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Introduction: Infections caused by carbapenem-resistant Enterobacterales (CRE) and carbapenem-resistant Pseudomonas aeruginosa , including isolates producing acquired carbapenemases, constitute a prevalent health problem worldwide. The primary objective of this study was to determine the distribution of the different carbapenemases among carbapenemase-producing Enterobacterales (CPE, specifically Escherichia coli , Klebsiella pneumoniae , Enterobacter cloacae complex, and Klebsiella aerogenes ) and carbapenemase-producing P. aeruginosa (CPPA) in Spain from January 2014 to December 2018., Methods: A national, retrospective, cross-sectional multicenter study was performed. The study included the first isolate per patient and year obtained from clinical samples and obtained for diagnosis of infection in hospitalized patients. A structured questionnaire was completed by the participating centers using the REDCap platform, and results were analyzed using IBM SPSS Statistics 29.0.0., Results: A total of 2,704 carbapenemase-producing microorganisms were included, for which the type of carbapenemase was determined in 2692 cases: 2280 CPE (84.7%) and 412 CPPA (15.3%), most often using molecular methods and immunochromatographic assays. Globally, the most frequent types of carbapenemase in Enterobacterales and P. aeruginosa were OXA-48-like, alone or in combination with other enzymes (1,523 cases, 66.8%) and VIM (365 cases, 88.6%), respectively. Among Enterobacterales, carbapenemase-producing K. pneumoniae was reported in 1821 cases (79.9%), followed by E. cloacae complex in 334 cases (14.6%). In Enterobacterales, KPC is mainly present in the South and South-East regions of Spain and OXA-48-like in the rest of the country. Regarding P. aeruginosa , VIM is widely distributed all over the country. Globally, an increasing percentage of OXA-48-like enzymes was observed from 2014 to 2017. KPC enzymes were more frequent in 2017-2018 compared to 2014-2016., Discussion: Data from this study help to understand the situation and evolution of the main species of CPE and CPPA in Spain, with practical implications for control and optimal treatment of infections caused by these multi-drug resistant organisms., Competing Interests: LM-M has been a consultant for MSD, Shionogi and Fastinov, has served as speaker for Merck, Astra-Zeneca, Astellas, and Becton Dickinson and has received research support from MSD, Shionogi, Janssen-Cilag and Pfizer. JD-R is an employee of MSD Spain. RC has participated in educational programs organized by MSD, Pfizer and Shionogi and has received research support form MSD, and Venatrox. NL-E has been a consultant for MSD, Menarini, Shionogi and Fastinov and has served as a speaker for MSD, Pfizer, Menarini, Shionogi, Biomerieux and Accelerate Diagnostics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gracia-Ahufinger, López-González, Vasallo, Galar, Siller, Pitart, Bloise, Torrecillas, Gijón-Cordero, Viñado, Castillo-García, Campo, Mulet, Madueño-Alonso, Chamizo-López, Arrastia-Erviti, Galán-Sánchez, Fernández-Quejo, Rodríguez-Díaz, Gutiérrez-Zufiaurre, Rodríguez-Maresca, Ortega-Lafont, Yagüe-Guirao, Chaves-Blanco, Colomina-Rodríguez, Vidal-Acuña, Portillo, Franco-Álvarez de Luna, Centelles-Serrano, Azcona-Gutiérrez, Delgado-Iribarren García Campero, Rey-Cao, Muñoz, Calvo-Montes, Zboromyrska, Grandioso, Càmara, Cantón, Larrosa-Escartín, Díaz-Regañón and Martínez-Martínez.)

Objectives: To assess the microbiological characteristics of Escherichia coli causing healthcare-associated bacteraemia of urinary origin (HCA-BUO) in Spain (ITUBRAS-2 project), with particular focus on ESBL producers and isolates belonging to ST131 high-risk clone (HiRC). Clinical characteristics and outcomes associated with ST131 infection were investigated., Methods: A total of 222 E. coli blood isolates were prospectively collected from patients with HCA-BUO from 12 tertiary-care hospitals in Spain (2017-19). Antimicrobial susceptibility and ESBL/carbapenemase production were determined. ST131 subtyping was performed. A subset of 115 isolates were selected for WGS to determine population structure, resistome and virulome. Clinical charts were reviewed., Results: ESBL-producing E. coli prevalence was 30.6% (68/222). ST131 represented 29.7% (66/222) of E. coli isolates and accounted for the majority of ESBL producers (46/68, 67.6%). The C2/H30-Rx subclone accounted for most ST131 isolates (44/66) and was associated with CTX-M-15 (37/44) and OXA-1 enzymes (27/44). Cluster C1-M27 was identified in 4/10 isolates belonging to subclade C1/H30-R1 and associated with CTX-M-27. Additionally, ST131 isolates showed a high content of other acquired resistance genes, and clade C/ST131 isolates carried characteristic QRDR mutations. They were categorized as uropathogenic E. coli and had higher aggregate virulence scores. ST131 infection was associated with more complex patients, prior use of cephalosporins and inadequate empirical treatment but was not associated with worse clinical outcomes., Conclusions: ST131 HiRC is the main driver of ESBL-producing E. coli causing HCA-BUO in Spain, mainly associated with the expansion of subclade CTX-M-15-C2/H30-Rx and the emergence of CTX-M-27-C1/H30-R1 (Cluster C1-M27)., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To determine susceptibility to the novel β-lactam/β-lactamase inhibitor combination imipenem/relebactam in clinical isolates recovered from intra-abdominal (IAI), urinary (UTI), respiratory (RTI) and bloodstream (BSI) infections in the SMART (Study for Monitoring Antimicrobial Resistance Trends) study in SPAIN during 2016 - 2020., Methods: Broth microdilution MICs for imipenem/relebactam and comparators were determined by a central laboratory against isolates of Enterobacterales and Pseudomonas aeruginosa. MICs were interpreted using EUCAST-2021 breakpoints., Results: In total, 5,210 Enterobacterales and 1,418 P. aeruginosa clinical isolates were analyzed. Imipenem/relebactam inhibited 98.8% of Enterobacterales. Distinguishing by source of infection susceptibility was 99.1% in BSI, 99.2% in IAI, 97.9% in RTI, and 99.2% in UTI. Of intensive care unit isolates (ICU) 97.4% were susceptible and of non-ICU isolates 99.2% were susceptible. In Enterobacterales, activity against Class A, Class B and Class D carbapenemases was 96.2%, 15.4% and 73.2%, respectively. In P. aeruginosa, imipenem/relebactam was active in 92.2% of isolates. By source of infection it was 94.8% in BSI, 92.9% in IAI, 91.7% in RTI, and 93.1% in UTI. An 88.7% of ICU isolates and 93.6% of non-ICU isolates were susceptible to imipenem/relebactam. Imipenem/relebactam remained active against P. aeruginosa ceftazidime-resistant (76.3%), cefepime-resistant (73.6%), imipenem-resistant (71.5%) and piperacillin-resistant (78.7%) isolates. Of all multidrug-resistant or difficult-to-treat resistance P. aeruginosa isolates, 75.1% and 46.2%, respectively, were susceptible to imipenem/relebactam., Conclusions: Imipenem/relebactam showed high rates of susceptibility in Enterobacterales and P. aeruginosa isolates from different sources of infection as well as depending on patients' location (ICU or non-ICU scenarios)., (©The Author 2023. Published by Sociedad Española de Quimioterapia. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)(https://creativecommons.org/licenses/by-nc/4.0/).)

Objectives: To study the in vitro activity of imipenem/relebactam and comparators and the imipenem/relebactam resistance mechanisms in a Pseudomonas aeruginosa collection from Portugal (STEP, 2017-18) and Spain (SUPERIOR, 2016-17) surveillance studies., Methods: P. aeruginosa isolates (n = 474) were prospectively recovered from complicated urinary tract (cUTI), complicated intra-abdominal (cIAI) and lower respiratory tract (LRTI) infections in 11 Portuguese and 8 Spanish ICUs. MICs were determined (ISO broth microdilution). All imipenem/relebactam-resistant P. aeruginosa isolates (n = 30) and a subset of imipenem/relebactam-susceptible strains (n = 32) were characterized by WGS., Results: Imipenem/relebactam (93.7% susceptible), ceftazidime/avibactam (93.5% susceptible) and ceftolozane/tazobactam (93.2% susceptible) displayed comparable activity. The imipenem/relebactam resistance rate was 6.3% (Portugal 5.8%; Spain 8.9%). Relebactam restored imipenem susceptibility to 76.9% (103/134) of imipenem-resistant isolates, including MDR (82.1%; 32/39), XDR (68.8%; 53/77) and difficult-to-treat (DTR) isolates (67.2%; 45/67). Among sequenced strains, differences in population structure were detected depending on the country: clonal complex (CC)175 and CC309 in Spain and CC235, CC244, CC348 and CC253 in Portugal. Different carbapenemase gene distributions were also found: VIM-20 (n = 3), VIM-1 (n = 2), VIM-2 (n = 1) and VIM-36 (n = 1) in Spain and GES-13 (n = 13), VIM-2 (n = 3) and KPC-3 (n = 2) in Portugal. GES-13-CC235 (n = 13) and VIM type-CC175 (n = 5) associations were predominant in Portugal and Spain, respectively. Imipenem/relebactam showed activity against KPC-3 strains (2/2), but was inactive against all GES-13 producers and most of the VIM producers (8/10). Mutations in genes affecting porin inactivation, efflux pump overexpression and LPS modification might also be involved in imipenem/relebactam resistance., Conclusions: Microbiological results reinforce imipenem/relebactam as a potential option to treat cUTI, cIAI and LRTI caused by MDR/XDR P. aeruginosa isolates, except for GES-13 and VIM producers., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Imipenem-relebactam is a novel β-lactam-β-lactamase inhibitor combination. We evaluated the in vitro activity of imipenem-relebactam and comparators against Enterobacterales clinical isolates recovered in 8 Spanish and 11 Portuguese intensive care units (ICUs) (SUPERIOR, 2016-2017; STEP, 2017-2018). Overall, 747 Enterobacterales isolates (378 Escherichia coli, 252 Klebsiella spp., 64 Enterobacter spp., and 53 other species) were prospectively collected from ICU patients with complicated intraabdominal (cIAI), complicated urinary tract (cUTI), and lower respiratory tract (LRTI) infections. MICs were determined (ISO-broth microdilution), and whole-genome sequencing (WGS) was performed in a subset of isolates displaying susceptible and resistant imipenem-relebactam MICs. Imipenem-relebactam (98.7% susceptible) showed similar activity to ceftazidime-avibactam (99.5% susceptible) and higher than ceftolozane-tazobactam (86.9% susceptible). Imipenem-relebactam was inactive against 1.3% (10/747) isolates, all of them due to carbapenemase production (9 K. pneumoniae and 1 E. cloacae). Imipenem-relebactam was active against 100% of extended-spectrum β-lactamase (ESBL)-E. coli and ESBL-Klebsiella spp. isolates and 80.4% of carbapenemase-Klebsiella spp. producers. Carbapenemase genes were confirmed by WGS in 41 Klebsiella spp.: OXA-48 (20/41), KPC-3 (14/41), OXA-181 (4/41), NDM-1 (1/41), OXA-48 + VIM-2 (1/41), and KPC-3 + VIM-2 (1/41). In Klebsiella spp. isolates, relebactam restored imipenem susceptibility in all KPC-3 producers, and resistant isolates (7/41) were mostly OXA-48 + CTX-M-15-K. pneumoniae high-risk clones (7/9). Intercountry differences were detected as follows: OXA-48 (17/21) was dominant in Spain, unlike KPC-3 (14/15) in Portugal. Imipenem-relebactam was 100% active against CTX-M-15-ST131-H30Rx-E. coli high-risk clone, predominant in both countries. Our results depict the potential role of imipenem-relebactam in ICU patients with cIAIs, cUTIs, and LRTIs due to wild-type ESBL- and carbapenemase-producing Enterobacterales , particularly KPC producers. IMPORTANCE We comparatively evaluate the in vitro activity of a drug combination consisting of a carbapenem (imipenem) and a novel inhibitor of beta-lactamases (relebactam), a mechanism that destroys beta-lactam antibiotics. We assess the activity against a collection of Enterobacterales clinical isolates recovered from difficult-to-treat infections in patients admitted to different intensive care units in Portugal and Spain. Imipenem-relebactam shows excellent activity in avoiding common resistance mechanisms in this setting, such as extended-spectrum beta-lactamases and carbapenemases widely distributed, including KPCs. We show few resistant isolates (<2%). Molecular characterization by whole-genome sequencing shows that most of the resistant isolates produced specific carbapenemase, such as OXA-48 or metalo-betalactamases. Our study updates the activity of imipenem-relebactam in light of current epidemiology in a hospital setting in which the use of this combination is needed due to the presence of infections due to multidrug-resistant isolates.

Background: Pseudomonas aeruginosa (PSA) infection often occurs in immunocompromised patients, which also face an increased risk of multidrug-resistant (MDR) bacteria. A deeper knowledge of the risk factors for MDR-PSA infection in this patient population may help to choose appropriate empirical antibiotic therapy. Methods: a single-center case-control (1:2) retrospective study that included 48 patients with underlying immunosuppression developing MDR-PSA infection (cases) and 96 patients also immunocompromised that were infected with non-MDR-PSA (controls) was conducted. Both groups were matched by site of infection, clinical features and type of immunosuppression. Risk factors for MDR-PSA were assessed by logistic regression. Clinical outcomes were also compared between both groups. Results: immunosuppression was due to solid cancer in 63 (43.8%) patients, solid organ transplantation in 39 (27.1%), hematological disease in 35 (24.3%) and other causes in 7 (4.9%). Independent risk factors for MDR-PSA infection were diabetes mellitus (odds ratio [OR]: 4.74; 95% confidence interval [CI]: 1.63−13.79; p = 0.004), antibiotic therapy in the previous 3 months (OR: 5.32; 95% CI: 1.93−14.73; p = 0.001), previous MDR-PSA colonization (OR: 42.1; 95% CI: 4.49−394.8; p = 0.001) and septic shock (OR: 3.73; 95% CI: 1.36−10.21; p = 0.010). MDR-PSA cases were less likely to receive adequate empirical therapy (14 [29.2%] vs. 69 [71.9%]; p < 0.001). 30-day clinical improvement was less common in MDR-PSA cases (25 [52.1%] vs. 76 [79.2%]; p = 0.001). Conclusions: diabetes mellitus, previous MDR-PSA colonization, prior receipt of antibiotics and septic shock acted as risk factors for developing MDR-PSA infections in immunocompromised patients, who have a poorer outcome than those infected with non-MDR-PSA strains.

Objectives: Multidrug-resistant Pseudomonas aeruginosa (MDR-PSA) constitutes an emerging health problem. A predictive score of MDR-PSA infection would allow an early adaptation of empirical antibiotic therapy., Methods: We performed a single-centre case-control (1:2) retrospective study including 100 patients with MDR-PSA and 200 with a non-MDR-PSA infection. Cases and controls were matched by site of infection, clinical characteristics and immunosuppression. A point risk score for prediction of MDR-PSA infection was derived from a logistic regression model. Secondary outcomes (clinical improvement, complications and discharge) were also compared., Results: Cases with MDR-PSA infection were younger than controls (67.5 vs. 73.0 y; P = 0.031) and have more frequent cirrhosis (9% vs. 2%; P = 0.005). Independent risk factors for MDR-PSA infection were prior antibiotic treatment (80% vs. 50.5%; P < 0.001), prior colonisation with MDR bacteria (41% vs. 13.5%; P < 0.001), hospital-acquired infection (63% vs. 47%; P = 0.009) and septic shock at diagnosis (33% vs. 14%; P < 0.001). Adequate therapy was less frequent in MDR-PSA infections (31% vs. 66.5% for empirical therapy; P < 0.001). The risk score included: previous MDR-PSA isolation (11 points), prior antibiotic use (3 points), hospital-acquired infection (2 points) and septic shock at diagnosis (2 points). It showed an area under the curve of 0.755 (95% CI: 0.70-0.81) and allowed to classify individual risk into various categories: 0-2 points (<20%), 3-5 points (25%-45%), 7-11 points (55%-60%), 13-16 points (75%-87%) and a maximum of 18 points (93%)., Conclusion: Infections due to MDR-PSA have a poorer prognosis than those produced by non-MDR-PSA. Our score could guide empirical therapy for MDR-PSA when P. aeruginosa is isolated., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Carbapenem-resistant Gram-negative (CRGN) infections are a major public health problem in Spain, often implicated in complicated, healthcare-associated infections that require the use of potentially toxic antibacterial agents of last resort. The objective of this study was to assess the clinical management of complicated infections caused by CRGN bacteria in Spanish hospitals., Methods: The study included: 1) a survey assessing the GN infection and antibacterial susceptibility profile in five participating Spanish hospitals and 2) a non-interventional, retrospective single cohort chart review of 100 patients with complicated urinary tract infection (cUTI), complicated intra-abdominal infection (cIAI), or hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia (HABP/VABP) attributable to CRGN pathogens., Results: In the participating hospitals CRGN prevalence was 9.3% amongst complicated infections. In the retrospective cohort, 92% of infections were healthcare-associated, and Klebsiella pneumoniae and Pseudomonas aeruginosa were the most common pathogens. OXA was the most frequently detected carbapenemase type (71.4%). We found that carbapenems were frequently used to treat cUTI, cIAI, HABP/VABP caused by CRGN pathogens. Carbapenem use, particularly in combination with other agents, persisted after confirmation of carbapenem resistance. Clinical cure was 66.0%, mortality during hospitalization 35.0%, mortality at the time of chart review 62.0%, and 6-months-post-discharge readmission 47.7%., Conclusions: Our results reflect the high burden and unmet needs associated with the management of complicated infections attributable to CRGN pathogens in Spain and highlight the urgent need for enhanced clinical management of these difficult-to-treat infections., (©The Author 2021. Published by Sociedad Española de Quimioterapia. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)(https://creativecommons.org/licenses/by-nc/4.0/).)

Introduction: Healthcare-associated (HCA) infections represent a growing public health problem. The aim of this study was to compare community-onset healthcare associated (CO-HCA) bacteremic urinary tract infections (BUTI) and hospital-acquired (HA)-BUTI with special focus on multidrug resistances (MDR) and outcomes., Methods: ITUBRAS-project is a prospective multicenter cohort study of patients with HCA-BUTI. All consecutive hospitalized adult patients with CO-HCA-BUTI or HA-BUTI episode were included in the study. Exclusion criteria were: patients < 18 years old, non-hospitalized patients, bacteremia from another source or primary bacteremia, non-healthcare-related infections and infections caused by unusual pathogens of the urinary tract. The main outcome variable was 30-day all-cause mortality with day 1 as the first day of positive blood culture. Logistic regression was used to analyze factors associated with clinical cure at hospital discharge and with receiving inappropriate initial antibiotic treatment. Cox regression was used to evaluate 30-day all-cause mortality., Results: Four hundred forty-three episodes were included, 223 CO-HCA-BUTI. Patients with CO-HCA-BUTI were older (p < 0.001) and had more underlying diseases (p = 0.029) than those with HA-BUTI. The severity of the acute illness (Pitt score) was also higher in CO-HCA-BUTI (p = 0.026). Overall, a very high rate of MDR profiles (271/443, 61.2%) was observed, with no statistical differences between groups. In multivariable analysis, inadequate empirical treatment was associated with MDR profile (aOR 3.35; 95% CI 1.77-6.35), Pseudomonas aeruginosa (aOR 2.86; 95% CI 1.27-6.44) and Charlson index (aOR 1.11; 95% CI 1.01-1.23). Mortality was not associated with the site of acquisition of the infection or the presence of MDR profile. However, in the logistic regression analyses patients with CO-HCA-BUTI (aOR 0.61; 95% CI 0.40-0.93) were less likely to present clinical cure., Conclusion: The rate of MDR infections was worryingly high in our study. No differences in MDR rates were found between CO-HCA-BUTI and HA-BUTI, in the probability of receiving inappropriate empirical treatment or in 30-day mortality. However, CO-HCA-BUTIs were associated with worse clinical cure., (© 2021. The Author(s).)

Objective: To analyse the susceptibility to ceftolozane-tazobactam and comparators in Enterobacterales and Pseudomonas aeruginosa isolates recovered from intraabdominal (IAI), urinary (UTI), respiratory (RTI) and bloodstream infection (BSI) in the SMART (Study for Monitoring Antimicrobial Resistance Trends) study., Methods: The susceptibility of 5,351 isolates collected in 11 Spanish hospitals (2016-2018) were analysed (EUCAST-2020 criteria) by broth microdilution and were phenotypically studied for the presence of extended-spectrum beta-lactamases (ESBL). Ceftolozane-tazobactam and/or carbapenem resistant isolates were genetically characterized for ESBL and carbapenemases., Results: Escherichia coli was the most frequent pathogen (49.3% IAI, 54.9% UTI, 16.7% RTI and 50% BSI), followed by Klebsiella pneumoniae (11.9%, 19.1%, 13.1% and 15.4%, respectively). P. aeruginosa was isolated in 9.3%, 5.6%, 32% and 9%, respectively. The frequency of isolates with ESBLs (2016-2017) was: 30.5% K. pneumoniae, 8.6% E. coli, 2.3% Klebsiella oxytoca and 0.7% Proteus mirabilis. Ceftolozane-tazobactam was very active against non-ESBL-(99.3% susceptible) and ESBL-(95.2%) producing E. coli being less active against K. pneumoniae (98% and 43.1%, respectively) isolates. CTX-M-15 was the most prevalent ESBL in E. coli (27.5%) and K. pneumoniae (51.9%) frequently associated with OXA-48-like carbapenemase. Overall, 93% of P. aeruginosa isolates were susceptible to ceftolozane-tazobactam, preserving this activity (>75%) in isolates resistant to other beta-lactams except in those resistant to meropenen or ceftazidime-avibactam. GES-5, PER-1, VIM-1/2 were the most prevalent enzymes in isolates resistant to ceftolozane-tazobactam., Conclusions: Ceftolozane-tazobactam showed high activity rates against isolates recovered in the SMART study although it was affected in K. pneumoniae and P. aeruginosa isolates with ESBL and/or carbapenemases., (©The Author 2021. Published by Sociedad Española de Quimioterapia. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)(https://creativecommons.org/licenses/by-nc/4.0/).)

CrpP enzymes have been recently described as a novel ciprofloxacin-resistance mechanism. We investigated by whole genome sequencing the presence of crpP -genes and other mechanisms involved in quinolone resistance in MDR/XDR- Pseudomonas aeruginosa isolates ( n = 55) with both ceftolozane-tazobactam susceptible or resistant profiles recovered from intensive care unit patients during the STEP (Portugal) and SUPERIOR (Spain) surveillance studies. Ciprofloxacin resistance was associated with mutations in the gyrA and parC genes. Additionally, plasmid-mediated genes ( qnrS2 and aac(6')-Ib-cr ) were eventually detected. Ten chromosomal crpP-like genes contained in related pathogenicity genomic islands and 6 different CrpP (CrpP1-CrpP6) proteins were found in 65% (36/55) of the isolates. Dissemination of CrpP variants was observed among non-related clones of both countries, including the CC175 (Spain) high-risk clone and CC348 (Portugal) clone. Interestingly, 5 of 6 variants (CrpP1-CrpP5) carried missense mutations in an amino acid position (Gly7) previously defined as essential conferring ciprofloxacin resistance, and decreased ciprofloxacin susceptibility was only associated with the novel CrpP6 protein. In our collection, ciprofloxacin resistance was mainly due to chromosomal mutations in the gyrA and parC genes. However, crpP genes carrying mutations essential for protein function (G7, I26) and associated with a restored ciprofloxacin susceptibility were predominant. Despite the presence of crpP genes is not always associated with ciprofloxacin resistance, the risk of emergence of novel CrpP variants with a higher ability to affect quinolones is increasing. Furthermore, the spread of crpP genes in highly mobilizable genomic islands among related and non-related P. aeruginosa clones alert the dispersion of MDR pathogens in hospital settings.

Objectives: To analyse the epidemiology, the resistome and the virulome of ceftolozane/tazobactam-susceptible or -resistant Pseudomonas aeruginosa clinical isolates recovered from surveillance studies in Portugal (STEP, 2017-18) and Spain (SUPERIOR, 2016-17)., Methods: P. aeruginosa isolates were recovered from intra-abdominal, urinary tract and lower respiratory tract infections in ICU patients admitted to 11 Portuguese and 8 Spanish hospitals. MICs were determined (ISO-standard broth microdilution, EUCAST 2020 breakpoints). A subset of 28 ceftolozane/tazobactam-resistant P. aeruginosa isolates were analysed and compared with 28 ceftolozane/tazobactam-susceptible P. aeruginosa strains by WGS., Results: Clonal complex (CC) 235 (27%) and CC175 (18%) were the most frequent, followed by CC244 (13%), CC348 (9%), CC253 (5%) and CC309 (5%). Inter-hospital clonal dissemination was observed, limited to a geographical region (CC235, CC244, CC348 and CC253 in Portugal and CC175 and CC309 in Spain). Carbapenemases were detected in 25 isolates (45%): GES-13 (13/25); VIM type (10/25) [VIM-2 (4/10), VIM-20 (3/10), VIM-1 (2/10) and VIM-36 (1/10)]; and KPC-3 (2/25). GES-13-CC235 (13/15) and VIM type-CC175 (5/10) associations were observed. Interestingly, KPC-3 and VIM-36 producers showed ceftolozane/tazobactam-susceptible phenotypes. However, ceftolozane/tazobactam resistance was significantly associated with GES-13 and VIM-type carbapenemase production. Six non-carbapenemase producers also displayed ceftolozane/tazobactam resistance, three of them showing known ceftolozane/tazobactam resistance-associated mutations in the PBP3 gene, ftsI (R504C and F533L). Overall, an extensive virulome was identified in all P. aeruginosa isolates, particularly in carbapenemase-producing strains., Conclusions: GES-13-CC235 and VIM type-CC175 were the most frequent MDR/XDR P. aeruginosa clones causing infections in Portuguese and Spanish ICU patients, respectively. Ceftolozane/tazobactam resistance was mainly due to carbapenemase production, although mutations in PBP-encoding genes may additionally be involved., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: To analyse by WGS the ceftolozane/tazobactam (C/T) resistance mechanisms in Escherichia coli and Klebsiella spp. isolates recovered from complicated intra-abdominal and urinary tract infections in patients from Spanish ICUs (SUPERIOR surveillance study, 2016-17)., Methods: The clonal relatedness, the resistome and the virulome of 45 E. coli and 43 Klebsiella spp. isolates with different C/T susceptibility profiles were characterized., Results: In E. coli , two (C/T susceptible) carbapenemase producers (VIM-2-CC23, OXA-48-ST38) were detected. The most relevant clone was ST131-B2-O25:H4-H30 (17/45), particularly the CTX-M-15-ST131-H30-Rx sublineage (15/17). ST131 strains were mainly C/T susceptible (15/17) and showed an extensive virulome. In non-ST131 strains (28/45), CTX-M enzymes [CTX-M-14 (8/24); CTX-M-15 (6/24); CTX-M-1 (3/24); CTX-M-32 (2/24)] were found in different clones. C/T resistance was detected in non-clonal E. coli isolates (13%, 6/45) with ESBL (4/6) and non-ESBL (2/6) genotypes. Among Klebsiella spp., Klebsiella pneumoniae (42/43) and Klebsiella michiganensis (1/43) species were identified; 42% (18/43) were carbapenemase producers and 58% showed a C/T resistance phenotype (25/43). OXA-48-ST11 (12/18), OXA-48-ST392 (2/18), OXA-48-ST15 (2/18), NDM-1-ST101 (1/18) and OXA-48+VIM-2-ST15 (1/18) isolates were found, all C/T resistant. Correlation between carbapenemase detection and resistance to C/T was demonstrated ( P  < 0.001). In non-carbapenemase-producing K. pneumoniae (25/43), C/T resistance (28%, 7/25) was detected in ESBL (3/7) and AmpC (2/7) producers. Overall, an extensive virulome was found and was correlated with carbapenemase carriage ( P  < 0.001) and C/T resistance ( P  < 0.05), particularly in OXA-48-ST11 strains ( P  < 0.05)., Conclusions: Prediction of antimicrobial susceptibility profiles using WGS is challenging. Carbapenemase-encoding genes are associated with C/T resistance in K. pneumoniae , but other resistance mechanisms might be additionally involved., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.)

Patients in intensive care units (ICUs) present a high risk of developing an infection caused by multidrug-resistant bacteria. Consequently, new antimicrobials and combinations are required. In this study, the activity of ceftolozane/tazobactam (C/T) was evaluated against Enterobacterales (n = 400) and Pseudomonas aeruginosa (n = 80) clinical isolates collected from patients in Spanish ICUs with complicated urinary tract infections (cUTI) and complicated intra-abdominal infections (cIAI). Overall susceptibility to C/T in P. aeruginosa isolates by infection type was 95.7% in cUTI (MIC 50/90 , 1/4 mg/L) and 85.3% in cIAI (MIC 50/90 , 1/64 mg/L). Activity against P. aeruginosa was maintained regardless of its resistance pattern, confirming that C/T is one of the best antipseudomonal agents along with colistin and amikacin. Susceptibility to C/T in Enterobacterales by infection type was 79.5/81.9% and 89.3/92.3% (EUCAST/CLSI) in cIAI and cUTI isolates, respectively. Activity was excellent against wild-type organisms, with 100% susceptible and inhibited at MIC ≤1 mg/L. Nevertheless, C/T susceptibility decreased against extended-spectrum β-lactamase (ESBL)-producing isolates: Escherichia coli (80.4/84.8% susceptible by EUCAST/CLSI) and Klebsiella pneumoniae (59.1/77.3% susceptible by EUCAST/CLSI). No activity of C/T was observed in carbapenemase-producing isolates. The in vitro activity of C/T observed in this surveillance study suggests that this agent can be considered as a therapeutic option for cUTI and cIAI due to Enterobacterales and P. aeruginosa in ICU patients, particularly when carbapenemase-producing isolates are not involved., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: Continuous antimicrobial resistance surveillance is recommended by Public Health authorities. We up-dated data from the SMART (Study for Monitoring Antimicrobial Resistance Trends) surveillance study in Spain., Methods: The antimicrobial susceptibility data and extended-spectrum beta-lactamase (ESBL) production in isolates recovered from intra-abdominal (IAI) (n=1,429) and urinary tract (UTI) (n=937) infections during the 2016- 2017 SMART study in 10 Spanish hospitals were analysed., Results: Escherichia coli was the most frequently microorganism isolated (48.3% and 53.7%) followed by Klebsiella spp. (11.5% and 21.9%) in IAIs and UTIs, respectively. Figures for Pseudomonas aeruginosa were 9.0% and 6.1%, being more frequently recovered from patients with nosocomial infections. Overall, 9.9% (IAI) and 14.0% (UTI) of E. coli, Klebsiella spp. and Proteus mirabilis isolates were ESBL-producers, being Klebsiella pneumoniae (34.5%) from UTI of nosocomial origin the most frequent. ESBL-producers were higher in patients >60 years in both IAIs and UTIs. As in previous years, amikacin (96.3%-100% susceptibility), ertapenem (84.2%-100%) and imipenem (70.3%- 100%) were the most active antimicrobials tested among Enterobacterales species. The activity of amoxicillin-clavulanic, piperacillin-tazobactam, and ciprofloxacin susceptibility was lower, particularly among ESBL-producers. Ertapenem susceptibility (88.9%-100%) was retained in ESBL-E. coli isolates that were resistant to these antimicrobials but decreased (28.6%-100%) in similar isolates of K. pneumoniae., Conclusions: Continuous antimicrobial resistance surveillance from the SMART study reveals overall maintenance of ESBL-producers in Spain, although with higher presence in isolates from UTIs than from IAIs. Moreover, ertapenem activity was high in E. coli irrespective of ESBL production but decreased in K. pneumoniae, particularly among ESBL-producers., (©The Author 2019. Published by Sociedad Española de Quimioterapia. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)(https://creativecommons.org/licenses/by-nc/4.0/).)

The increasing rates of carbapenemase-producing Enterobacteriaceae (CPE) represent an important threat to health care systems and treatment of CPE infections is a challenge. The aim of the infection-carbapenem resistance evaluation surveillance trial (iCREST) was to determinate the prevalence of CPE in urine specimens in Spain and to evaluate the in vitro activity of ceftazidime-avibactam. Urine specimens (n = 11 826) were included and activity of ceftazidime-avibactam and comparators were investigated by broth microdilution in CPE. Carbapenemases were characterised by polymerase chain reaction (PCR) and sequencing as well as by whole genome sequencing (WGS). Overall prevalence of CPE was 1.6%. OXA-48 was the most prevalent (86.8%), followed by KPC (6.9%), VIM (4.8%), NDM (1.1%) and IMP (0.6%) carbapenemases. Klebsiella pneumoniae was the most common carbapenemase producer (87.8%). An uncommon carbapenemase type (IMP-8) in Spain was identify by WGS in an Enterobacter cloacae isolate, reinforcing the utility of surveillance programmes as effectives tools to detect unexpected genes that encode antimicrobial resistance. Ceftazidime-avibactam showed 100% susceptibility in KPC and OXA-48 producers and the rates of susceptibility in CPE non-susceptible to ceftazidime or meropenem were 92.1% and 96.9%, respectively. Ceftazidime-avibactam could be considered an adequate treatment option for urinary tract infections caused by KPC and OXA-48 producers., (Copyright © 2018 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.)

Objectives: To compare the concordance of ceftaroline MIC values by reference broth microdilution (BMD) and Etest (bioMérieux, France) for MSSA and MRSA isolates obtained from PREMIUM (D372SL00001), a European multicentre study., Methods: Ceftaroline MICs were determined by reference BMD and by Etest for 1242 MSSA and MRSA isolates collected between February and May 2012 from adult patients with community-acquired pneumonia or complicated skin and soft tissue infections; tests were performed across six European laboratories. Selected isolates with ceftaroline resistance in broth (MIC >1 mg/L) were retested in three central laboratories to confirm their behaviour., Results: Overall concordance between BMD and Etest was good, with >97% essential agreement and >95% categorical agreement. Nevertheless, 12 of the 26 MRSA isolates found resistant by BMD scored as susceptible by Etest, with MICs ≤1 mg/L, thus counting as very major errors, whereas only 5 of 380 MRSA isolates found ceftaroline susceptible in BMD were miscategorized as resistant by Etest. Twenty-one of the 26 isolates with MICs of 2 mg/L by BMD were then retested twice by each of three central laboratories: BMD MICs of 2 mg/L were consistently found for 19 of the 21 isolates. Among 147 Etest results for these 21 isolates (original plus six repeats per isolate) 112 were >1 mg/L., Conclusions: BMD and Etest have good overall agreement for ceftaroline against Staphylococcus aureus; nevertheless, reliable Etest-based discrimination of the minority of ceftaroline-resistant (MIC 2 mg/L) MRSA is extremely challenging, requiring careful reading of strips, ideally with duplicate testing., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.)

Objectives: To determine the in vitro inhibitory effect of several Gram-negative and Gram-positive microorganisms against Helicobacter pylori clinical isolates., Methods: The in vitro effect of 32 microorganisms against H. pylori clinical isolates was determined by a diffusion method. Time-kill assay was performed with two Staphylococcus spp. strains., Results: Anti-H. pylori activity was detected with Saccharomyces cerevisiae, Bacillus spp., 1 Enterococcus faecium and 2 Lactobacillus spp. against 7, 11, 1, 5 and 6 H. pylori strains tested. All Staphylococcus spp. showed an anti-H. pylori effect: one Staphylococcus auricularis and two Staphylococcus epidermidis against all H. pylori tested; Staphylococcus aureus, Staphylococcus hominis and S. auricularis against six, five and seven H. pylori strains; and two other coagulase-negative Staphylococcus against one H. pylori strain. An inhibitory effect was detected with one Escherichia coli against one H. pylori. Klebsiella pneumoniae, Salmonella spp. and Acinetobacter baumannii showed activity against four H. pylori strains, and Enterobacter cloacae and Stenotrophomonas maltophilia showed activity against 14 H. pylori isolates. No anti-H. pylori activity was detected with one Lactobacillus spp., two Lactococcus lactis, four Streptococcus spp., one Bacillus cereus, one E. faecium, one Enterococcus faecalis, one E. coli, Pseudomonas aeruginosa and Klebsiella oxytoca. Time-kill assay showed bactericidal activity at 24 h with the two Staphylococcus spp. strains tested., Conclusions: Several strains of human pathogens or commensal bacteria are able to inhibit H. pylori growth in vitro and it is a strain-dependent phenomenon.

Cardiac contusion following blunt chest trauma is not rare, and the works in the literature report incidence rates between 5 and 50%. Traffic accidents are the most frequent cause of cardiac contusion followed by violent fall impacts, aggressions and the practice of risky sports. The spectrum of post-traumatic cardiac lesions varies greatly, ranging from no symptoms to decrease in cardiac function. Cardiogenic shock is a rarely encountered manifestation of blunt cardiac contusion. We review our experience of cardiac contusion after blunt chest trauma, and we describe two very severe cases that manifested as cardiogenic shock. We emphasize an early diagnosis by continuous electrocardiographic monitoring, serial electrocardiograms, echocardiography, serum determination of biochemical cardiac markers, radionuclide imaging and coronary angiography. The treatment includes continuous monitoring of cardiac rhythm, use of inotropic drugs, insertion of a catheter in the pulmonary artery for continuous assessment of cardiac output and, in extreme cases, the insertion of a contrapulsation balloon to maintain haemodynamics until improvement of cardiac function.

Clarithromycin, amoxicillin, tetracycline and metronidazole are the most frequently used antimicrobials for Helicobacter pylori infection treatment. While tetracycline and amoxicillin resistance are rare, clarithromycin and metronidazole resistance vary in different populations and are considered factors for treatment failure. The aim of this study was to determine the in vitro activity of furazolidone and nitrofurantoin in 164 H. pylori clinical isolates by agar dilution and to determine the spontaneous mutation rate. Metronidazole and clarithromycin resistance were 23.77% (CI95%: 18.96-29.14) and 16.78% (CI95%: 12.64-21.62), respectively; moreover, 1.4% (CI95%: 0.38-3.54) were intermediate to clarithromycin. All the isolates were susceptible to amoxicillin and tetracycline. Furazolidone and nitrofurantoin resistance rates were 1.82% (CI95%: 0.37-5.25) and 0.6% (CI95%: 0-3.35), respectively. The three furazolidone-resistant strains were nitrofurantoine-susceptible (MIC 4 mg/l for furazolidone and 2 mg/l for nitrofurantoin) and the nitrofurantoin-resistant strains were furazolidone-susceptible (MIC 4 mg/l for nitrofurantoin and 1 mg/l for furazolidone). These four strains were metronidazole-resistant (MIC 16 mg/l). Furazolidone or nitrofurantoin spontaneous mutants were not detected in the eight H. pylori strains tested. However, mutants with resistance to metronidazole were found with all the strains with a mutation rate of 7.4 x 10(-10) to 9.4 x 10(-10). Furazolidone and nitrofurantoin showed an excellent in vitro activity against the H. pylori clinical isolates included herein, supporting the usefulness of furazolidone as second-line antimicrobial after treatment failure or as first-line therapy in populations with low economical resources.

Objective: Alveolar distraction osteogenesis is a relatively novel tissue regeneration technique that remains, in some respects, at an experimental stage. The selection of an experimental animal biomodel is not clearly defined, with reports in the reviewed literature on dogs, sheep, and monkeys. The present objective was to compare 2 experimental biomodels (dog and minipig) using an alveolar distraction protocol with a novel prototype distractor., Study Design: Three beagle dogs and 3 Göttingen minipigs were evaluated, placing the distractor at the right hemimandible alveolar ridge after previous extraction of premolars. The radiological examination was carried out immediately after the distraction and at 2 weeks of consolidation., Results: Satisfactory clinical and radiological results were obtained in 2 of 3 beagle dogs after the previous unilateral extraction of mandibular and maxillary premolars. During the consolidation, a height gain of approximately 5 mm was observed, with the appearance of radiodense bone trabeculae in the distraction chamber. The distraction failed in all of the minipigs., Conclusion: The minipig was not an appropriate biomodel for the study of alveolar distraction because the investigators were not able to maintain the seal of the distraction chamber or the stability of the distractor.

Gastric rupture following blunt abdominal trauma is rare, with a reported incidence of 0.02-1.7%. Road traffic accidents remain the most frequent cause. The factors most often implicated in the genesis of this entity are: a history of a recent meal, trauma to the left side of the body and an inappropriate use of seat belts. Splenic injury is generally the most common associated injury. The high morbidity and mortality are directly related to the number of associated injuries, delays in diagnosis and the development of intraabdominal sepsis. We performed a retrospective study of 1300 patients with blunt trauma to the abdomen from 1973 to 2001. Seven patients sustained a gastric rupture (five men and two women). The following associated characteristics were analysed: mechanism of injury, clinical presentation, possible associated injuries and postoperative complications, diagnosis methods and surgical treatment. We found an incidence of gastric rupture of 0.5%. We emphasise an early diagnosis and aggressive surgical treatment as a key to decreasing the mortality and morbidity from this injury. However, in our series, the morbidity is mainly from associated injuries.