Tackling the unyielding: testing two novel approaches against NDM-producing Enterobacterales and Pseudomonas aeruginosa isolates collected in India
ABSTRACT The in vitro activity of two novel antibiotics with different modes of action, (i) siderophore cefiderocol and (ii) β-lactam-enhancer mechanism-based cefepime/zidebactam, was tested against New Delhi Metallo-β-lactamase (NDM)-producing Enterobacterales and Pseudomonas aeruginosa collected i...
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American Society for Microbiology
2025-01-01
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| Series: | Microbiology Spectrum |
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| Online Access: | https://journals.asm.org/doi/10.1128/spectrum.00497-24 |
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| author | Yamuna Devi Bakthavatchalam Bijayini Behera Anand Shah Purva Mathur Raja Ray Bashir Ahmed Fomda Kamini Walia Balaji Veeraraghavan |
| author_facet | Yamuna Devi Bakthavatchalam Bijayini Behera Anand Shah Purva Mathur Raja Ray Bashir Ahmed Fomda Kamini Walia Balaji Veeraraghavan |
| author_sort | Yamuna Devi Bakthavatchalam |
| collection | DOAJ |
| description | ABSTRACT The in vitro activity of two novel antibiotics with different modes of action, (i) siderophore cefiderocol and (ii) β-lactam-enhancer mechanism-based cefepime/zidebactam, was tested against New Delhi Metallo-β-lactamase (NDM)-producing Enterobacterales and Pseudomonas aeruginosa collected in India. Minimum inhibitory concentrations of antibiotics against multicentric NDM-producing Escherichia coli (n = 117), Klebsiella pneumoniae (n = 103), and P. aeruginosa (n = 72) were determined by the reference broth microdilution method. Among E. coli, 111 isolates were NDM-alone, and six were NDM + OXA-48-like producers. Among K. pneumoniae, 47 and 56 isolates were NDM-alone and NDM + OXA-48-like producers, respectively. All E. coli isolates harbored four amino acid inserts in their penicillin-binding protein 3. Using the highest susceptible breakpoint among CLSI, FDA, and EUCAST interpretive criteria, cefiderocol susceptibility was 39.3%, ≤80%, and 57%, for NDM ± OXA-48-like-producing E. coli, NDM ± OXA-48-like-producing K. pneumoniae, and NDM-producing P. aeruginosa, respectively. At a cefepime break point of ≤8 mg/L, 100% of Enterobacterales and ≥90% of P. aeruginosa isolates were cefepime/zidebactam-susceptible. NDM being a dominant carbapenemase among Enterobacterales and P. aeruginosa in India, the variable activity of cefiderocol against NDM producers is a concern. Post approval, cefepime/zidebactam could offer a promising treatment option against NDM producers.IMPORTANCEMetallo-β-lactamases are therapeutically challenging due to the limited treatment options. Against such isolates, currently approved newer β-lactam/β-lactamase inhibitor combinations are ineffective. In this study, we tested siderophore cephalosporin, cefiderocol, which utilizes an unconventional iron uptake pathway for efficient cellular penetration, and cefepime/zidebactam that utilizes novel β-lactam enhancer mechanisms for overcoming diverse carbapenemases. Cefiderocol showed limited activity against Escherichia coli isolates co-harboring New Delhi metallo-β-lactamase (NDM) with PBP3 insert, dual carbapenemase (NDM with OXA-48 like)-producing Klebsiella pneumoniae, and NDM-producing Pseudomonas aeruginosa isolates, while cefepime/zidebactam potently inhibited NDM-producing Enterobacterales and P. aeruginosa isolates. NDM being a dominant carbapenemase among Enterobacterales and P. aeruginosa in India, the variable activity of cefiderocol against NDM producers is a concern. Post approval, cefepime/zidebactam could offer a promising treatment option against NDM producers. |
| format | Article |
| id | doaj-art-cf74ab7f841347cf91e695f2721d726d |
| institution | Kabale University |
| issn | 2165-0497 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | American Society for Microbiology |
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| series | Microbiology Spectrum |
| spelling | doaj-art-cf74ab7f841347cf91e695f2721d726d2025-01-07T14:05:18ZengAmerican Society for MicrobiologyMicrobiology Spectrum2165-04972025-01-0113110.1128/spectrum.00497-24Tackling the unyielding: testing two novel approaches against NDM-producing Enterobacterales and Pseudomonas aeruginosa isolates collected in IndiaYamuna Devi Bakthavatchalam0Bijayini Behera1Anand Shah2Purva Mathur3Raja Ray4Bashir Ahmed Fomda5Kamini Walia6Balaji Veeraraghavan7Department of Clinical Microbiology, Christian Medical College, Vellore, Tamil Nadu, IndiaDepartment of Microbiology, All India Institute of Medical Sciences, Bhubaneswar, Odisha, IndiaDepartment of Microbiology, Zydus Hospitals, Ahmedabad, Gujarat, IndiaDepartment of Clinical Microbiology, All India Institute of Medical Sciences, New Delhi, IndiaDepartment of Microbiology, Institute of Post Graduate Medical Education and Research, Kolkata, IndiaDepartment of Microbiology, Sher-i-Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, IndiaDivision of Epidemiology and Communicable Diseases, Indian Council of Medical Research, New Delhi, IndiaDepartment of Clinical Microbiology, Christian Medical College, Vellore, Tamil Nadu, IndiaABSTRACT The in vitro activity of two novel antibiotics with different modes of action, (i) siderophore cefiderocol and (ii) β-lactam-enhancer mechanism-based cefepime/zidebactam, was tested against New Delhi Metallo-β-lactamase (NDM)-producing Enterobacterales and Pseudomonas aeruginosa collected in India. Minimum inhibitory concentrations of antibiotics against multicentric NDM-producing Escherichia coli (n = 117), Klebsiella pneumoniae (n = 103), and P. aeruginosa (n = 72) were determined by the reference broth microdilution method. Among E. coli, 111 isolates were NDM-alone, and six were NDM + OXA-48-like producers. Among K. pneumoniae, 47 and 56 isolates were NDM-alone and NDM + OXA-48-like producers, respectively. All E. coli isolates harbored four amino acid inserts in their penicillin-binding protein 3. Using the highest susceptible breakpoint among CLSI, FDA, and EUCAST interpretive criteria, cefiderocol susceptibility was 39.3%, ≤80%, and 57%, for NDM ± OXA-48-like-producing E. coli, NDM ± OXA-48-like-producing K. pneumoniae, and NDM-producing P. aeruginosa, respectively. At a cefepime break point of ≤8 mg/L, 100% of Enterobacterales and ≥90% of P. aeruginosa isolates were cefepime/zidebactam-susceptible. NDM being a dominant carbapenemase among Enterobacterales and P. aeruginosa in India, the variable activity of cefiderocol against NDM producers is a concern. Post approval, cefepime/zidebactam could offer a promising treatment option against NDM producers.IMPORTANCEMetallo-β-lactamases are therapeutically challenging due to the limited treatment options. Against such isolates, currently approved newer β-lactam/β-lactamase inhibitor combinations are ineffective. In this study, we tested siderophore cephalosporin, cefiderocol, which utilizes an unconventional iron uptake pathway for efficient cellular penetration, and cefepime/zidebactam that utilizes novel β-lactam enhancer mechanisms for overcoming diverse carbapenemases. Cefiderocol showed limited activity against Escherichia coli isolates co-harboring New Delhi metallo-β-lactamase (NDM) with PBP3 insert, dual carbapenemase (NDM with OXA-48 like)-producing Klebsiella pneumoniae, and NDM-producing Pseudomonas aeruginosa isolates, while cefepime/zidebactam potently inhibited NDM-producing Enterobacterales and P. aeruginosa isolates. NDM being a dominant carbapenemase among Enterobacterales and P. aeruginosa in India, the variable activity of cefiderocol against NDM producers is a concern. Post approval, cefepime/zidebactam could offer a promising treatment option against NDM producers.https://journals.asm.org/doi/10.1128/spectrum.00497-24cefiderocolcefepime/zidebactamNDMIndia |
| spellingShingle | Yamuna Devi Bakthavatchalam Bijayini Behera Anand Shah Purva Mathur Raja Ray Bashir Ahmed Fomda Kamini Walia Balaji Veeraraghavan Tackling the unyielding: testing two novel approaches against NDM-producing Enterobacterales and Pseudomonas aeruginosa isolates collected in India Microbiology Spectrum cefiderocol cefepime/zidebactam NDM India |
| title | Tackling the unyielding: testing two novel approaches against NDM-producing Enterobacterales and Pseudomonas aeruginosa isolates collected in India |
| title_full | Tackling the unyielding: testing two novel approaches against NDM-producing Enterobacterales and Pseudomonas aeruginosa isolates collected in India |
| title_fullStr | Tackling the unyielding: testing two novel approaches against NDM-producing Enterobacterales and Pseudomonas aeruginosa isolates collected in India |
| title_full_unstemmed | Tackling the unyielding: testing two novel approaches against NDM-producing Enterobacterales and Pseudomonas aeruginosa isolates collected in India |
| title_short | Tackling the unyielding: testing two novel approaches against NDM-producing Enterobacterales and Pseudomonas aeruginosa isolates collected in India |
| title_sort | tackling the unyielding testing two novel approaches against ndm producing enterobacterales and pseudomonas aeruginosa isolates collected in india |
| topic | cefiderocol cefepime/zidebactam NDM India |
| url | https://journals.asm.org/doi/10.1128/spectrum.00497-24 |
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