Activity of Cefepime, Carbapenems and New β-lactam/β-lactamase Inhibitor Combinations on Enterobacter Cloacae Complex and Klebsiella Aerogenes in Spain (SMART 2016–2022)

Activity of cefepime, carbapenems and new β-lactam/β-lactamase inhibitor combinations on Enterobacter cloacae complex and Klebsiella aerogenes in Spain (SMART 2016–2022) Ángel Rodríguez-Villodres 1,2,3 *, Esperanza Lepe-Balsalobre 4 , José Manuel Ortiz De La Rosa 1,2,3 , Salvador Giner Almaraz 5 , Elisa González De Herrero 3,6 , Emilia Cercenado 7,8 , Sergio García-Fernández 3,9 , Rafael Benito 10 , Ricardo Ponz Mir 11 , Rafael Cantón 3,12 and José Antonio Lepe 1,2,3,13 1 Clinical Unit of Infectious Diseases, Microbiology and Parasitology, University Hospital Virgen del Rocío, Seville, Spain; 2 Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain; 3 Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain; 4 Servicio de Laboratorio, Hospital de Riotinto, Huelva, Spain; 5 Servicio de Microbiología, Hospital Universitari y Politécnic La Fe, Valencia, Spain; 6 Servicio de Microbiología, Hospital Son Espases, IdISBa, CIBERINFEC, Palma de Mallorca, Mallorca, Spain; 7 Servicio de Microbiología Clínica y Enfermedades Infecciosas, Hospital Universitario Gregorio Marañón, Madrid, Spain; 8 Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain; 9 Servicio de Microbiología, Hospital Universitario Marqués de Valdecilla-IDIVAL, Santander, Spain; 10 Hospital Clínico Universitario Lozano Blesa, Zaragoza, Departamento de Microbiología, Universidad de Zaragoza, Instituto de Investigación Sanitaria de Aragón, Zaragoza, Spain; 11 Departamento Médico, MSD, Madrid, Spain; 12 Servicio de Microbilogía, Hospital Universitario Ramón y Cajal and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain; 13 Department of Microbiology, University of Seville, Seville, Spain *Corresponding author. E-mail: [email protected] @1797Angel Received 4 March 2024; accepted 15 May 2024 Objectives: To analyse the susceptibility profile to cefepime, carbapenems and new β-lactam/β-lactamase inhibitor combinations in Enterobacter cloacae complex and Klebsiella aerogenes isolated from intra-abdominal, urinary, respiratory and bloodstream infections in the SMART (Study for Monitoring Antimicrobial Resistance Trends) surveillance study in Spain. Methods: The susceptibilities of 759 isolates (473 E. cloacae complex and 286 K. aerogenes) collected in 11 Spanish hospitals from 2016 to 2022 were analysed following the EUCAST 2023 criteria. Molecular characterization looking for β-lactamase genes was performed through PCR and DNA sequencing analysis. Results: E. cloacae complex showed resistance to third-generation cephalosporins in 25% of the cases, whereas K. aerogenes was resistant in 35%. Regarding cefepime, resistance in E. cloacae was higher (10%) than in K. aerogenes (2%). Carbapenems showed >85% activity in both microorganisms. Ceftazidime/avibactam, imipenem/relebactam and meropenem/vaborbactam had good activity against these microorganisms (>95%). In contrast, the activity of ceftolozane/tazobactam was lower (80%). A high proportion of the isolates resistant to new β-lactam/β-lactamase inhibitor combinations carried a carbapenemase, mainly OXA-48-like and VIM-1. Conclusions: Ceftazidime/avibactam, imipenem/relebactam and meropenem/vaborbactam show high activity against both E. cloacae complex and K. aerogenes isolates recovered in the SMART-Spain study. In contrast, differences have been found in the case of cefepime, showing more activity against K. aerogenes than E. cloacae complex. These results are useful for antimicrobial stewardship programmes and for the implementation of local and national guidelines. © The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/ by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction Antimicrobial resistance is a major problem worldwide. A recent study has estimated that there were 4.95 million deaths associated with bacterial antimicrobial resistance (AMR), in 2019 alone. 1 Of these, 1.27 million deaths were attributable directly to AMR. Another study from the ECDC estimated that, in 2015, there were 671 689 infections by MDR bacteria, causing 33 000 deaths. 2 1 of 6 JAC Antimicrob Resist https://doi.org/10.1093/jacamr/dlae087 JAC- Antimicrobial Resistance Downloaded from https://academic.oup.com/jacamr/article/6/3/dlae087/7688594 by guest on 15 October 2024 Remarkably, more than 50% were healthcare-related infections. These types of infections have a major clinical impact because they affect patients with severe comorbidities, in which management is difficult, increasing mortality. 3 In this sense, surveillance programmes can help to develop antimicrobial stewardship programmes, inform treatment decisions, guide national and local policies and clinical guidelines, and direct efforts to develop new treatment options, improving the clinical outcome of the patients. 4 The Study for Monitoring Antimicrobial Resistance Trends (SMART) is one of the largest and longest-standing AMR surveillance programmes. It has been operating since 2002, monitoring trends of antimicrobial susceptibility of aerobic and facultative Gram-negative bacilli from intra-abdominal infections, urinary tract infections, lowerrespiratory tract infections and bloodstream infections. 4,5 In recent years, Enterobacter species and Klebsiella aerogenes (formerly Enterobacter aerogenes) have acquired relevance among the microorganisms causing healthcare-related infections due to their ability to develop AMR. 6 The presence of an inducible chromosomal AmpC β-lactamase confers extended resistance to third-generation cephalosporins (such as ceftazidime, ceftriaxone or cefotaxime) and piperacillin/tazobactam, when it is overexpressed, limiting the therapeutic options for patients. 7 Cefepime is the antibiotic of choice to treat infections caused by these type of microorganisms because of its low ability to induce AmpC β-lactamases. 8 Carbapenems also are considered to treat infections by these microorganisms. 8 The IDSA recommends using carbapenems when MICs of cefepime are higher than 2 mg/L due to the high risk of co-producing an ESBL enzyme. 8 However, some studies have reported resistance to both cefepime and carbapenems in E. cloacae and K. aerogenes. 9–11 New β-lactam/β-lactamase inhibitor combinations, such as ceftazidime/avibactam, imipenem/relebactam or meropenem/vaborbactam, also could be alternative options for the treatment of Enterobacter spp. and/or K. aerogenes infections, especially when they are hyperproducing AmpC and exhibit carbapenem resistance that is not due to MBLs. 8 Despite these recommendations, there are few recent studies monitoring the activity of these antibiotics against Enterobacter spp. and K. aerogenes. 12,13 In this study, we analysed the susceptibility trend to cefepime, carbapenems and new β-lactam/ β-lactamase inhibitor combinations in Enterobacter spp. and K. aerogenes during a 7 year period (2016–2022), focusing also on the molecular profile associated with resistance to these antibiotics. Material and methods Bacterial isolates and antimicrobial susceptibility testing Clinical isolates of E. cloacae complex and K. aerogenes were recovered at 11 Spanish hospitals from 2016 to 2022. Isolates were subsequently shipped to a central laboratory (IHMA, Schaumburg, IL, USA) for identification by MALDI-TOF and antimicrobial susceptibility testing (AST) by broth microdilution, following the standard ISO recommendations. The following antibiotics were tested: piperacillin/tazobactam, ceftazidime, ceftriaxone, cefepime, ertapenem, imipenem, meropenem, ceftolozane/tazobactam, ceftazidime/avibactam, imipenem/relebactam and meropenem/ vaborbactam. The EUCAST 2023 clinical breakpoints were used to analyse the susceptibility/resistance criteria. To see if there is a trend in the susceptibility profile over the years, we ran a weighted least squares analysis accounting for serial data autocorrelation with Joinpoint Regression v.5.1.0. (Statistical Methodology and Applications Branch, Surveillance Research Program, National Cancer Institute, USA). The time trends for each variable were analysed to find whether the slope significantly increased or decreased over time, or on the contrary, stayed steady over time, which indicates no significant differences among all the annual data in the series. We used a first-order autocorrelation parameter estimated from the data with a permutation test as the model selection method. 14 Molecular characterization Molecular testing was also centralized at IHMA and included all the isolates resistant to at least one of the following antibiotics: imipenem, imipenem/relebactam or ceftolozane/tazobactam. Molecular testing consisted of screening the following β-lactamase genes through PCR and DNA sequencing: class A ESBLs (TEM, SHV, CTX-M, VEB, PER and GES); class C plasmid AmpC (ACC, ACT, CMY, DHA, FOX, MIR and MOX) and carbapenemases (KPC, GES, NDM, IMP, VIM, GIM, SPM and OXA-48-like), as previously described. 15,16 Results Clinical isolates features A total of 759 isolates encompassing 473 (62.3%) E. cloacae complex and 286 (37.7%) K. aerogenes were included in the study. These microorganisms were isolated mainly from respiratory samples (n = 366), followed by intra-abdominal (n = 182), blood (n = 76) and urinary tract (n = 63) (Table S1, available as Supplementary data at JAC-AMR Online). Susceptibility profile to classic antibiotics Table 1shows the susceptibility profile of both microorganisms. Around 75% of the E. cloacae complex and 65% of the K. aerogenes isolates were susceptible to third-generation cephalosporins and piperacillin/tazobactam (Table 1). Regarding cefepime, there were notable differences between the microorganisms, despite it having good activity against both: E. cloacae complex remained less susceptible (90%) than K. aerogenes (98%). Overall, carbapenems (ertapenem, imipenem and meropenem) showed very good activity (>90%) whereas ertapenem activity was lower (86%) for E. cloacae complex (Table 1). Activity of new β-lactam/β-lactamase inhibitor combinations Ceftazidime/avibactam, imipenem/relebactam and meropenem/ vaborbactam showed good activity against E. cloacae complex and K. aerogenes clinical isolates (>95%). Furthermore, this activity had remained stable over recent years (Table 1). In contrast, ceftolozane/tazobactam had less activity against both genera of microorganisms (around 80%). Rodríguez-Villodres et al. 2 of 6 Downloaded from https://academic.oup.com/jacamr/article/6/3/dlae087/7688594 by guest on 15 October 2024 Molecular characterization E. cloacae complex The molecular resistance profile for the E. cloacae complex is presented in Table 2. In summary, 47 of the 473 isolates (10%) were resistant to cefepime. Of these, 26 (55.3%) harboured a carbapenemase gene, 3 (6.4%) an ESBL gene, and another 3 (6.4%) a combination of an ESBL plus a plasmidic AmpC β-lactamase. In the remaining isolates (n = 15, 31.9%) no β-lactamases were found, except for the chromosomal ampC gene encoding the AmpC β-lactamase, characteristic of these microorganisms. Eighteen isolates showed resistance to imipenem and 23 to meropenem. Among these, one and one isolates, respectively, did not carry any carbapenemase gene (Table 2). Regarding new β-lactam/β-lactamase inhibitor combinations, a total of 10, 16 and 7 isolates were resistant to ceftazidime/ avibactam, imipenem/relebactam and meropenem/vaborbactam, respectively. The molecular analysis revealed that only one of these isolates carried a bla ACT-type instead of a carbapenemase gene. The main carbapenemase found in these isolates was VIM-1 (n = 11) followed by OXA-48-like (n = 5) (Table 2). On the other hand, 91 isolates (19.2%) were resistant to ceftolozane/tazobactam, of which 32 isolates (35%) harboured an ACT-type or a plasmidic AmpC β-lactamase (MIR-type), 31 isolates (34%) harboured a carbapenemase and 6 isolates harboured an ESBL gene (Table 2). Regarding the remaining 22 isolates, no β-lactamase genes were found except the chromosomal bla ACT . K. aerogenes In the case of K. aerogenes only 5 of the 286 isolates (1.7%) showed resistance to cefepime. Of these, one isolate carried a plasmidic ampC gene, one isolate an NDM carbapenemase, and three isolates did not carry any acquired β-lactamase (Table 3). Ten isolates were resistant to imipenem and seven resistant to meropenem. Regarding new β-lactam/β-lactamase inhibitor combinations, all the isolates were susceptible to meropenem/vaborbactam, two isolates were resistant to imipenem/relebactam and only one was resistant to ceftazidime/avibactam (Table 3). Of these three isolates, only one carried a carbapenemase (NDM). On the other hand, 48 isolates (16.8%) were resistant to ceftolozane/tazobactam, of which only 7 isolates (14.5%) harboured a plasmidic AmpC β-lactamase (MIR-type) and 2 (4.1%) harboured a carbapenemase (Table 3). In the remaining 39 isolates only the chromosomal AmpC β-lactamase gene was found. Discussion In this study, we reported data from the SMART surveillance study in Spain that focused on the activity of cefepime, carbapenems Table 1. Weighted least squares regression trend analysis of the percent susceptibility profile in Enterobacter cloacae complex and Klebsiella aerogenes % Susceptibility Microorganism Year Number of isolates TZP CAZ CRO FEP ETP IPM MEM C/T CZA IPM/ REL MEM/ VAB Enterobacter cloacae 2016 117 69 65 63 90 83 97 98 79 —99 — 2017 54 77 75 72 84 85 94 99 79 —94 — 2018 70 81 77 74 93 87 95 95 85 100 95 — 2019 66 72 66 65 91 84 97 97 80 97 98 98 2020 44 68 65 59 89 81 93 93 77 95 93 97 2021 43 69 65 65 93 81 97 97 74 100 97 100 2022 79 82 82 81 91 90 95 94 84 95 95 98 Total 473 75 75 72 90 86 97 97 81 97 97 97 Trend slope (SE) 1.16 (1.08) 1.33 (1.17) 1.91 (1.27) 0.66 (0.28) 0.63 (0.50) 0.08 (0.10) −0.64 (0.35) −0.27 (0.69) −0.39 (0.55) −0.14 (0.25) 0.67 (0.22) P value 0.332 0.304 0.192 0.068 0.261 0.487 0.127 0.714 0.532 0.604 0.091 Klebsiella aerogenes 2016 58 69 65 67 100 98 100 100 86 —100 — 2017 40 72 65 67 95 95 95 95 85 —95 — 2018 28 57 53 64 100 100 100 100 82 100 100 — 2019 37 64 64 62 100 91 94 97 78 100 100 100 2020 41 58 56 56 95 85 92 95 75 100 100 100 2021 52 57 57 57 100 94 94 94 82 98 100 100 2022 30 80 73 73 97 96 100 100 93 100 100 100 Total 286 65 68 64 98 94 91 99 83 99 99 100 Trend slope (SE) −0.19 (1.55) 0.13 (1.08) −0.35 (1.23) 0.01 (0.27) −0.82 (0.95) −0.42 (0.60) −0.34 (0.35) 0.68 (1.46) −0.36 (0.15) 0.49 (0.22) 0.00 (0.00) P value 0.907 0.91 0.785 0.975 0.426 0.509 0.365 0.663 0.095 0.077 0.99 CAZ, ceftazidime; CRO, ceftriaxone; C/T, ceftolozane/tazobactam; CZA, ceftazidime/avibactam; ETP, ertapenem; FEP, cefepime; IPM, imipenem; IPM/REL, imipenem/relebactam; MEM, meropenem; MEM/VAB, meropenem/vaborbactam; SE, standard error; TZP, piperacillin/tazobactam. Antimicrobial activity in Enterobacter spp. and K. aerogenes 3 of 6 Downloaded from https://academic.oup.com/jacamr/article/6/3/dlae087/7688594 by guest on 15 October 2024 and new β-lactam/β-lactamase inhibitor combinations against Enterobacter spp. and K. aerogenes. Around 25% of the E. cloacae complex and around 35% of the K. aerogenes were resistant to third-generation cephalosporins. These data for E. cloacae complex are similar to those reported previously (24.3%), although they are slightly higher than those reported for K. aerogenes (23.3%). 17 These resistance percentages have undergone variations over the years for both microorganisms, but without any clear trend (P > 0.05) (Table 1). Regarding cefepime, differences have been observed among both kinds of microorganisms, with E. cloacae complex being more resistant than K. aerogenes (10% versus 2%). When the molecular characterization was performed, 15 of 47 (32%) cefepime-resistant E. cloacae isolates did not carry any β-lactamase, except for the chromosomal AmpC, suggesting that cefepime resistance also could be mediated by this β-lactamase or by another non-enzymatic mechanism, such as porin loss, as has been previously reported. 9,18,19 Resistance to carbapenems was variable (1%–14%) in E. cloacae complex and K. aerogenes isolates, with meropenem being the most active carbapenem in both microorganisms (Table 1). Molecular characterization found the presence of at least one Table 2. Molecular profiles associated with resistant isolates of Enterobacter cloacae Microorganism Total isolates (n) FEP IPM MEM C/T CZA IPM/REL MEM/VAB Enterobacter cloacae 473 47 18 22 91 10 16 7 cAmpC (variants) ACT-type 32 3 1 1 30 0 0 1 pAmpC MIR-type 4 0 0 0 2 0 0 0 ESBL CTX-M/SHV-ESBL 5 3 0 0 3 0 0 0 ESBL + AmpC CTX-M + ACT/MIR-type 3 3 0 0 3 0 0 0 Carbapenemases OXA-48 3 0 0 1 2 0 0 0 AmpC + carbapenemases P AmpC/ACT-type + OXA48 5 0 1 2 3 0 1 0 P AmpC/ACT-type + VIM-1 1 1 1 1 1 1 1 1 ESBL + carbapenemases CTX-M + OXA-48 5 5 3 2 5 0 2 0 CTX-M + GES-6 1 1 0 0 1 0 0 0 CTX-M/SHV-BLEE + VIM-1 5 5 5 5 5 2 5 5 AmpC + ESBL + carbapenemases P AmpC/ACT-type + CTX-M + OXA-48 7 7 1 4 7 ND 1 ND P AmpC/ACT-type + CTX-M + VIM-1 6 6 5 5 6 6 5 0 P AmpC/ACT-type + CTX-M + VIM-1 + OXA-48 1 1 1 1 1 1 1 0 cAmpC, chromosomal AmpC; C/T, ceftolozane/tazobactam; CZA, ceftazidime/avibactam; FEP, cefepime; IPM, imipenem; IPM/REL, imipenem/relebactam; MEM, meropenem; MEM/VAB, meropenem/vaborbactam; ND, not determined; pAmpC, plasmidic AmpC. Table 3. Molecular profiles associated with resistant isolates of Klebsiella aerogenes Microorganism Total isolates (n) FEP IPM MEM C/T CZA IPM/REL MEM/VAB Klebsiella aerogenes 286 5 10 7 48 1 2 0 cAmpC (variants) ACT-type 1 0 0 0 1 0 0 0 pAmpC MIR-type 7 1 1 0 7 0 0 0 AmpC + carbapenemases P AmpC + NDM 1 1 1 1 1 ND 1 ND ESBL + carbapenemases CTX-M + OXA-48 1 0 0 0 1 0 0 0 cAmpC, chromosomal AmpC; C/T, ceftolozane/tazobactam; CZA, ceftazidime/avibactam; FEP, cefepime; IPM, imipenem; IPM/REL, imipenem/relebactam; MEM, meropenem; MEM/VAB, meropenem/vaborbactam; ND, not determined; pAmpC, plasmidic AmpC. Rodríguez-Villodres et al. 4 of 6 Downloaded from https://academic.oup.com/jacamr/article/6/3/dlae087/7688594 by guest on 15 October 2024 carbapenemase in most of them. A recent study has reported a worrying increase in carbapenemase-producing E. cloacae in the south of Spain from 2014 to 2022. 20 However, based on our data we did not observe an increase in the carbapenem resistance percentage. This apparent discrepancy may be due to this increment occurring only in Andalusia, and not in the rest of the country, from where a large proportion of our data was collected. Finally, resistance to new β-lactam/β-lactamase inhibitor combinations in E. cloacae complex and K. aerogenes was low in general, except for ceftolozane/tazobactam (Table 1). It is known that ceftolozane/tazobactam has lower activity in E. cloacae complex and K. aerogenes when AmpC β-lactamase is hyperproduced. 13 This is because tazobactam inhibits AmpC β-lactamases less efficiently. 8 In the case of ceftazidime/avibactam, only 11 of 759 isolates (1.4%) (10 E. cloacae complex and 1 K. aerogenes) showed resistance, of which all except 2 (1 E. cloacae and 1 K. aerogenes) carried a VIM-1 carbapenemase (Tables 2and 3). The remaining two isolates did not carry any acquired β-lactamase, except the chromosomal AmpC. Resistance to ceftazidime/avibactam mediated by AmpC β-lactamases has been reported previously, but only in one study with one isolate from a patient treated with cefepime. 21 Further studies are therefore needed to determine whether this β-lactamase is involved in resistance to this antibiotic. For imipenem/relebactam and meropenem/vaborbactam the situation was similar to ceftazidime/avibactam. From 18 (2.3%) isolates resistant to imipenem/relebactam and from 7 isolates resistant to meropenem/vaborbactam, only 1 K. aerogenes and 1 E. cloacae complex isolate, respectively, did not have any carbapenemase gene. Thus, ceftazidime/avibactam, imipenem/ relebactam and meropenem/vaborbactam showed high activity in those isolates that do not carry any carbapenemase. Resistance to ceftazidime/avibactam not due to carbapenemases has already been reported in E. cloacae. 22,23 This resistance was mainly associated with one or more amino acid deletions in helix H10 of the AmpC β-lactamase. However, to our knowledge, there are no studies describing the associated resistance mechanisms to imipenem/relebactam and meropenem/vaborbactam. Further studies are therefore needed to clarify this issue. This study has one main limitation, i.e the molecular characterization was based on resistance to only three antibiotics (imipenem, imipenem/relebactam or ceftolozane/tazobactam), which may underestimate the real number of carbapenemaseproducer strains. In conclusion, there are differences in the microbiological characteristics between E. cloacae complex and K. aerogenes. In general, E. cloacae complex shows a more resistant profile than K. aerogenes, especially with cefepime. However, ceftazidime/ avibactam, imipenem/relebactam and meropenem/vaborbactam combinations have high activity against both microorganisms. More studies are necessary to analyse the molecular mechanisms that drive resistance to these antibiotics. Acknowledgements We thank MSD Spain and IHMA (International Health Management Associates, S.A., Schaumburg, IL, USA) for providing access to the database of the SMART epidemiological surveillance study and microbiological data. Funding The SMART surveillance programme is sponsored by MSD. Writing of this manuscript has been performed through a contract of services between MSD Spain and Fundación Pública Andaluza para la Gestion de la Investigación de Sevilla (FISEVI). A.R.-V. is supported by the Subprograma Juan Rodés, Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spain (JR20/00023). Transparency declarations A.R.-V. has participated in educational programmes organized by Pfizer. E.C. has participated in educational programmes organized by MSD, Pfizer and Shionogi and had a research project funded by MSD and Shionogi. R.C. has participated in educational programmes organized by Menarini, MSD and Pfizer and has had research projects funded by MSD and Shionogi. All other authors: none to declare. Supplementary data Table S1 is available as Supplementary data at JAC-AMR Online. 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