report demonstrated excellent in vitro activity of aztreonam/avibactam against Enterobacterales isolates producing dual-carbapenemases (MBL + class A carbapenemase, n = 14; MBL + class D carbapenemase, n = 35). The study revealed 100% susceptibility, with overall MIC 50 and MIC 90 values of ≤ 0.25 mg/L and 0.5 mg/L, respectively ( 26 ). In other international surveillance studies, 100% susceptibility was observed for the new combination, followed by cefiderocol (83%), with the majority of isolates were KPC- type carbapenemase-producing isolates. (28/49) ( 27 ). In all these studies, the majority of the strains examined were resistant to aztreonam, and susceptibility to aztreonam/avibactam was assessed using synergy testing methods. In our study, we evaluated susceptibility to the combination using the gradient strip stacking method and determined the MIC through gradient concentration strips. We observed synergy in 58% of the strains. However, when differentiating between those that were aztreonam susceptible (S or I) (MIC ≤ 4; n = 16/31) and those that were aztreonam resistant (MIC > 4; n = 15/31), we found that the percentage of strains exhibiting synergy was significantly higher in the aztreonam resistant group (100%; n = 15/15) compared to the aztreonam susceptible strains (18.8%; n = 3/16). This result aligns with the expected mechanism of action of the combination. The 3 aztreonam susceptible strains that exhibited synergy with the combination had aztreonam MIC values ranging from 1 to ≤ 4 mg/L, suggesting the presence of some β-lactamase in their resistome. Similar results have been observed in other studies, albeit with a significantly smaller number of strains.( 1 ). However, when susceptibility to aztreonam/avibactam was determined using gradient concentration strips, we observed that all the MBL-producing Enterobacterales strains studied were susceptible according to the EUCAST breakpoints. No difference was found in the MICs when comparing those strains that exhibited synergy with those that did not. Therefore, if susceptibility to aztreonam/avibactam is assessed solely by using gradient concentration strips, it will not be possible to differentiate those strains that would benefit from the combination (aztreonam resistant strains) from those for which the combination likely offers no additional benefit (the majority of ztreonam susceptible strains). However, further studies will be necessary to determine the potential benefit of the aztreonam/avibactam combination in these aztreonam susceptible strains, such as a possible reduction in the mutant prevention concentration (MPC)( 28 ). In our study, of the 31 Enterobacterales strains analyzed, resistance to ceftazidime/avibactam (CZA) was high, as expected, due to the inhibitory profile of avibactam (93.5%). However, previous reports have indicated a limited proportion of MBL producers Enterobacterales and MBL Pseudomonas aeruginosa strains, susceptible to CZA ( 29 ). This CZA susceptibility may be explained by the presence of weak promoters that affect the gene expression as has been previously described ( 30 ). This is interesting because, in the presence of a multidrug-resistant microorganism, the production of a MBL does not necessarily exclude the use of CZA, which could become a valuable therapeutic option when no other treatments are available. Conversely, lower rates of aztreonam/avibactam susceptibility have been reported previously among carbapenem-non-susceptible (72.2–83%) and MBL-producers Pseudomonas aeruginosa isolates (55.8–72.5%). Findings that are consistent with data published by Carola et al., where MIC 50 and MIC 90 of 0.125 mg/L to 0.25 mg/L for Enterobacterales and 16 to 32 mg/L for P. aeruginosa were observed, respectively ( 31 ). These findings are consistent with the results obtained in our study, where synergy in Pseudomonas spp strains was observed in only one sample (14.3%). Using gradient concentration strips of the new combination, only this strain exhibited a MIC value of ≤ 4 mg/L. This difference in susceptibility when compared to the Enterobacteriaceae group, could be due to the presence of multiple resistance mechanisms commonly detected in Pseudomonas spp , such as overexpression of efflux systems, production of PDC-like, PER-like and OXA-like β-lactamase variants and loss of porins. Consequently, these data might suggest the use of aztreonam/avibactam mainly for the treatment of infections sustained by MBL-producers Enterobacterales. Above all, the emergence of strains producing carbapenemases posed a significant challenge in treating CRE and CR-PS. The novel combination of ceftazidime/aztreonam offers a valuable addition to the armamentarium for MBL-producers Enterobacteriaceae infections especially those with resistance to aztreonam; however, it does not appear to be an optimal choice for the treatment of Pseudomonas spp. MBL producers, where cefiderocol plays a crucial role. Further studies are needed to analyze the role of the aztreonam/avibactam combination in Enterobacteriaceae strains that are susceptible to aztreonam, where the role of the new inhibitor avibactam does not seem to provide significant benefit. The main limitation of our study is the low number of strains analyzed, particularly in the case of MBL-producers Pseudomonas spp. strains. Declarations Conflict of interest The authors have no relevant financial or non financial interest to disclose. Funding The authors declare that no funds, grands, or other support were received during the preparation of this manuscript. Author Contribution A.C.B., AB.G.S., C.P.C. and I.DyC. made substantial contributions to the conception, design of the work; the acquisition, analysis, and interpretation of data.A.C.B., A.M.V., MI.Z.C. and M.S.S. drafted the work or revised it critically for important intellectual content.M.S.S.approved the version to be published. References Khan A, Erickson SG, Pettaway C, Arias CA, Miller WR, Bhatti MM. Evaluation of Susceptibility Testing Methods for Aztreonam and Ceftazidime-Avibactam Combination Therapy on Extensively Drug-Resistant Gram-Negative Organisms. Antimicrob Agents Chemother. 18 de octubre de 2021;65(11):e00846-21. F. Mojica M, A. Bonomo R, Fast W. B1-Metallo-β-Lactamases: Where Do We Stand? Curr Drug Targets. 19 de mayo de 2016;17(9):1029-50. Khan S, Das A, Vashisth D, Mishra A, Vidyarthi AJ, Gupta R, et al. 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Evaluation of two gradient diffusion tests to determine susceptibility to aztreonam and ceftazidime–avibactam in combination. Tamma PD, editor. Antimicrob Agents Chemother. 5 de marzo de 2025;69(3):e01736-24. Lemon JK, Jankowsi-Romano C, Duong S, Juretschko S, Streva VA. Evaluation of gradient strip diffusion for susceptibility testing of aztreonam–avibactam in metallo-β-lactamase-producing Enterobacterales. Simner PJ, editor. J Clin Microbiol. 13 de noviembre de 2024;62(11):e00649-24. Cointe A, Bonacorsi S, Truong J, Hobson C, Doit C, Monjault A, et al. Detection of Carbapenemase-Producing Enterobacteriaceae in Positive Blood Culture Using an Immunochromatographic RESIST-4 O.K.N.V. Assay. Antimicrob Agents Chemother. diciembre de 2018;62(12):e01828-18. Gao N, Zhou J, Li G, Liu R, Lu G, Shen J. Methodological Evaluation of Carbapenemase Detection by Different Methods. Pol J Microbiol. 1 de septiembre de 2024;73(3):383-94. Sopirala MM, Mangino JE, Gebreyes WA, Biller B, Bannerman T, Balada-Llasat JM, et al. Synergy Testing by Etest, Microdilution Checkerboard, and Time-Kill Methods for Pan-Drug-Resistant Acinetobacter baumannii. Antimicrob Agents Chemother. noviembre de 2010;54(11):4678-83. Sopena N, Larrosa N, Castella L, Padilla E, Smithson A, Lopez M, et al. Surveillance of MRSA, ESBL-producing Klebsiella pneumoniae, carbapenem-resistant Enterobacteriaceae, and Clostridioides difficile in Catalan Hospitals: Findings from the VINCat Program. Enfermedades Infecc Microbiol Clin Engl Ed. mayo de 2025;43:S60-8. Sopena N, Larrosa N, Castella L, Padilla E, Smithson A, Lopez M, et al. Surveillance of MRSA, ESBL-producing Klebsiella pneumoniae, carbapenem-resistant Enterobacteriaceae, and Clostridioides difficile in Catalan Hospitals: Findings from the VINCat Program. Enfermedades Infecc Microbiol Clin Engl Ed. mayo de 2025;43:S60-8. Paul M, Carrara E, Retamar P, Tängdén T, Bitterman R, Bonomo RA, et al. European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines for the treatment of infections caused by multidrug-resistant Gram-negative bacilli (endorsed by European society of intensive care medicine). Clin Microbiol Infect. abril de 2022;28(4):521-47. Tamma PD, Heil EL, Justo JA, Mathers AJ, Satlin MJ, Bonomo RA. Infectious Diseases Society of America 2024 Guidance on the Treatment of Antimicrobial-Resistant Gram-Negative Infections. Clin Infect Dis. 7 de agosto de 2024;ciae403. Longshaw C, Manissero D, Tsuji M, Echols R, Yamano Y. In vitro activity of the siderophore cephalosporin, cefiderocol, against molecularly characterized, carbapenem-non-susceptible Gram-negative bacteria from Europe. JAC-Antimicrob Resist. 1 de septiembre de 2020;2(3):dlaa060. Sader HS, Kimbrough JH, Mendes RE, Castanheira M. Antimicrobial susceptibility of enterobacterales causing bloodstream infection in United States medical centres: comparison of aztreonam-avibactam with beta-lactams active against carbapenem-resistant enterobacterales. BMC Infect Dis. 5 de noviembre de 2024;24(1):1242. Sader HS, Mendes RE, Ryan Arends SJ, Doyle TB, Castanheira M. Activity of Aztreonam-avibactam and other β-lactamase inhibitor combinations against Gram-negative bacteria isolated from patients hospitalized with pneumonia in United States medical centers (2020–2022). BMC Pulm Med. 24 de enero de 2025;25(1):38. Delgado-Valverde M, Portillo-Calderón I, Recacha E, Pérez-Palacios P, Pascual A. In Vitro Activity of Cefiderocol Compared to Other Antimicrobials against a Collection of Metallo-Beta-Lactamase-Producing Gram-Negative Bacilli from Southern Spain. Craney A, editor. Microbiol Spectr. 15 de junio de 2023;11(3):e04936-22. Delgado-Valverde M, Portillo-Calderón I, Recacha E, Pérez-Palacios P, Pascual A. In Vitro Activity of Cefiderocol Compared to Other Antimicrobials against a Collection of Metallo-Beta-Lactamase-Producing Gram-Negative Bacilli from Southern Spain. Craney A, editor. Microbiol Spectr. 15 de junio de 2023;11(3):e04936-22. Wu Y, Chen J, Zhang G, Li J, Wang T, Kang W, et al. In-vitro activities of essential antimicrobial agents including aztreonam/avibactam, eravacycline, colistin and other comparators against carbapenem-resistant bacteria with different carbapenemase genes: A multi-centre study in China, 2021. Int J Antimicrob Agents. noviembre de 2024;64(5):107341. Vázquez-Ucha JC, Alonso-Garcia I, Guijarro-Sánchez P, Lasarte-Monterrubio C, Álvarez-Fraga L, Cendón-Esteve A, et al. Activity of aztreonam in combination with novel β-lactamase inhibitors against metallo-β-lactamase-producing Enterobacterales from Spain. Int J Antimicrob Agents. abril de 2023;61(4):106738. Santerre Henriksen A, Jeannot K, Oliver A, Perry JD, Pletz MW, Stefani S, et al. In vitro activity of cefiderocol against European Pseudomonas aeruginosa and Acinetobacter spp., including isolates resistant to meropenem and recent β-lactam/β-lactamase inhibitor combinations. Müller R, editor. Microbiol Spectr. 2 de abril de 2024;12(4):e03836-23. Wong DW. Practical Application of Aztreonam-Avibactam as a Treatment Strategy for Ambler Class B Metallo-β-Lactamase Producing Enterobacteriaceae. Antibiotics. 14 de agosto de 2024;13(8):766. Blanco-Martín T, López-Hernández I, Aracil B, González-Pinto L, Aja-Macaya P, Alonso-García I, et al. Assessment of the activity and mechanisms of resistance to cefiderocol and combinations of β-lactams and the novel β-lactamase inhibitors avibactam, taniborbactam, zidebactam, nacubactam, xeruborbactam, and ANT3310 in emerging double-carbapenemase-producing Enterobacterales. Poirel L, editor. Antimicrob Agents Chemother. 6 de noviembre de 2024;68(11):e00924-24. Sader HS, Kimbrough JH, Mendes RE, Castanheira M. Antimicrobial susceptibility of enterobacterales causing bloodstream infection in United States medical centres: comparison of aztreonam-avibactam with beta-lactams active against carbapenem-resistant enterobacterales. BMC Infect Dis. 5 de noviembre de 2024;24(1):1242. Feng K, Jia N, Zhu P, Sy S, Liu Y, Dong D, et al. Aztreonam/avibactam effect on pharmacodynamic indices for mutant selection of Escherichia coli and Klebsiella pneumoniae harbouring serine- and New Delhi metallo-β-lactamases. J Antimicrob Chemother. 11 de octubre de 2021;76(11):2875-83. Karlowsky JA, Kazmierczak KM, Valente MLNDF, Luengas EL, Baudrit M, Quintana A, et al. In vitro activity of ceftazidime-avibactam against Enterobacterales and Pseudomonas aeruginosa isolates collected in Latin America as part of the ATLAS global surveillance program, 2017–2019. Braz J Infect Dis. noviembre de 2021;25(6):101647. Papagiannitsis CC, Tzouvelekis LS, Miriagou V. Relative Strengths of the Class 1 Integron Promoter Hybrid 2 and the Combinations of Strong and Hybrid 1 with an Active P2 Promoter. Antimicrob Agents Chemother. enero de 2009;53(1):277-80. Mauri C, Maraolo AE, Di Bella S, Luzzaro F, Principe L. The Revival of Aztreonam in Combination with Avibactam against Metallo-β-Lactamase-Producing Gram-Negatives: A Systematic Review of In Vitro Studies and Clinical Cases. Antibiotics. 20 de agosto de 2021;10(8):1012. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6856947","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":474983427,"identity":"3efb2c71-eab7-4d37-9c43-1038e5f4ccca","order_by":0,"name":"Ana Collazos Blanco","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/0lEQVRIiWNgGAWjYHACxgMPQJQEcwOIkgMREBE84EACWAsjWIsxQoRYLYlgEp8W/vbDBw4k1NTJyc9ubPxcUGOTPj/s8EOgIXZyug3YtUicSUs4kHCMzdjgzsFm6RnH0nI33k4zAGpJNjY7gMOaGzxABWw8iRskEhukeRsO526cnQDSciBxGw4t8mAt/yQS589IbP4N1JJuODv9A14tBiAtiW0GiQ03EttAtiTIS+fgt8UQ5JfEvgSQX9qseY6lGW6Qzik4kGCA2y9yxw8ffPDhGyjEmg/f5qmxkZefnb75w4cKOzmc3sd0KlilAbHKQUC+gRTVo2AUjIJRMBIAAPuHaAkFInszAAAAAElFTkSuQmCC","orcid":"","institution":"Hospital Central de la Defensa Gómez Ulla","correspondingAuthor":true,"prefix":"","firstName":"Ana","middleName":"Collazos","lastName":"Blanco","suffix":""},{"id":474983428,"identity":"1fdda6bd-5a96-4d20-aba2-10d378d9a984","order_by":1,"name":"Ana Belén García Sáez","email":"","orcid":"","institution":"Hospital Central de la Defensa Gómez Ulla","correspondingAuthor":false,"prefix":"","firstName":"Ana","middleName":"Belén García","lastName":"Sáez","suffix":""},{"id":474983429,"identity":"7ea6f4ae-303b-4002-bd01-4b90004ba07d","order_by":2,"name":"Carolina Plaza Cristobal","email":"","orcid":"","institution":"Hospital Central de la Defensa Gómez Ulla","correspondingAuthor":false,"prefix":"","firstName":"Carolina","middleName":"Plaza","lastName":"Cristobal","suffix":""},{"id":474983430,"identity":"07cf42f4-0892-4ca6-b667-32747d3ab0db","order_by":3,"name":"Ismael Darid y Cerón","email":"","orcid":"","institution":"Hospital Central de la Defensa Gómez Ulla","correspondingAuthor":false,"prefix":"","firstName":"Ismael","middleName":"Darid y","lastName":"Cerón","suffix":""},{"id":474983431,"identity":"737ffbdd-8e99-43a3-a321-d51926af8fa6","order_by":4,"name":"Alicia Macías Valcayo","email":"","orcid":"","institution":"Hospital Central de la Defensa Gómez Ulla","correspondingAuthor":false,"prefix":"","firstName":"Alicia","middleName":"Macías","lastName":"Valcayo","suffix":""},{"id":474983432,"identity":"4da37064-1218-43eb-9f3d-db384b509111","order_by":5,"name":"María Isabel Zamora Cintas","email":"","orcid":"","institution":"Hospital Central de la Defensa Gómez Ulla","correspondingAuthor":false,"prefix":"","firstName":"María","middleName":"Isabel Zamora","lastName":"Cintas","suffix":""},{"id":474983433,"identity":"7aaf86bc-7fc2-44a0-a601-29e490594273","order_by":6,"name":"María Simón Sacristán","email":"","orcid":"","institution":"Hospital Central de la Defensa Gómez Ulla","correspondingAuthor":false,"prefix":"","firstName":"María","middleName":"Simón","lastName":"Sacristán","suffix":""}],"badges":[],"createdAt":"2025-06-09 18:53:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6856947/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6856947/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":87676518,"identity":"4ec69928-83e0-4220-aa5c-a145377ce214","added_by":"auto","created_at":"2025-07-27 17:08:44","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1126094,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6856947/v1/1ba773d0-f65c-4e71-b926-0077601c3413.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eEvaluating the Susceptibility of MBL Carbapenemase-Producing Enterobacteriaceae and Pseudomonas spp. to Ceftazidime/Avibactam plus aztreonam and Cefiderocol: A Synergy Study Using the gradient strip stacking method and Susceptibility profile to the novel combination by gradient Concentration Strips.\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCarbapenem-resistant Gram-negatives pose a significant threat to global public health, especially due to carbapenemases. Carbapenem-resistant Enterobacterales (CRE) and \u003cem\u003ePseudomonas spp\u003c/em\u003e (CR-PS) have become serious causes of recalcitrant health care-associated infections that are often resistant to common therapeutic options (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSpecifically, the metallo-β-lactamases (MBL) confer multiple resistance to β-lactam drugs and their increasing prevalence complicates the clinical and therapeutical management(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAztreonam/avibactam (ATM/AVI) recently emerged as a promising option, which restores the monobactam effectiveness against specific β-lactamases, enhancing their antimicrobial activity with a non-β-lactam β-lactamase inhibitor (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). The combination ATM/AVI allows aztreonam to act against MBL (whose activity cannot inhibit monobactams) and avibactam to contrast the contextual presence of SHV, TEM, CTX-M, AmpC, KPC and OXA (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Recent data documented ATM/AVI resistance mechanisms among \u003cem\u003eEscherichia coli\u003c/em\u003e isolates due to acquired PBP mutations (PBP-3), decreased membrane permeability, efflux pump activation or β-lactamases enzymes active against aztreonam but refractory to avibactam (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). In the year 2022, the European Society of Clinical Microbiology and Infectious Diseases (ESCMID), in its guidelines, has recommended using the above combination against MBL-producing Enterobacterales (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). However, it is imperative to demonstrate AZT synergy in the presence of AVI in an in-vitro test before using the above regimen in patients.\u003c/p\u003e \u003cp\u003eCarbapenem resistance in \u003cem\u003eP. aeruginosa\u003c/em\u003e is most commonly mediated by noncarbapenemase mechanisms that include the overproduction of AmpC, porin loss, and drug efflux, although some isolates also produce carbapenemases (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe European Medicines Agency (EMA) has recommended marketing authorization for Aztreonam/avibactam (Emblaveo\u0026reg;) in the European Union to treat multi-drug resistant Gram-negatives complicated infections.\u003c/p\u003e \u003cp\u003eCurrently, there is no practical and widely accepted antimicrobial susceptibility testing (AST) method available for use in clinical laboratories for assessing the efficacy of the ATM-CZA combination. Established testing methods to evaluate combinations like the checkerboard assay or time-kill assays are complex, labor intensive, and difficult to interpret. But some methods like the gradient strip stacking and gradient strip crossing, although more expensive, could be the test(s) of choice for a clinical lab that already has established workflows for susceptibility testing using gradient strips (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e)(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe aim of this study was to evaluate the in vitro activity of the combination aztreonam and ceftazidime/Avibactam using the gradient strip stacking method and compare results with the aztreonam/avibactam MICs determined by epsilon test method recently commercialized. At the same time, cefiderocol susceptibility was determined to analyze the susceptibility profile of the strains studied.\u003c/p\u003e"},{"header":"Material and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStrain collection\u003c/h2\u003e \u003cp\u003eOur collection included 38 nonduplicated strains, Enterobacterales group (n\u0026thinsp;=\u0026thinsp;31) and \u003cem\u003ePseudomonas\u003c/em\u003e spp (n\u0026thinsp;=\u0026thinsp;7) with decreased susceptibility to carbapenems (at least to one among imipenem or meropenem) collected from clinical patients during routine clinical diagnostics in the Hospital Central de la Defensa Gomez Ulla (CSVE) across 2 years period (from January 1, 2023 to November 31, 2024). All strains were confirmed carbapenemase producers.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSusceptibility testing and MIC determination\u003c/h3\u003e\n\u003cp\u003eAll isolates were identified using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (Bruker Daltonik, Bremen, Germany). Antimicrobial susceptibility testing was conducted following the recommendations of the European Committee on Antimicrobial Susceptibility testing (EUCAST). Susceptibility testing was performed using the MicroScan WalkAway Plus automated system (Beckman Coulter).\u003c/p\u003e \u003cp\u003eQuality control (QC) strains \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e ATCC 27853 and \u003cem\u003eEscherichia coli\u003c/em\u003e ATCC 25922 were utilized for each experimental sitting.\u003c/p\u003e \u003cp\u003eCarbapenemases were detected using immunochromatographic RESIST-5 O.K.N.V.I assay (Coris)(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) or Xpert\u0026reg; Carba-R test (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe cefiderocol susceptibility tests were performed by the disc diffusion method (Liofilchem, Roseto degli Abruzzi, Italy) on Mueller\u0026ndash;Hinton medium plates (MH agar plates). The results were interpreted according to the breakpoints proposed by EUCAST for the cefiderocol 30 \u0026micro;g disk: zone diameters of \u0026ge;\u0026thinsp;23 mm into enterobacterales group and \u0026ge;\u0026thinsp;22 mm in \u003cem\u003ePseudomonas\u003c/em\u003e spp that correspond to minimum inhibitory concentration (MIC) values below the PK-PD breakpoint of S\u0026thinsp;\u0026le;\u0026thinsp;2 mg/L (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.eucast.org/clinical_breakpoints\u003c/span\u003e\u003cspan address=\"https://www.eucast.org/clinical_breakpoints\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e, accessed on may 2025).\u003c/p\u003e \u003cp\u003eThe aztreonam-avibactam susceptibility tests were performed by the epsilon test diffusion method (Biomerieux) on Mueller\u0026ndash;Hinton medium plates (MH agar plates). The results were interpreted according to the breakpoints proposed by EUCAST for enterobacterales S\u0026thinsp;\u0026le;\u0026thinsp;4 mg/L if the concentration of avibactam is fixed at 4 mg/L.\u003c/p\u003e\n\u003ch3\u003eThe Synergy test\u003c/h3\u003e\n\u003cp\u003eSynergy analyses were performed using the gradient strip stacking method. The fractional inhibitory concentration (FIC) index (FICI) was calculated for the E-test by using the following formula: FICI\u0026thinsp;=\u0026thinsp;FIC of agent A\u0026thinsp;+\u0026thinsp;FIC B, where FIC A is the MIC of the combination/MIC of drug A alone, and FIC B is the MIC of the combination/MIC of drug B alone. FICI results were interpreted with the following criteria: synergy, FICI\u0026thinsp;\u0026le;\u0026thinsp;0.5; independent interaction, FICI 0.5- \u0026le; 4; and antagonism, FICI\u0026thinsp;\u0026gt;\u0026thinsp;4(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e \u003cb\u003eAntimicrobial Susceptibility and Characteristics of Carbapenemases producers Enterobacterales strains.\u003c/b\u003e \u003c/p\u003e \u003cp\u003eAll 31 isolates were collected from our hospital, comprising 15 (48.4%) \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e (\u003cem\u003eK. pneumoniae)\u003c/em\u003e, 6 (19.4%) \u003cem\u003eEscherichia coli\u003c/em\u003e (\u003cem\u003eE. coli)\u003c/em\u003e, \u003cem\u003e5\u003c/em\u003e (16.1%) \u003cem\u003eEnterobacter cloacae (E. cloacae), 3 (9.7%) Klebsiella oxytoca (K.oxytoca), 1\u003c/em\u003e(3.2%) \u003cem\u003eCitrobacter frendii (C. freundii) and 1\u003c/em\u003e(3.2%) \u003cem\u003eSerratia marcenses (S. marcenses)\u003c/em\u003e isolate. All strains demonstrated resistance to \u003cem\u003eβ\u003c/em\u003e-lactams including any carbapenems. Additionally, they exhibited partial resistance to other antimicrobial agents such as amikacin and ciprofloxacin. In contrast, tigecycline and Cefiderocol (27/31, 93.5%) maintained high susceptibility levels. The results were summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Cefiderocol resistance was confirmed by microdilution method (UMIC\u0026reg; Cefiderocol, Bruker).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAntimicrobial Susceptibility profile.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpecie strain (n)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAntimicrobial\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNumber and % of isolates Susceptible (S) or Susceptible Increase Exposure (I)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"7\" rowspan=\"8\"\u003e \u003cp\u003e\u003cem\u003eK. pneumoniae\u003c/em\u003e (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAmikacin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11 (73.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCiprofloxacin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3 (20.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTigecycline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e15 (100.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAztreonam\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5 (33.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMeropenem\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10 (66.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCeftolozane/tazobactam\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCeftazidime/avibactam\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2 (13.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCefiderocol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e15 (100.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"7\" rowspan=\"8\"\u003e \u003cp\u003e\u003cem\u003eE.coli\u003c/em\u003e (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAmikacin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4 (66.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCiprofloxacin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1 (16.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTigecycline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6 (100.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAztreonam\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4 (66.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMeropenem\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4 (66.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCeftolozane /tazobactam\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCeftazidime/avibactam\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCefiderocol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5 (83.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"7\" rowspan=\"8\"\u003e \u003cp\u003e\u003cem\u003eE.cloacae\u003c/em\u003e (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAmikacin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4 (80.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCiprofloxacin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1 (20.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTigecycline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5 (100.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAztreonam\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3 (60.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMeropenem\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3 (60.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCeftolozane /tazobactam\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCeftazidime/avibactam\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCefiderocol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4 (80.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"7\" rowspan=\"8\"\u003e \u003cp\u003e\u003cem\u003eK.oxytoca\u003c/em\u003e (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAmikacin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3 (100.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCiprofloxacin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1 (33.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTigecycline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3 (100.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAztreonam\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2 (66.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMeropenem\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1 (33.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCeftolozane /tazobactam\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCeftazidime/avibactam\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCefiderocol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3 (100.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"7\" rowspan=\"8\"\u003e \u003cp\u003e\u003cem\u003eC. freundii\u003c/em\u003e (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAmikacin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1 (100.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCiprofloxacin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1 (100.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTigecycline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1 (100.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAztreonam\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1 (100.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMeropenem\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1 (100.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCeftolozane /tazobactam\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCeftazidime/avibactam\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCefiderocol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1 (100.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"7\" rowspan=\"8\"\u003e \u003cp\u003e\u003cem\u003eS. marscenses\u003c/em\u003e (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAmikacin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1 (100.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCiprofloxacin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTigecycline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAztreonam\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1 (100.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMeropenem\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCeftolozane /tazobactam\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCeftazidime/avibactam\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCefiderocol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1 (100.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"7\" rowspan=\"8\"\u003e \u003cp\u003e\u003cem\u003ePseudomonas spp.\u003c/em\u003e (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAmikacin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7 (100.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCiprofloxacin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTigecycline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAztreonam\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7 (100.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMeropenem\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1 (14.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCeftolozane /tazobactam\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCeftazidime/avibactam\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCefiderocol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7 (100.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe results of the RESIST-5 O.K.N.V.I assay (Coris) and Xpert\u0026reg; Carba-R test revealed that 28 strains produced carbapenemase VIM type and 3 strains produced carbapenemase NDM type.\u003c/p\u003e\n\u003ch3\u003eSynergy study\u003c/h3\u003e\n\u003cp\u003eTo the study of the synergistic effects of ATM in combination with CZA the gradient strip stacking method, was used against the respective strains.\u003c/p\u003e \u003cp\u003eAmong enterobacterales group 16/31 (51.6%) were susceptible (S) or Susceptible, increased exposure (I) to aztreonam and 15/31 (48.4%) were resistant to aztreonam (R\u0026thinsp;\u0026gt;\u0026thinsp;4 mg/L) according to EUCAST breakpoints.\u003c/p\u003e \u003cp\u003eAmong the 16 susceptible strains to aztreonam, synergy effect was observed in only 3 (18.8%) strains (two \u003cem\u003eE. cloacae\u003c/em\u003e and one \u003cem\u003eK. oxytoca\u003c/em\u003e). These strains were carbapenemase VIM type producers and they have aztreonam MIC between 1\u0026ndash;4 mg/L, so they were susceptible exposure increased (I). Indifference was observed in 13 (81.2%) strains. In aztreonam resistant group, all strains demonstrated synergy effect 15/15 (100%).\u003c/p\u003e \u003cp\u003eMost of the strains demonstrated resistance (29/31; 93.5%) to Caftazidime/Avibactam as expected because all of our strains were metallo-β-lactamases producers (MBL).\u003c/p\u003e \u003cp\u003eThe results of the synergy study are shown in the Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eResults of synergy analysis with the fixed proportion with the E-test method.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpecie\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCarbapenemase type\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMIC Aztreonam (mg/L)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMIC Ceftazidime/Avibactam (mg/L)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIFIC\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eInterpretation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMIC Aztreonam/Avibactam\u003c/p\u003e \u003cp\u003e(Embableo\u0026reg;) (mg/L)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eK.pneumoniae\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVIM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,0017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSYNERGY\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0,016\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eK.pneumoniae\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVIM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0,047\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1,0002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eINDIFERENCE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0,023\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eE. coli\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNDM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,0059\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSYNERGY\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0,75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eE. coli\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVIM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0,094\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,6811\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eINDIFERENCE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0,047\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eK.pneumoniae\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVIM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0,38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,2503\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSYNERGY\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0,094\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eE. cloacae\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVIM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e128\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,0027\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSYNERGY\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0,094\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eK.pneumoniae\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVIM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0,064\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1,0003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eINDIFERENCE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0,047\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eS. marscenses\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVIM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0,094\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1,3302\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eINDIFERENCE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0,25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eK.pneumoniae\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVIM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,0024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSYNERGY\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0,064\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eK.pneumoniae\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVIM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,0012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSYNERGY\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0,064\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eK. oxytoca\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVIM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,0015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSYNERGY\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0,19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eK.pneumoniae\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVIM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,0013\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSYNERGY\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0,047\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eK.pneumoniae\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVIM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0,19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1,0007\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eINDIFERENCE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0,094\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eK.pneumoniae\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVIM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,0029\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSYNERGY\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0,016\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eE. cloacae\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVIM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,1920\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSYNERGY\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0,19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eK.pneumoniae\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVIM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0,19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1,0007\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eINDIFERENCE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0,125\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eK. oxytoca\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVIM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1,5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,1674\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSYNERGY\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0,125\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eK.pneumoniae\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVIM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,0017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSYNERGY\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0,094\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eE. coli\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNDM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,0098\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSYNERGY\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0,5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eK.pneumoniae\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNDM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e192\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,0010\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSYNERGY\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0,047\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eK. oxytoca\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVIM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0,125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,7524\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eINDIFERENCE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0,047\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eE. cloacae\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVIM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e128\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,0029\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSYNERGY\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0,094\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eK.pneumoniae\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVIM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0,064\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1,4691\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eINDIFERENCE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0,047\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eE. coli\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVIM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0,38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,5007\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eINDIFERENCE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0,064\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eE. cloacae\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVIM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0,125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1,0004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eINDIFERENCE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0,064\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eC.freundii\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVIM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0,25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,7605\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eINDIFERENCE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0,047\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eE. coli\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVIM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0,125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1,0002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eINDIFERENCE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0,064\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eE. coli\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVIM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0,125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,5123\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eINDIFERENCE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0,023\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eK.pneumoniae\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVIM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,0063\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSYNERGY\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0,047\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eE. cloacae\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVIM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1,5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,3353\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSYNERGY\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0,064\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eK.pneumoniae\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVIM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0,25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,2619\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSYNERGY\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0,125\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eP.fluorescens\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVIM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,9375\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eINDIFERENCE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eP.aeruginosa\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVIM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1,375\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eINDIFERENCE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eP.aeruginosa\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVIM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1,125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eINDIFERENCE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eP.putida\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVIM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,7917\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eINDIFERENCE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eP.aeruginosa\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIMP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,1784\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSYNERGY\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eP.monteilli\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVIM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,8333\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eINDIFERENCE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eP.aeruginosa\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVIM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0,7292\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eINDIFERENCE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eWe determined the susceptibility to the novel combination aztreonam/avibactam using the epsilon test method as described above. All 31 strains were susceptible to this combination according to the EUCAST breakpoints (S\u0026thinsp;\u0026le;\u0026thinsp;4 mg/L). When comparing the main parameters of the strains that showed synergy using the fixed proportion with the E-test method, with those that did not, no significant differences were observed (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \n\u003cp\u003eTable 3 Results of the novel combination Aztreonam/avibactam (Emblaveo\u0026Ograve;) among enterobacterales group.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"710\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width: 236px;\"\u003e\n \u003ch3\u003eETEST\u003csup\u003e\u0026reg;\u003c/sup\u003e Aztreonam/Avibactam (AZA)\u003c/h3\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 226px;\"\u003e\n \u003cp\u003eAztreonam S/I (16/31, 51.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 249px;\"\u003e\n \u003cp\u003eAztreonam R (15/31; 48.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eSynergy\u003c/p\u003e\n \u003cp\u003e(3/16, 18.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003eIndifference\u003c/p\u003e\n \u003cp\u003e(13/18, 81.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003eSynergy\u003c/p\u003e\n \u003cp\u003e(15/15; 100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eIndifference\u003c/p\u003e\n \u003cp\u003e(0/15; 0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"6\" valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003ep50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e0.125\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003e0.047\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0.094\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003ep90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e0.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003e0.125\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003eMin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e0.064\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003e0.023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0.016\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003eMax\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e0.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003e0.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0.75\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003eRage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e0.126\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003e0.227\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e0.734\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n \u003cp\u003e \u003cb\u003eAntimicrobial Susceptibility and Characteristics of Carbapenemase producers\u003c/b\u003e \u003cb\u003ePseudomonas\u003c/b\u003e \u003cb\u003espp strains.\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe results of the RESIST-5 O.K.N.V.I assay (Coris) and Xpert\u0026reg; Carba-R test revealed that 6/7 (85.7%) strains produced carbapenemase VIM type and 1 (14.3) carbapenemase IMP type.\u003c/p\u003e \u003cp\u003eAll strains demonstrated resistance to the principal antipseudomonic \u003cem\u003eβ\u003c/em\u003e-lactams including any carbapenems. Additionally, they exhibited partial resistance to other antimicrobial agents such as ciprofloxacin. Cefiderocol was the most susceptible agent (7/7, 100%). The results were summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eAll strains were susceptible increased exposure to aztreonam according to the EUCAST breakpoints (S\u0026thinsp;\u0026le;\u0026thinsp;0.001\u0026ndash;16 mg/L) and all of them were resistant to Ceftazidime/Avibactam (\u0026le;\u0026thinsp;8 mg/L).\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eSinergy study\u003c/h2\u003e \u003cp\u003eTo the study of the synergistic effects of ATM in combination with CZA the gradient strip stacking method, was used against the respective strains.\u003c/p\u003e \u003cp\u003eAmong \u003cem\u003ePsudomonas\u003c/em\u003e spp group, in 6/7 strains (85.7%) indifference effect were observed and only in one strain (14.3%) synergy effect were observed. This strain was \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e IMP carbapenemase producer.\u003c/p\u003e \u003cp\u003eWe determined the susceptibility to the novel combination aztreonam/avibactam by epsilon test method as described above. 7/7 (100.0%) Strains were susceptible to this novel combination according to the EUCAST ECOFF for \u003cem\u003ePseudomonas\u003c/em\u003e spp (16 mg/L) however, higher MIC values were observed compared with Enterobacterales group.. The results of the synergy study are shown in the Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eDuring the 2023\u0026ndash;2024 study period, strains producing metallo-β-lactamase (MBL) carbapenemases, mainly of the VIM type, increased in our hospital and in other regions of Spain (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e)(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). The growing challenge of antibiotic resistance has accelerated the development of new drugs and novel β-lactam/β-lactamase inhibitor combinations like cefiderocol and Aztreonam/Avibactam.\u003c/p\u003e \u003cp\u003eCurrent guidelines recommend treating MBL-producing CRE infections with a combination of ceftazidime-avibactam and the simultaneous infusion of aztreonam or cefiderocol(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e)(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn this study, we analyzed a well-characterized collection of 31 \u003cem\u003eEnterobacterales\u003c/em\u003e MBL producers and 7 \u003cem\u003ePseudomonas\u003c/em\u003e spp MBL producers obtained from clinical samples.\u003c/p\u003e \u003cp\u003eCefiderocol exhibited the most potent in vitro activity against carbapenemase-producing Enterobacterales (CRE) and carbapenemase-resistant \u003cem\u003ePseudomonas\u003c/em\u003e spp (CR-PS), with susceptibility rates of 93.5% and 100.0% respectively, according to EUCAST breakpoints as previous reported (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eCefiderocol activity has shown variability across different studies. In the CREDIBLE-CR and APEKS-NP trials, clinical cure of infections caused by MBL-producing Gram-negative bacteria was achieved in only 70.8% of cases (17/24). When focusing specifically on MBL producers \u003cem\u003eEnterobacteriaceae\u003c/em\u003e, the clinical success rate was 73% (11/15 cases). However, other surveillance studies have demonstrated excellent in vitro activity of cefiderocol against carbapenem-resistant Gram-negative bacteria (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e)(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e)(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eA surveillance study by M. Delgado-Valverde et al. reported that cefiderocol was active against 80% of 160 carbapenem-resistant \u003cem\u003eEnterobacterales\u003c/em\u003e (CRE) isolates. However, susceptibility was lower among NDM and VIM-producing strains, with only 86% (49/57) and 76.9%, categorized as susceptible. (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn the SIDERO study, the overall susceptibility of cefiderocol against carbapenem-resistant \u003cem\u003eEnterobacterales\u003c/em\u003e (Carb-NS) was 81.6%. However, when susceptibility was analyzed according to carbapenemase type, the lowest activity was observed against NDM-producing isolates, with a susceptibility rate of only 51.4% (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) so data suggest that NDM-producing \u003cem\u003eEnterobacteriaceae\u003c/em\u003e tend to have higher MICs to cefiderocol compared to isolates producing other metalo β-lactamases. In our study, only three NDM-type carbapenemase-producing isolates were identified, and just one of them was resistant to cefiderocol.\u003c/p\u003e \u003cp\u003eAztreonam/avibactam (Emblaveo, Pfizer) is a novel combination consisting of a monobactam that interferes with bacterial cell wall synthesis and a non-β-lactam β-lactamase inhibitor active against class A, class C, and some class D β-lactamases. It was approved by the European Medicines Agency (EMA) in April 2024 for the treatment of multidrug-resistant (MDR) infections in patients with limited therapeutic options, including complicated intra-abdominal infections (cIAI), hospital-acquired pneumonia (HAP), and complicated urinary tract infections (cUTI).\u003c/p\u003e \u003cp\u003eAlthough aztreonam is not hydrolyzed by metallo-β-lactamases, co-expression of MBLs with other Ambler class β-lactamases capable of hydrolyzing aztreonam is common. As a result, aztreonam monotherapy is often ineffective against MBL-producing strains.\u003c/p\u003e \u003cp\u003eSeveral studies have evaluated the in vitro activity of aztreonam/avibactam against worldwide isolates of \u003cem\u003eEnterobacterales\u003c/em\u003e exhibiting carbapenem non-susceptibility and/or MBL production. (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e)(\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e)(\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e)(\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAccording to the 2024 EUCAST/CLSI breakpoints, a recent report demonstrated excellent in vitro activity of aztreonam/avibactam against \u003cem\u003eEnterobacterales\u003c/em\u003e isolates producing dual-carbapenemases (MBL\u0026thinsp;+\u0026thinsp;class A carbapenemase, n\u0026thinsp;=\u0026thinsp;14; MBL\u0026thinsp;+\u0026thinsp;class D carbapenemase, n\u0026thinsp;=\u0026thinsp;35). The study revealed 100% susceptibility, with overall MIC\u003csub\u003e50\u003c/sub\u003e and MIC\u003csub\u003e90\u003c/sub\u003e values of \u0026le;\u0026thinsp;0.25 mg/L and 0.5 mg/L, respectively (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn other international surveillance studies, 100% susceptibility was observed for the new combination, followed by cefiderocol (83%), with the majority of isolates were KPC- type carbapenemase-producing isolates. (28/49) (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn all these studies, the majority of the strains examined were resistant to aztreonam, and susceptibility to aztreonam/avibactam was assessed using synergy testing methods. In our study, we evaluated susceptibility to the combination using the gradient strip stacking method and determined the MIC through gradient concentration strips. We observed synergy in 58% of the strains. However, when differentiating between those that were aztreonam susceptible (S or I) (MIC\u0026thinsp;\u0026le;\u0026thinsp;4; n\u0026thinsp;=\u0026thinsp;16/31) and those that were aztreonam resistant (MIC\u0026thinsp;\u0026gt;\u0026thinsp;4; n\u0026thinsp;=\u0026thinsp;15/31), we found that the percentage of strains exhibiting synergy was significantly higher in the aztreonam resistant group (100%; n\u0026thinsp;=\u0026thinsp;15/15) compared to the aztreonam susceptible strains (18.8%; n\u0026thinsp;=\u0026thinsp;3/16). This result aligns with the expected mechanism of action of the combination.\u003c/p\u003e \u003cp\u003eThe 3 aztreonam susceptible strains that exhibited synergy with the combination had aztreonam MIC values ranging from 1 to \u0026le;\u0026thinsp;4 mg/L, suggesting the presence of some β-lactamase in their resistome. Similar results have been observed in other studies, albeit with a significantly smaller number of strains.(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eHowever, when susceptibility to aztreonam/avibactam was determined using gradient concentration strips, we observed that all the MBL-producing \u003cem\u003eEnterobacterales\u003c/em\u003e strains studied were susceptible according to the EUCAST breakpoints. No difference was found in the MICs when comparing those strains that exhibited synergy with those that did not.\u003c/p\u003e \u003cp\u003eTherefore, if susceptibility to aztreonam/avibactam is assessed solely by using gradient concentration strips, it will not be possible to differentiate those strains that would benefit from the combination (aztreonam resistant strains) from those for which the combination likely offers no additional benefit (the majority of ztreonam susceptible strains).\u003c/p\u003e \u003cp\u003eHowever, further studies will be necessary to determine the potential benefit of the aztreonam/avibactam combination in these aztreonam susceptible strains, such as a possible reduction in the mutant prevention concentration (MPC)(\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn our study, of the 31 \u003cem\u003eEnterobacterales\u003c/em\u003e strains analyzed, resistance to ceftazidime/avibactam (CZA) was high, as expected, due to the inhibitory profile of avibactam (93.5%). However, previous reports have indicated a limited proportion of MBL producers \u003cem\u003eEnterobacterales\u003c/em\u003e and MBL \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e strains, susceptible to CZA (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). This CZA susceptibility may be explained by the presence of weak promoters that affect the gene expression as has been previously described (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThis is interesting because, in the presence of a multidrug-resistant microorganism, the production of a MBL does not necessarily exclude the use of CZA, which could become a valuable therapeutic option when no other treatments are available.\u003c/p\u003e \u003cp\u003eConversely, lower rates of aztreonam/avibactam susceptibility have been reported previously among carbapenem-non-susceptible (72.2\u0026ndash;83%) and MBL-producers \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e isolates (55.8\u0026ndash;72.5%). Findings that are consistent with data published by Carola et al., where MIC\u003csub\u003e50\u003c/sub\u003e and MIC\u003csub\u003e90\u003c/sub\u003e of 0.125 mg/L to 0.25 mg/L for \u003cem\u003eEnterobacterales\u003c/em\u003e and 16 to 32 mg/L for \u003cem\u003eP. aeruginosa\u003c/em\u003e were observed, respectively (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThese findings are consistent with the results obtained in our study, where synergy in \u003cem\u003ePseudomonas\u003c/em\u003e spp strains was observed in only one sample (14.3%). Using gradient concentration strips of the new combination, only this strain exhibited a MIC value of \u0026le;\u0026thinsp;4 mg/L.\u003c/p\u003e \u003cp\u003eThis difference in susceptibility when compared to the \u003cem\u003eEnterobacteriaceae\u003c/em\u003e group, could be due to the presence of multiple resistance mechanisms commonly detected in \u003cem\u003ePseudomonas spp\u003c/em\u003e, such as overexpression of efflux systems, production of PDC-like, PER-like and OXA-like β-lactamase variants and loss of porins.\u003c/p\u003e \u003cp\u003eConsequently, these data might suggest the use of aztreonam/avibactam mainly for the treatment of infections sustained by MBL-producers Enterobacterales.\u003c/p\u003e \u003cp\u003eAbove all, the emergence of strains producing carbapenemases posed a significant challenge in treating CRE and CR-PS. The novel combination of ceftazidime/aztreonam offers a valuable addition to the armamentarium for MBL-producers \u003cem\u003eEnterobacteriaceae\u003c/em\u003e infections especially those with resistance to aztreonam; however, it does not appear to be an optimal choice for the treatment of \u003cem\u003ePseudomonas spp.\u003c/em\u003e MBL producers, where cefiderocol plays a crucial role.\u003c/p\u003e \u003cp\u003eFurther studies are needed to analyze the role of the aztreonam/avibactam combination in \u003cem\u003eEnterobacteriaceae\u003c/em\u003e strains that are susceptible to aztreonam, where the role of the new inhibitor avibactam does not seem to provide significant benefit.\u003c/p\u003e \u003cp\u003eThe main limitation of our study is the low number of strains analyzed, particularly in the case of MBL-producers \u003cem\u003ePseudomonas spp.\u003c/em\u003e strains.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflict of interest\u003c/h2\u003e \u003cp\u003eThe authors have no relevant financial or non financial interest to disclose.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThe authors declare that no funds, grands, or other support were received during the preparation of this manuscript.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eA.C.B., AB.G.S., C.P.C. and I.DyC. made substantial contributions to the conception, design of the work; the acquisition, analysis, and interpretation of data.A.C.B., A.M.V., MI.Z.C. and M.S.S. drafted the work or revised it critically for important intellectual content.M.S.S.approved the version to be published.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKhan A, Erickson SG, Pettaway C, Arias CA, Miller WR, Bhatti MM. 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Antimicrobial susceptibility of enterobacterales causing bloodstream infection in United States medical centres: comparison of aztreonam-avibactam with beta-lactams active against carbapenem-resistant enterobacterales. BMC Infect Dis. 5 de noviembre de 2024;24(1):1242. \u003c/li\u003e\n\u003cli\u003eFeng K, Jia N, Zhu P, Sy S, Liu Y, Dong D, et al. Aztreonam/avibactam effect on pharmacodynamic indices for mutant selection of Escherichia coli and Klebsiella pneumoniae harbouring serine- and New Delhi metallo-\u0026beta;-lactamases. J Antimicrob Chemother. 11 de octubre de 2021;76(11):2875-83. \u003c/li\u003e\n\u003cli\u003eKarlowsky JA, Kazmierczak KM, Valente MLNDF, Luengas EL, Baudrit M, Quintana A, et al. In vitro activity of ceftazidime-avibactam against Enterobacterales and Pseudomonas aeruginosa isolates collected in Latin America as part of the ATLAS global surveillance program, 2017\u0026ndash;2019. Braz J Infect Dis. noviembre de 2021;25(6):101647. \u003c/li\u003e\n\u003cli\u003ePapagiannitsis CC, Tzouvelekis LS, Miriagou V. Relative Strengths of the Class 1 Integron Promoter Hybrid 2 and the Combinations of Strong and Hybrid 1 with an Active P2 Promoter. Antimicrob Agents Chemother. enero de 2009;53(1):277-80. \u003c/li\u003e\n\u003cli\u003eMauri C, Maraolo AE, Di Bella S, Luzzaro F, Principe L. The Revival of Aztreonam in Combination with Avibactam against Metallo-\u0026beta;-Lactamase-Producing Gram-Negatives: A Systematic Review of In Vitro Studies and Clinical Cases. Antibiotics. 20 de agosto de 2021;10(8):1012. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"aztreonam/avibactam, synergy, cefiderocol, carbapenemase","lastPublishedDoi":"10.21203/rs.3.rs-6856947/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6856947/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eThis study investigates the in vitro effectiveness of the combination aztreonam and ceftazidime/avibactam (ATM/CZA) against metallo-β-lactamase (MBL)-producing Enterobacterales and \u003cem\u003ePseudomonas\u003c/em\u003e spp., using the gradient strip stacking method to evaluate synergy, and compares it with the novel aztreonam/avibactam (ATM/AVI) combination. Susceptibility to cefiderocol and other antimicrobials was studied.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA total of 38 non-duplicate strains were analyzed: 31 Enterobacterales and 7 \u003cem\u003ePseudomonas\u003c/em\u003e spp., all confirmed carbapenemase MBL producers.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eATM/AVI showed 100% susceptibility among Enterobacterales using epsilon test method according to EUCAST breakpoints, although synergy AZT plus CZA was found in only 58% of the strains. The 100% of aztreonam-resistant strains showed synergy, compared to only 18.8% of aztreonam-susceptible strains, suggesting that the combination provides greater benefit in resistant strains. In contrast, \u003cem\u003ePseudomonas\u003c/em\u003e spp. strains showed minimal synergy as previous reported(14.3%) and low susceptibility (1/7 strains) to the ATM/AVI combination, highlighting the limited efficacy of this therapy against these organisms. Cefiderocol, however, demonstrated high activity: 93.5% susceptibility in Enterobacterales group and 100% in \u003cem\u003ePseudomonas\u003c/em\u003e spp.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe study emphasizes that gradient strips test may not reveal which aztreonam-susceptible strains would benefit from the ATM/AVI combination, therefore, synergy testing remains crucial. Ultimately, ATM/AVI is a promising option for treating infections caused by MBL-producing Enterobacterales, while cefiderocol remains a important agent against MBL-producing \u003cem\u003ePseudomonas\u003c/em\u003e spp.\u003c/p\u003e","manuscriptTitle":"Evaluating the Susceptibility of MBL Carbapenemase-Producing Enterobacteriaceae and Pseudomonas spp. to Ceftazidime/Avibactam plus aztreonam and Cefiderocol: A Synergy Study Using the gradient strip stacking method and Susceptibility profile to the novel combination by gradient Concentration Strips.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-24 08:43:54","doi":"10.21203/rs.3.rs-6856947/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"effa24ba-89a0-4f88-90e4-816bbd0aba46","owner":[],"postedDate":"June 24th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-07-27T17:08:23+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-24 08:43:54","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6856947","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6856947","identity":"rs-6856947","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}
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