Study on antimicrobial resistance profile and <i>in vitro</i> bactericidal assays of aztreonam combined with avibactam for carbapenem-resistant <i>Enterobacter</i> spp._West China Medical Journal

Authors：

WU Shikai ¹ , XIAO Yuling ² , WEI Li ³ , HE Yanling ¹ , WANG Chengcheng ¹ , WU Wenjing ⁴ , WEN Hongxia ⁵ , LIU Lu ⁶ , TANG Guangmin ¹ ,  ZONG Zhiyong ^1,5

1. Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
2. Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
3. Department of Infection Control, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
4. Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
5. Center for Pathogen Research, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
6. Division of Pediatric Infectious Diseases, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

ZONG Zhiyong, Email: zongzhiy@scu.edu.cn

Keywords：

Carbapenem-resistance; Enterobacter spp.; colistin; aztreonam; avibactam

DOI：

10.7507/1002-0179.202301099

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Objective To investigate antimicrobial resistance profiles of carbapenem-resistant Enterobacter spp. (CREn) and the bactericidal effects of aztreonam combined with avibactam. Methods The CREn strains isolated from the West China Hospital of Sichuan University between 2016 and 2021 were identified by gyrB gene amplification and subsequent sequencing. The drug sensitivity results, sample types and distribution of relevant patient departments of these strains were summarized. Colistin-resistant and -intermediate strains were selected to carry out the bactericidal test of colistin and aztreonam combined with avibactam. Results A total of 110 clinical strains of CREn were included. The most common strain was Enterobacter xiangfangensis (91 strains), the highest proportion was in the intensive care unit (27.27%), and the proportion of respiratory tract samples was more than 40%. The antimicrobial sensitivity results showed that CREns were all resistant to carbapenems, the resistance rate to colistin was 23.64%, and the resistance rate to aztreonam combined with avibactam was 0. Among other antimicrobial agents, the antimicrobial resistance rate of amikacin and tigecycline were less than 10%. The time-kill curve showed that for colistin-intermediate strains, colistin could achieve bactericidal effect in a shorter time than aztreonam combined with avibactam. However, whether the strain was resistant to colistin or not, the bactericidal rate of 2 μg/mL aztreonam combined with avibactam in 24 hours could exceed 99%. Conclusion CREn is resistant to most commonly used clinical antibacterial drugs, but remains sensitive to aztreonam combined with avibactam, and aztreonam combined with avibactam has bactericidal effect on it.

Citation： WU Shikai, XIAO Yuling, WEI Li, HE Yanling, WANG Chengcheng, WU Wenjing, WEN Hongxia, LIU Lu, TANG Guangmin, ZONG Zhiyong. Study on antimicrobial resistance profile and in vitro bactericidal assays of aztreonam combined with avibactam for carbapenem-resistant Enterobacter spp.. West China Medical Journal, 2023, 38(3): 364-369. doi: 10.7507/1002-0179.202301099 Copy

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2.	Nordmann P, Poirel L. Epidemiology and diagnostics of carbapenem resistance in Gram-negative bacteria. Clin Infect Dis, 2019, 69(Suppl 7): S521-S528.
3.	Zong Z, Feng Y, McNally A. Carbapenem and colistin resistance in Enterobacter: determinants and clones. Trends Microbiol, 2021, 29(6): 473-476.
4.	Tooke CL, Hinchliffe P, Bragginton EC, et al. β-lactamases and β-lactamase inhibitors in the 21st century. J Mol Biol, 2019, 431(18): 3472-3500.
5.	Lohans CT, Brem J, Schofield CJ. New Delhi metallo-β-lactamase 1 catalyzes avibactam and aztreonam hydrolysis. Antimicrob Agents Chemother, 2017, 61(12): e01224-17.
6.	Ehmann DE, Jahic H, Ross PL, et al. Kinetics of avibactam inhibition against class A, C, and D β-lactamases. J Biol Chem, 2013, 288(39): 27960-27971.
7.	Mendes RE, Doyle TB, Streit JM, et al. Investigation of mechanisms responsible for decreased susceptibility of aztreonam/avibactam activity in clinical isolates of Enterobacterales collected in Europe, Asia and Latin America in 2019. J Antimicrob Chemother, 2021, 76(11): 2833-2838.
8.	Yamamoto S, Harayama S. PCR amplification and direct sequencing of gyrB genes with universal primers and their application to the detection and taxonomic analysis of Pseudomonas putida strains. Appl Environ Microbiol, 1995, 61(3): 1104-1109.
9.	Delmas J, Breysse F, Devulder G, et al. Rapid identification of Enterobacteriaceae by sequencing DNA gyrase subunit B encoding gene. Diagn Microbiol Infect Dis, 2006, 55(4): 263-268.
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14.	Fan Y, Li Y, Chen Y, et al. Pharmacokinetics and pharmacodynamics of colistin methanesulfonate in healthy chinese subjects after multi-dose regimen. Antibiotics (Basel), 2022, 11(6): 798.
15.	Davin-Regli A, Lavigne JP, Pagès JM. Enterobacter spp. : update on taxonomy, clinical aspects, and emerging antimicrobial resistance. Clin Microbiol Rev, 2019, 32(4): e00002-19.
16.	Wang Q, Wang X, Wang J, et al. Phenotypic and genotypic characterization of carbapenem-resistant Enterobacteriaceae: data from a longitudinal large-scale CRE study in China (2012-2016). Clin Infect Dis, 2018, 67(Suppl 2): S196-S205.
17.	Zhang R, Liu L, Zhou H, et al. Nationwide surveillance of clinical carbapenem-resistant Enterobacteriaceae (CRE) strains in China. EBioMedicine, 2017, 19: 98-106.
18.	Cai Y, Chen C, Zhao M, et al. High prevalence of metallo-β-lactamase-producing Enterobacter cloacae from three tertiary hospitals in China. Front Microbiol, 2019, 10: 1610.
19.	Paul M, Carrara E, Retamar P, 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, 2022, 28(4): 521-547.
20.	Tamma PD, Aitken SL, Bonomo RA, et al. Infectious Diseases Society of America guidance on the treatment of extended-spectrum β-lactamase producing Enterobacterales (ESBL-E), carbapenem-resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with difficult-to-treat resistance (DTR-P.aeruginosa). Clin Infect Dis, 2021, 72(7): 1109-1116.
21.	Sader HS, Carvalhaes CG, Arends SJR, et al. Aztreonam/avibactam activity against clinical isolates of Enterobacterales collected in Europe, Asia and Latin America in 2019. J Antimicrob Chemother, 2021, 76(3): 659-666.
22.	Wang X, Zhang F, Zhao C, et al. In vitro activities of ceftazidime-avibactam and aztreonam-avibactam against 372 Gram-negative bacilli collected in 2011 and 2012 from 11 teaching hospitals in China. Antimicrob Agents Chemother, 2014, 58(3): 1774-1778.
23.	Mauri C, Maraolo AE, Di Bella S, et al. 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 (Basel), 2021, 10(8): 1012.
24.	Bocanegra-Ibarias P, Camacho-Ortiz A, Garza-González E, et al. Aztreonam plus ceftazidime-avibactam as treatment of NDM-1-producing Klebsiella pneumoniae bacteraemia in a neutropenic patient: last resort therapy?. J Glob Antimicrob Resist, 2020, 23: 417-419.
25.	Hong YK, Lee JY, Ko KS. Colistin resistance in Enterobacter spp. isolates in Korea. J Microbiol, 2018, 56(6): 435-440.
26.	Ma K, Feng Y, McNally A, et al. Struggle to survive: the choir of target alteration, hydrolyzing enzyme, and plasmid expression as a novel aztreonam-avibactam resistance mechanism. mSystems, 2020, 5(6): e00821-20.
27.	Satapoomin N, Dulyayangkul P, Avison MB. Klebsiella pneumoniae mutants resistant to ceftazidime-avibactam plus aztreonam, imipenem-relebactam, meropenem-vaborbactam, and cefepime-taniborbactam. Antimicrob Agents Chemother, 2022, 66(4): e0217921.

1. Doi Y. Treatment options for carbapenem-resistant Gram-negative bacterial infections. Clin Infect Dis, 2019, 69(Suppl 7): S565-S575.
2. Nordmann P, Poirel L. Epidemiology and diagnostics of carbapenem resistance in Gram-negative bacteria. Clin Infect Dis, 2019, 69(Suppl 7): S521-S528.
3. Zong Z, Feng Y, McNally A. Carbapenem and colistin resistance in Enterobacter: determinants and clones. Trends Microbiol, 2021, 29(6): 473-476.
4. Tooke CL, Hinchliffe P, Bragginton EC, et al. β-lactamases and β-lactamase inhibitors in the 21st century. J Mol Biol, 2019, 431(18): 3472-3500.
5. Lohans CT, Brem J, Schofield CJ. New Delhi metallo-β-lactamase 1 catalyzes avibactam and aztreonam hydrolysis. Antimicrob Agents Chemother, 2017, 61(12): e01224-17.
6. Ehmann DE, Jahic H, Ross PL, et al. Kinetics of avibactam inhibition against class A, C, and D β-lactamases. J Biol Chem, 2013, 288(39): 27960-27971.
7. Mendes RE, Doyle TB, Streit JM, et al. Investigation of mechanisms responsible for decreased susceptibility of aztreonam/avibactam activity in clinical isolates of Enterobacterales collected in Europe, Asia and Latin America in 2019. J Antimicrob Chemother, 2021, 76(11): 2833-2838.
8. Yamamoto S, Harayama S. PCR amplification and direct sequencing of gyrB genes with universal primers and their application to the detection and taxonomic analysis of Pseudomonas putida strains. Appl Environ Microbiol, 1995, 61(3): 1104-1109.
9. Delmas J, Breysse F, Devulder G, et al. Rapid identification of Enterobacteriaceae by sequencing DNA gyrase subunit B encoding gene. Diagn Microbiol Infect Dis, 2006, 55(4): 263-268.
10. Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing; thirtieth informational supplement. M100-S30. Wayne: Clinical and Laboratory Standards Institute, 2022.
11. Clinical and laboratory Standards Institute. Methods for determining bactericidal activity of antimicrobial agents; approved guideline. M26-A. Wayne: Clinical and laboratory Standards Institute, 1999.
12. Wu S, Zong Z. Aztreonam-avibactam: an option against carbapenem-resistant Enterobacterales with emerging resistance. Precis Clin Med, 2022, 5(4): pbac029.
13. 孙玥, 郑永贵, 隗志翔, 等. 头孢他啶-阿维巴坦对肠杆菌科细菌和铜绿假单胞菌的体外杀菌活性研究. 中国感染与化疗杂志, 2021, 21(3): 314-318.
14. Fan Y, Li Y, Chen Y, et al. Pharmacokinetics and pharmacodynamics of colistin methanesulfonate in healthy chinese subjects after multi-dose regimen. Antibiotics (Basel), 2022, 11(6): 798.
15. Davin-Regli A, Lavigne JP, Pagès JM. Enterobacter spp. : update on taxonomy, clinical aspects, and emerging antimicrobial resistance. Clin Microbiol Rev, 2019, 32(4): e00002-19.
16. Wang Q, Wang X, Wang J, et al. Phenotypic and genotypic characterization of carbapenem-resistant Enterobacteriaceae: data from a longitudinal large-scale CRE study in China (2012-2016). Clin Infect Dis, 2018, 67(Suppl 2): S196-S205.
17. Zhang R, Liu L, Zhou H, et al. Nationwide surveillance of clinical carbapenem-resistant Enterobacteriaceae (CRE) strains in China. EBioMedicine, 2017, 19: 98-106.
18. Cai Y, Chen C, Zhao M, et al. High prevalence of metallo-β-lactamase-producing Enterobacter cloacae from three tertiary hospitals in China. Front Microbiol, 2019, 10: 1610.
19. Paul M, Carrara E, Retamar P, 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, 2022, 28(4): 521-547.
20. Tamma PD, Aitken SL, Bonomo RA, et al. Infectious Diseases Society of America guidance on the treatment of extended-spectrum β-lactamase producing Enterobacterales (ESBL-E), carbapenem-resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with difficult-to-treat resistance (DTR-P.aeruginosa). Clin Infect Dis, 2021, 72(7): 1109-1116.
21. Sader HS, Carvalhaes CG, Arends SJR, et al. Aztreonam/avibactam activity against clinical isolates of Enterobacterales collected in Europe, Asia and Latin America in 2019. J Antimicrob Chemother, 2021, 76(3): 659-666.
22. Wang X, Zhang F, Zhao C, et al. In vitro activities of ceftazidime-avibactam and aztreonam-avibactam against 372 Gram-negative bacilli collected in 2011 and 2012 from 11 teaching hospitals in China. Antimicrob Agents Chemother, 2014, 58(3): 1774-1778.
23. Mauri C, Maraolo AE, Di Bella S, et al. 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 (Basel), 2021, 10(8): 1012.
24. Bocanegra-Ibarias P, Camacho-Ortiz A, Garza-González E, et al. Aztreonam plus ceftazidime-avibactam as treatment of NDM-1-producing Klebsiella pneumoniae bacteraemia in a neutropenic patient: last resort therapy?. J Glob Antimicrob Resist, 2020, 23: 417-419.
25. Hong YK, Lee JY, Ko KS. Colistin resistance in Enterobacter spp. isolates in Korea. J Microbiol, 2018, 56(6): 435-440.
26. Ma K, Feng Y, McNally A, et al. Struggle to survive: the choir of target alteration, hydrolyzing enzyme, and plasmid expression as a novel aztreonam-avibactam resistance mechanism. mSystems, 2020, 5(6): e00821-20.
27. Satapoomin N, Dulyayangkul P, Avison MB. Klebsiella pneumoniae mutants resistant to ceftazidime-avibactam plus aztreonam, imipenem-relebactam, meropenem-vaborbactam, and cefepime-taniborbactam. Antimicrob Agents Chemother, 2022, 66(4): e0217921.

West China Medical Journal

Study on antimicrobial resistance profile and in vitro bactericidal assays of aztreonam combined with avibactam for carbapenem-resistant Enterobacter spp.

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