IN VITRO SUSCEPTIBILITY PROFILES OF FTOLOZANE–TAZOBACTAM AND CEFTAZIDIME–AVIBACTAM AGAINST AMPC/ ESBL PRODUCING ENTEROBACTERIACEAE
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Abstract
Background: Antimicrobial resistance (AMR) among Gram-negative bacteria (GNB)—especially those producing AmpC β-lactamases and Extended-Spectrum Beta-Lactamases (ESBLs)—represents a major threat to global public health. These resistant organisms significantly limit available treatment options and contribute to increased morbidity and mortality. The study examined and compared the in vitro susceptibility profiles of carbapenem-sensitive ESBL- and AmpC-producing Enterobacteriaceae isolates against two newer β-lactam/β-lactamase inhibitor combinations.
Methods: Seventy-eight non-repetitive bacterial isolates were procured from clinical settings. Routine conventional microbiological methods were used for identification of all isolates. Kirby–Bauer disc diffusion (KBDD) method was used for antimicrobial susceptibility testing. Molecular detection of the blaNDM-1 gene was done through Polymerase Chain Reaction (PCR) for carbapenem-resistant isolates. The minimum inhibitory concentrations for C/A and C/T were established by E-tests. Data was analyzed using SPSS version 17.0 with P-value of <0.05 was considered statistically significant.
Results: The study included 78 patients (51 male, 27 female), with swab (43) being the most common sample type. Isolates comprised 34 Escherichia coli (E. coli) and 38 Klebsiella pneumonia (K. pneumonia). C/A demonstrated statistically superior overall activity against E. coli (88.2% susceptible) compared to C/T (79.4% susceptible) (P = 0.004). Similarly, against K. pneumoniae, C/A showed higher susceptibility (57.9%) than C/T (50.0%) (P = 0.049). When stratified by phenotype, both C/A and C/T demonstrated 100% in vitro susceptibility against ESBL-producing E. coli. C/A demonstrated significantly higher susceptibility against AMPc-producing E. coli (50% vs. 33.3%; P = 0.008) and AMPc-producing K. pneumoniae (52.6% vs. 21.1%; P = 0.338). For ESBL+AMPc co-producers, C/A showed 94.4% susceptibility against E. coli and 85.7% against K. pneumoniae, generally outperforming C/T. Overall, C/A showed 52% susceptibility against AMPc-producing isolates compared to 24% for C/T (P = 0.007). Notably, C/T exhibited better activity against NDM Negative isolates (58.3% susceptible) than C/A (8.3% susceptible).
Conclusion: Compared to C/T, C/A showed superior activity against E. coli and K. pneumoniae, particularly in isolates producing AmpC β-lactamase. While both agents were highly effective against ESBL producers, C/A consistently showed higher susceptibility rates across various categories, with a notable exception for NDM Negative isolates where C/T was more active. The findings emphasize the need for region-specific susceptibility data to optimize empirical and definitive therapy against MDR GRB.
References
2. Yezli S, Shibl AM, Memish ZA. The molecular basis of b-lactamase production in Gram-negative bacteria from Saudi Arabia. J Med Microbiol 2015;64(2):127–36.
3. Paterson DL, Bonomo RA. Extended-spectrum -lactamases: a clin- ical update. Clin Microbiol Rev. 2005 Oct 1;18(4):657–686.
4. Isler, B., Ezure, Y., Romero, J., Harris, P., Stewart, A. G., & Paterson, D. (2020). Is Ceftazidime/Avibactam an Option for Serious Infections Due Due to Extended-Spectrum-β-Lactamase- and AmpC-Producing Enterobacterales?: a Systematic Review and Meta-analysis. Antimicrobial Agents and Chemotherapy, 65.
5. Jacoby GA. AmpC beta-lactamases. Clin Microbiol Rev. 2009;22(1):161–82 Table of Contents.
6. Lee J. H., Bae I. K., Lee S. H. (2012). New definitions of extended-spectrum beta-lactamase conferring worldwide emerging antibiotic resistance. Med. Res. Rev. 32, 216–232. 10.1002/med.20210.
7. Bush K., Jacoby G. A. (2010). Updated functional classification of beta-lactamases. Antimicrob. Agents Chemother. 54, 969–976. 10.1128/AAC.01009-09.
8. Bradford PA. Extended-spectrum beta-lactamases in the 21st century: characterization, epidemiology, and detection of this important resistance threat. Clin Microbiol Rev. 2001 Oct;14 (4):933–951.
9. Goodlet KJ, Nicolau DP, Nailor MD. Ceftolozane/tazobactam and ceftazidime/avibactam for the treatment of complicated intra-abdominal infections. Ther Clin Risk Manag 2016;12:1811–26.
10. van Duin D , Bonomo R. Ceftazidime/avibactam and ceftolozane/tazobactam: second generation β-lactam/β-lactamase inhibitor combinations. Clin Infect Dis 2016; 63: 234–41.
11. Ehman D , Jahić H, Ross P, Gu R, Hu J, Durand-Réville T, et al. Kinetics of avibactam inhibition against class A, C, and D β-lactamases. J Bio Chem 2013; 288: 27960–71.
12. Hidalgo J , Viluan C, Antony N. Ceftazidime/avibactam: a novel cephalosporin/nonbeta-lactam beta-lactamase inhibitor for the treatment of complicated urinary tract infections and complicated intra-abdominal infections. Drug Des Dev Ther 2016; 10: 2379–86.
13. Moyá B , Zamorano L, Juan C, Ge Y, Oliver A. Affinity of the New Cephalosporin CXA-101 to penicillin-binding proteins of Pseudomonas aeruginosa. Antimicrob Agents Chemother 2010; 54: 3933–7.
14. Schaumberg F , Bletz S, Mellmann A, Becker K, Idelevich E. Susceptibility of MDR Pseudomonas aeruginosa to ceftolozane/tazobactam and comparison of different susceptibility testing methods. J Antimicrob Chemother 2017; 72: 3079–84.
15. Hong, M.C.; Hsu, D.I.; Bounthavong, M. Ceftolozane/tazobactam: A novel antipseudomonal cephalosporin and β-lactamase-inhibitor combination. Infect. Drug Resist. 2013 , 29 , 215–223.
16. Giacobbe, D.R.; Mikulska, M.; Viscoli, C. Recent advances in the pharmacological management of infections due to multidrug-resistant Gram-negative bacteria. Expert Rev. Clin. Pharmacol. 2018 , 11 , 1219–1236.
17. Giacobbe DR, Bassetti M, De Rosa FG, Del Bono V, Grossi PA, Menichetti F, Pea F, Rossolini GM, Tumbarello M, Viale P, Viscoli C. Ceftolozane/tazobactam: place in therapy. Expert review of anti-infective therapy. 2018 Apr 3;16(4):307-20.
18. Koulenti, D.; Song, A.; Ellingboe, A.; Abdul-Aziz, M.H.; Harris, P.; Gavey, E.; Lipman, J. Infections by multidrug-resistant Gram-negative Bacteria: What’s new in our arsenal and what’s in the pipeline? Int. J. Antimicrob. Agents 2019 , 53 , 211–224.
19. Ho, S.; Nguyen, L.; Trinh, T.; MacDougall, C. Recognizing and Overcoming Resistance to New Beta-Lactam/Beta-Lactamase Inhibitor Combinations. Curr. Infect. Dis. Rep. 2019 , 9 , 39.
20. Lagacé-Wiens, P.; Walkty, A.; Karlowsky, J.A. Ceftazidime-avibactam: An evidence-based review of its pharmacology and potential use in the treatment of Gram-negative bacterial infections. Core Evid. 2014 , 9 , 13–25.
21. Liscio JL, Mahoney MV, Hirsch EB. Ceftolozane/tazobactam and ceftazidime/ avibactam: two novel beta-lactam/beta-lactamase inhibitor combination agents for the treatment of resistant Gram-negative bacterial infections. Int J Antimicrob Agents 2015;46:266–71.
22. Karlowsky, J. A., Kazmierczak, K. M., Young, K., Motyl, M. R., & Sahm, D. F. (2019). In vitro activity of ceftolozane/tazobactam against phenotypically defined extended-spectrum β-lactamase (ESBL)-positive isolates of Escherichia coli and Klebsiella pneumoniae isolated from hospitalized patients (SMART 2016). Diagnostic Microbiology & Infectious Disease, 96(4), 114925.
23. Popejoy, M., Paterson, D., Cloutier, D. J., Huntington, J. A., Miller, B., Bliss, C., Steenbergen, J., Hershberger, E., Umeh, O., & Kaye, K. (2017). Efficacy of ceftolozane/tazobactam against urinary tract and intra-abdominal infections caused by ESBL-producing Escherichia coli and Klebsiella pneumoniae: a pooled analysis of Phase 3 clinical trials. Journal of Antimicrobial Chemotherapy, 72, 268–272.
24. Jonge, B. D. d., Karlowsky, J., Kazmierczak, K., Biedenbach, D., Sahm, D., & Nichols, W. (2016). In Vitro Susceptibility to Ceftazidime-Avibactam of Carbapenem-Nonsusceptible Enterobacteriaceae Isolates Collected during the INFORM Global Surveillance Study (2012 to 2014). Antimicrobial Agents and Chemotherapy, 60, 3163-3169.
25. Sader, H., Castanheira, M., Shortridge, D., Mendes, R., & Flamm, R. (2017). Antimicrobial Activity of Ceftazidime-Avibactam Tested against Multidrug-Resistant Enterobacteriaceae and Pseudomonas aeruginosa Isolates from U.S. Medical Centers, 2013 to 2016. Antimicrobial Agents and Chemotherapy, 61.
26. Livermore, D., Mushtaq, S., Doumith, M., Jamrozy, D., Nichols, W., & Woodford, N. (2018). Selection of mutants with resistance or diminished susceptibility to ceftazidime/avibactam from ESBL- and AmpC-producing Enterobacteriaceae. Journal of Antimicrobial Chemotherapy, 73, 3336–334
27. Nordmann P, Poirel L, Carrër A, Toleman MA, Walsh TR. How to detect NDM-1 producers. Journal of clinical microbiology. 2011 Feb;49(2):718-21.
28. Mushtaq, S., Garello, P., Vickers, A., Woodford, N., & Livermore, D. M. (2021). Cefepime/tazobactam compared with other tazobactam combinations against problem Gram-negative bacteria. International Journal of Antimicrobial Agents, 57(5), 106318.
29. Gupta, V., Singh, M., Datta, P., Goel, A., Singh, S., Prasad, K., & Chander, J. (2020). Detection of various beta-lactamases in Escherichia coli and Klebsiella sp.: A study from Tertiary Care Centre of North India. Indian Journal of Medical Microbiology, 38(3-4), 390–396.
30. Rahim Khorasani, M., Rostami, S., Bakhshi, A., & Sheikhi, R. (2023). Global evaluation of the antibacterial activity of Ceftolozane/Tazobactam against ESBLs-producing Escherichia coli and Klebsiella pneumoniae: a systematic review and meta-analysis. Therapeutic Advances in Infectious Disease, 10, 1–14.
31. Bakthavatchalam, Y. D., Routray, A., Mane, A., Kamat, S., Gupta, A., Barid, A. K., Rohit, A., Poojary, A., Mukherjee, D. N., Sethuraman, N., Munshi, N., Shah, S., Balaji, V., & Gupta, Y. (2022). In vitro activity of Ceftazidime-Avibactam and its comparators against Carbapenem resistant Enterobacterales collected across India: results from ATLAS surveillance 2018 to 2019. Diagnostic Microbiology and Infectious Disease, 103(2), 115652.
32. Carvalho, T. N., Kobs, V. C., Hille, D., Deglmann, R. C., Melo, L. H., & de França, P. H. C. (2023). Evaluation of in-vitro susceptibility of β-lactam-resistant Gram-negative bacilli to ceftazidime-avibactam and ceftolozane-tazobactam from clinical samples of a general hospital in southern Brazil. Revista da Sociedade Brasileira de Medicina Tropical, 56, e0277-2022.
33. Singh, S., Sahu, C., Patel, S. S., Singh, A., & Yaduvanshi, N. (2020). A Comparative In Vitro Sensitivity Study of “Ceftriaxone-Sulbactam-EDTA” and Various Antibiotics against Gram-negative Bacterial Isolates from Intensive Care Unit. Indian Journal of Critical Care Medicine, 24(12), 1213–1217.
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Dr.Surbhi Kansal
Assistant Professor (Microbiology), Rajshree medical college, Barielly.
Mainsha Jain
Professor, (Microbiology), GB PANT INSTITUTE of postgraduate medical education and research (GPIMER), Delhi.
