Deciphering mechanisms affecting cefepime-taniborbactam in vitro activity in carbapenemase-producing Enterobacterales and carbapenem-resistant Pseudomonas spp. isolates recovered during a surveillance study in Spain.
Carbapenem-resistant Pseudomonas aeruginosa
Carbapenemase-producing Enterobacterales
Cefepime-taniborbactam resistance
Journal
European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology
ISSN: 1435-4373
Titre abrégé: Eur J Clin Microbiol Infect Dis
Pays: Germany
ID NLM: 8804297
Informations de publication
Date de publication:
02 Dec 2023
02 Dec 2023
Historique:
received:
17
08
2023
accepted:
27
10
2023
medline:
2
12
2023
pubmed:
2
12
2023
entrez:
2
12
2023
Statut:
aheadofprint
Résumé
To characterize the resistance mechanisms affecting the cefepime-taniborbactam combination in a collection of carbapenemase-producing Enterobacterales (CPE) and carbapenem-resistant Pseudomonas spp. (predominantly P. aeruginosa; CRPA) clinical isolates. CPE (n = 247) and CRPA (n = 170) isolates were prospectively collected from patients admitted to 8 Spanish hospitals. Susceptibility to cefepime-taniborbactam and comparators was determined by broth microdilution. Cefepime-taniborbactam was the most active agent, inhibiting 97.6% of CPE and 67.1% of CRPA (MICs ≤ 8/4 mg/L). All isolates with cefepime-taniborbactam MIC > 8/4 mg/L (5 CPE and 52 CRPA) and a subset with MIC ≤ 8/4 mg/L (23 CPE and 24 CRPA) were characterized by whole genome sequencing. A reduced cefepime-taniborbactam activity was found in two KPC-ST307-Klebsiella pneumoniae isolates with altered porins [KPC-62-K. pneumoniae (OmpA, OmpR/EnvZ), KPC-150-K. pneumoniae (OmpK35, OmpK36)] and one each ST133-VIM-1-Enterobacter hormaechei with altered OmpD, OmpR, and OmpC; IMP-8-ST24-Enterobacter asburiae; and NDM-5-Escherichia coli with an YRIN-inserted PBP3 and a mutated PBP2. Among the P. aeruginosa (68/76), elevated cefepime-taniborbactam MICs were mostly associated with GES-5-ST235, OXA-2+VIM-2-ST235, and OXA-2+VIM-20-ST175 isolates also carrying mutations in PBP3, efflux pump (mexR, mexZ) and AmpC (mpl) regulators, and non-carbapenemase-ST175 isolates with AmpD-T139M and PBP3-R504C mutations. Overall, accumulation of these mutations was frequently detected among non-carbapenemase producers. The reduced cefepime-taniborbactam activity among the minority of isolates with elevated cefepime-taniborbactam MICs is not only due to IMP carbapenemases but also to the accumulation of multiple resistance mechanisms, including PBP and porin mutations in CPE and chromosomal mutations leading to efflux pumps up-regulation, AmpC overexpression, and PBP modifications in P. aeruginosa.
Identifiants
pubmed: 38041722
doi: 10.1007/s10096-023-04697-4
pii: 10.1007/s10096-023-04697-4
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Instituto de Salud Carlos III
ID : CB21/13/00084
Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Références
Nordmann P, Naas T, Poirel L (2011) Global spread of carbapenemase-producing Enterobacteriaceae. Emerg Infect Dis 17:1791–1798 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3310682&tool=pmcentrez&rendertype=abstract10.3201/eid1710.110655
Horcajada JP, Montero M, Oliver A, Sorlí L, Luque S, Gómez-Zorrilla S et al (2019) Epidemiology and treatment of multidrug-resistant and extensively drug-resistant Pseudomonas aeruginosa infections. Clin Microbiol Rev 32:1–52. https://doi.org/10.1128/CMR.00031-19
doi: 10.1128/CMR.00031-19
Botelho J, Grosso F, Peixe L (2019) Antibiotic resistance in Pseudomonas aeruginosa – mechanisms, epidemiology and evolution. Drug Resist Updat 44:26–47. https://doi.org/10.1016/j.drup.2019.07.002
doi: 10.1016/j.drup.2019.07.002
Yahav D, Giske CG, Gramatniece A, Abodakpi H, Tam VH, Leibovici L (2021) New β-lactam–β-lactamase inhibitor combinations. Clin Microbiol Rev 1(34):1–61. https://doi.org/10.1128/CMR.00115-20
doi: 10.1128/CMR.00115-20
Vázquez-Ucha JC, Arca-Suárez J, Bou G, Beceiro A (2020) New carbapenemase inhibitors: clearing the way for the β-lactams. Int J Mol Sci 1(21):9308. https://doi.org/10.3390/ijms21239308
doi: 10.3390/ijms21239308
Liu B, Trout REL, Chu GH, Mcgarry D, Jackson RW, Hamrick JC et al (2020) Discovery of taniborbactam (VNRX-5133): a broad-spectrum serine- and metallo-β-lactamase inhibitor for carbapenem-resistant bacterial infections. J Med Chem 26(63):2789–2801. https://doi.org/10.1021/acs.jmedchem.9b01518
doi: 10.1021/acs.jmedchem.9b01518
Hamrick JC, Docquier J-D, Uehara T, Myers CL, Six DA, Chatwin CL et al (2020) VNRX-5133 (Taniborbactam), a broad-spectrum inhibitor of serine-and metallo-lactamases, restores activity of cefepime in Enterobacterales and Pseudomonas aeruginosa. Antimicrob Agents Chemother 64:e01963–e01919
doi: 10.1128/AAC.01963-19
pubmed: 31871094
pmcid: 7038240
Krajnc A, Brem J, Hinchliffe P, Calvopiña K, Panduwawala TD, Lang PA et al (2019) Bicyclic boronate VNRX-5133 inhibits metallo- and serine-β-lactamases. J Med Chem 26(62):8544–8556. https://doi.org/10.1021/acs.jmedchem.9b00911
doi: 10.1021/acs.jmedchem.9b00911
Hernández-García M, García-Castillo M, Ruiz-Garbajosa P, Bou G, Siller-Ruiz M, Pitart C, Gracia-Ahufinger I et al (2022) In vitro activity of cefepime-taniborbactam against carbapenemase-producing Enterobacterales and Pseudomonas aeruginosa isolates recovered in Spain. Antimicrob Agents Chemother 66(3):e0216121. https://doi.org/10.1128/aac.02161-21
Hernández-García M, García-Castillo M, García-Fernández S, Melo-Cristino J, Pinto MF, Goncalves E et al (2020) Distinct epidemiology and resistance mechanisms affecting ceftolozane / tazobactam in Pseudomonas aeruginosa isolates recovered from ICU patients in Spain and Portugal depicted by WGS. J Antimicrob Chemother 1–10. https://doi.org/10.1093/jac/dkaa430
Hernández-García M, García-fernández S, García-castillo M, Melo-Cristino J, Pinto MF, Goncalves E et al (2020) Confronting ceftolozane-tazobactam susceptibility in multidrug-resistant Enterobacterales isolates and whole-genome sequencing results (STEP study). Int J Antimicrob Agents. https://doi.org/10.1016/j.ijantimicag.2020.106259
Ondov BD, Treangen TJ, Melsted P, Mallonee AB, Bergman NH, Koren S et al (2016) Mash: fast genome and metagenome distance estimation using MinHash. Genome Biol 17:1–14. https://doi.org/10.1186/s13059-016-0997-x
doi: 10.1186/s13059-016-0997-x
Beghain J, Bridier-Nahmias A, Le NH, Denamur E, Clermont O (2018) ClermonTyping: an easy-to-use and accurate in silico method for Escherichia genus strain phylotyping. Microb Genom 4:1–8. https://doi.org/10.1099/mgen.0.000192
doi: 10.1099/mgen.0.000192
Lam MMC, Wick RR, Watts SC, Cerdeira LT, Wyres KL, Holt KE (2021) A genomic surveillance framework and genotyping tool for Klebsiella pneumoniae and its related species complex. Nat Commun 12:4188. https://doi.org/10.1038/s41467-021-24448-3
doi: 10.1038/s41467-021-24448-3
pubmed: 34234121
pmcid: 8263825
Zankari E, Allesøe R, Joensen KG, Cavaco LM, Lund O, Aarestrup FM (2017) PointFinder: a novel web tool for WGS-based detection of antimicrobial resistance associated with chromosomal point mutations in bacterial pathogens. J Antimicrob Chemother 72:2764–2768. https://doi.org/10.1093/jac/dkx217
doi: 10.1093/jac/dkx217
pubmed: 29091202
pmcid: 5890747
Tacconelli E, Carrara E, Savoldi A, Harbarth S, Mendelson M, Monnet DL et al (2018) Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect Dis 18:318–327. https://doi.org/10.1016/S1473-3099(17)30753-3
doi: 10.1016/S1473-3099(17)30753-3
pubmed: 29276051
Karlowsky JA, Hackel MA, Wise MG, Six DA, Uehara T, Daigle DM et al (2023) In vitro activity of cefepime-taniborbactam and comparators against clinical isolates of gram-negative bacilli from 2018 to 2020: results from the Global Evaluation of Antimicrobial Resistance via Surveillance (GEARS) Program. Antimicrob Agents Chemother 1:67. https://doi.org/10.1128/aac.01281-22
doi: 10.1128/aac.01281-22
Shields RK, Chen L, Cheng S, Chavda KD, Press EG (2016) Emergence of ceftazidime-avibactam resistance fue to plasmid-borne bla
doi: 10.1128/AAC.02097-16
Bianco G, Boattini M, Comini S, Iannaccone M, Bondi A, Cavallo R et al (2022) In vitro activity of cefiderocol against ceftazidime-avibactam susceptible and resistant KPC-producing Enterobacterales: cross-resistance and synergistic effects. Eur J Clin Microbiol Infect Dis 1(41):63–70. https://doi.org/10.1007/s10096-021-04341-z
doi: 10.1007/s10096-021-04341-z
Daigle D, Hamrick J, Chatwin C, Kurepina N, Kreiswirth BN, Shields RK, Oliver A, Clancy CJ, Nguyen MH, Pevear D, Xerri L (2018) Cefepime/VNRX-5133 broad-spectrum activity is maintained against emerging KPC- and PDC-variants in multidrug-resistant K. pneumoniae and P. aeruginosa. Open Forum Infect Dis Ther 5(Suppl):1
Castillo-Polo JA, Hernández-García M, Morosini MI, Pérez-Viso B, Soriano C, De Pablo R et al (2023) Outbreak by KPC-62-producing ST307 Klebsiella pneumoniae isolates resistant to ceftazidime/avibactam and cefiderocol in a university hospital in Madrid, Spain. J Antimicrob Chemother 25. https://doi.org/10.1093/jac/dkad086
Satapoomin N, Dulyayangkul P, Avison MB (2022) Klebsiella pneumoniae mutants resistant to ceftazidime- avibactam plus aztreonam, imipenem-relebactam, meropenem-vaborbactam, and cefepime-taniborbactam. Antimicrob Agents Chemother 1:66. https://doi.org/10.1128/aac.02179-21
doi: 10.1128/aac.02179-21
Alm RA, Johnstone MR, Lahiri SD (2014) Characterization of Escherichia coli NDM isolates with decreased susceptibility to aztreonam/avibactam: Role of a novel insertion in PBP3. J Antimicrob Chemother 20(70):1420–1428. https://doi.org/10.1093/jac/dku568
doi: 10.1093/jac/dku568
Sato T, Ito A, Ishioka Y, Matsumoto S, Rokushima M, Kazmierczak KM et al (2020) Escherichia coli strains possessing a four amino acid YRIN insertion in PBP3 identified as part of the SIDERO-WT-2014 surveillance study. JAC Antimicrob Resist 1:2. https://doi.org/10.1093/jacamr/dlaa081
doi: 10.1093/jacamr/dlaa081
Wang X, Zhao C, Wang Q, Wang Z, Liang X, Zhang F et al (2020) In vitro activity of the novel β-lactamase inhibitor taniborbactam (VNRX-5133), in combination with cefepime or meropenem, against MDR Gram-negative bacterial isolates from China. J Antimicrob Chemother 1(75):1850–1858. https://doi.org/10.1093/jac/dkaa053
doi: 10.1093/jac/dkaa053
Ranjitkar S, Reck F, Ke X, Zhu Q, McEnroe G, Lopez SL et al (2019) Identification of mutations in the mrdA gene encoding PBP2 that reduce carbapenem and diazabicyclooctane susceptibility of Escherichia coli clinical isolates with mutations in ftsI (PBP3) and which carry bla
doi: 10.1128/msphere.00074-19
Vázquez-Ucha JC, Lasarte-Monterrubio C, Guijarro-Sánchez P, Oviaño M, Álvarez-Fraga L, Alonso-García I et al (2022) Assessment of activity and resistance mechanisms to cefepime in combination with the novel β-lactamase inhibitors zidebactam, taniborbactam, and enmetazobactam against a multicenter collection of carbapenemase-producing Enterobacterales. Antimicrob Agents Chemother 1:66. https://doi.org/10.1128/AAC.01676-21
doi: 10.1128/AAC.01676-21
Le Terrier C, Nordmann P, Sadek M, Poirel L (2023) In vitro activity of cefepime/zidebactam and cefepime/taniborbactam against aztreonam/avibactam-resistant NDM-like-producing Escherichia coli clinical isolates. J Antimicrob Chemother 1(78):1191–1194. https://doi.org/10.1093/jac/dkad061
doi: 10.1093/jac/dkad061
Golden AR, Baxter MR, Karlowsky JA, Mataseje L, Mulvey MR, Walkty A et al (2022) Activity of cefepime/taniborbactam and comparators against whole genome sequenced ertapenem-non-susceptible Enterobacterales clinical isolates: CANWARD 2007-19. JAC Antimicrob Resist 1:4. https://doi.org/10.1093/jacamr/dlab197
doi: 10.1093/jacamr/dlab197
Le Terrier C, Nordmann P, Freret C, Seigneur M, Poirel L (2023) Impact of acquired broad spectrum b-lactamases on susceptibility to novel combinations made of β-lactams (aztreonam, cefepime, meropenem, and imipenem) and novel β-lactamase inhibitors in Escherichia coli and Pseudomonas aeruginosa. Antimicrob Agents Chemother 1:67. https://doi.org/10.1128/aac.00339-23
doi: 10.1128/aac.00339-23
Lasarte-Monterrubio C, Fraile-Ribot PA, Vázquez-Ucha JC, Cabot G, Guijarro-Sánchez P, Alonso-García I et al (2022) Activity of cefiderocol, imipenem/relebactam, cefepime/taniborbactam and cefepime/zidebactam against ceftolozane/tazobactam- and ceftazidime/avibactam-resistant Pseudomonas aeruginosa. J Antimicrob Chemother 1(77):2809–2815. https://doi.org/10.1093/jac/dkac241
doi: 10.1093/jac/dkac241
Pérez-Vázquez M, Sola-Campoy PJ, Zurita ÁM, Ávila A, Gómez-Bertomeu F, Solís S et al (2020) Carbapenemase-producing Pseudomonas aeruginosa in Spain: interregional dissemination of the high-risk clones ST175 and ST244 carrying bla
Hernández-García M, García-Castillo M, Melo-Cristino J, Pinto MF, Gonçalves E, Alves V et al (2022) In vitro activity of imipenem/relebactam against Pseudomonas aeruginosa isolates recovered from ICU patients in Spain and Portugal (SUPERIOR and STEP studies). J Antimicrob Chemother 1(77):3163–3172. https://doi.org/10.1093/jac/dkac298
doi: 10.1093/jac/dkac298
López-Causapé C, Cabot G, del Barrio-Tofiño E, Oliver A (2018) The versatile mutational resistome of Pseudomonas aeruginosa. Front Microbiol 6:9. https://doi.org/10.3389/fmicb.2018.00685
doi: 10.3389/fmicb.2018.00685