The state of the problem of developing combined antibacterial agents relating to bacterial pathogens of critical priority level (review of foreign literature data)

This review, based on data from international literature, is devoted to assessing the current state of development of combination antibacterial agents (ABAs) against bacterial pathogens of critical priority. Literature sources were searched in electronic databases such as PubMed, Google Scholar, and SpringerLink.

In May 2024, the World Health Organization published an updated “List of Priority Bacterial Pathogens”, which includes 15 families of antibiotic-resistant bacteria divided into groups of critical, high, and medium priority. Bacterial pathogens of critical priority, including gram-negative bacteria resistant to last-resort β-lactam antibiotics, occupy a special place in this list. These include Acinetobacter baumannii, which is resistant to carbapenems, and Enterobacterales, which are resistant to third-generation cephalosporins and carbapenems. Additionally, rifampicin-resistant Mycobacterium tuberculosis is classified as a pathogen of critical priority.

It has been established that between May 2017 and December 2023, four combination ABAs were approved by foreign regulatory authorities (cephalosporin Fetroja, carbapenems Vabomere and Recarbrio, and the combination agent Xacduro). Two drugs (Fetroja and Xacduro) are active against carbapenem-resistant A. baumannii; three drugs (Fetroja, Vabomere, and Recarbrio) are active against carbapenem-resistant Enterobacterales. For infections caused by Enterobacterales resistant to third-generation cephalosporins and M. tuberculosis resistant to rifamycins, new combination ABAs have not yet been introduced into clinical practice.

Fifteen combination ABAs are currently undergoing clinical trials at various phases (Phase III — six ABAs, Phase II — one ABA, Phase I — eight ABAs). Among the developer countries, the USA is the leader (eight ABAs), followed by Japan (six ABAs). Additional development efforts are underway in China, India, France, Germany, Italy, and Canada.

Contribution:
Alimov А.V. — edition;
Nogovitsyna L.V. — design of the study, data processing, writing the text;
Cherkashina N.V. — concept of the study, edition;
Kolchanova N.V. — collection of materials, data processing;
Kotel′nikov R.V. — collection of materials;
Zakharova Yu.A. — edition.
All co-authors — approval of the final version of the article, responsibility for the integrity of all parts of the article.

Funding source. This study was not supported by any external sources of funding.

Conflict of interest. The authors declare no apparent or potential conflicts of interest related to the publication of this article.

Received: 10.01.2026 / Accepted: 20.03.2026 / Published: 10.04.2026

1. WHO. Bacterial Priority Pathogens List, 2024: bacterial pathogens of public health importance to guide research, development and strategies to prevent and control antimicrobial resistance; 2024. Available at: https://who.int/publications/i/item/9789240093461

2. WHO. 2023 Antibacterial agents in clinical and preclinical development: an overview and analysis; 2024. Available at: https://who.int/publications/i/item/9789240094000

3. Butler M.S., Paterson D.L. Antibiotics in the clinical pipeline in October 2019. J. Antibiot. (Tokyo). 2020; 73(6): 329–64. https://doi.org/10.1038/s41429-020-0291-8

4. Theuretzbacher U., Bush K., Harbarth S., et al. Critical analysis of antibacterial agents in clinical development. Nat. Rev. Microbiol. 2020; 18(5): 286–98. https://doi.org/10.1038/s41579-020-0340-0

5. Butler M.S., Henderson I.R., Capon R.J., Blaskovich M.A.T. Antibiotics in the clinical pipeline as of December 2022. J. Antibiot. (Tokyo). 2023; 76(8): 431–73. https://doi.org/10.1038/s41429-023-00629-8

6. Shionogi. FETROJA® (cefiderocol) approved by the FDA for treatment of complicated urinary tract infections (cUTI) in adult patients with limited or no alternative treatment options. Press Release; 2019. Available at: https://shionogi.com/us/en/news/2019/11/fetroja-cefiderocol-approved-by-the-fda-for-treatment-of-complicated-urinary-tract-infections-cuti-in-adult-patients-with-limited-or-no-alternative-treatment-options.html

7. Pulmonology Advisor. Park B. Cefiderocol approved for hospital-acquired, ventilator-associated bacterial pneumonia; 2020. Available at: https://pulmonologyadvisor.com/news/fetroja-cefiderocol-approved-hospital-acquired-bacterial-pneumonia-bacterial-pneumonia/

8. Sato T., Yamawaki K. Cefiderocol: discovery, chemistry, and in vivo profiles of a novel siderophore cephalosporin. Clin. Infect. Dis. 2019; 69(Suppl. 7): S538–43. https://doi.org/10.1093/cid/ciz826

9. Karakonstantis S., Rousaki M., Vassilopoulou L., Kritsotakis E.I. Global prevalence of cefiderocol non-susceptibility in Enterobacterales, Pseudomonas aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia: а systematic review and meta-analysis. Clin. Microbiol. Infect. 2024; 30(2): 178–88. https://doi.org/10.1016/j.cmi.2023.08.029

10. Niño-Vega G.A., Ortiz-Ramírez J.A., López-Romero E. Novel antibacterial approaches and therapeutic strategies. Antibiotics (Basel). 2025; 14(4): 404. https://doi.org/10.3390/antibiotics14040404

11. Kaye K.S., Belley A., Barth P., et al. Effect of cefepime/enmetazobactam vs piperacillin/tazobactam on clinical cure and microbiological eradication in patients with complicated urinary tract infection or acute pyelonephritis: а randomized clinical trial. JAMA. 2022; 328(13): 1304–14. https://doi.org/10.1001/jama.2022.17034

12. Meletiadis J., Paranos P., Georgiou P.C., et al. In vitro comparative activity of the new beta-lactamase inhibitor taniborbactam with cefepime or meropenem against Klebsiella pneumoniae and cefepime against Pseudomonas aeruginosa metallo-beta-lactamase-producing clinical isolates. Int. J. Antimicrob. Agents. 2021; 58(5): 106440. https://doi.org/10.1016/j.ijantimicag.2021.106440

13. Roach E.J., Uehara T., Daigle D.M., et al. The next-generation β-lactamase inhibitor taniborbactam restores the morphological effects of cefepime in KPC-producing Escherichia coli. Microbiol. Spectr. 2021; 9(2): e0091821. https://doi.org/10.1128/Spectrum.00918-21

14. Hernández-García M., García-Castillo M., Ruiz-Garbajosa P., et al. In vitro activity of cefepime-taniborbactam against carbapenemase-producing Enterobacterales and Pseudomonas aeruginosa isolates recovered in Spain. Antimicrob. Agents Chemother. 2022; 66(3): e0216121. https://doi.org/10.1128/aac.02161-21

15. Moya B., Barcelo I.M., Bhagwat S., et al. Potent β-lactam enhancer activity of zidebactam and WCK 5153 against Acinetobacter baumannii, including carbapenemase-producing clinical isolates. Antimicrob. Agents Chemother. 2017; 61(11): e01238-17. https://doi.org/10.1128/aac.01238-17

16. Sader H.S., Mendes R.E., Duncan L.R., et al. Antimicrobial activity of cefepime/zidebactam (WCK 5222), a β-lactam/β-lactam enhancer combination, against clinical isolates of Gram-negative bacteria collected worldwide (2018–19). J. Antimicrob. Chemother. 2022; 77(10): 2642–9. https://doi.org/10.1093/jac/dkac233

17. Guo Y., Han R., Jiang B., et al. In vitro activity of new β-lactam–β-lactamase inhibitor combinations and comparators against clinical isolates of Gram-negative bacilli: Results from the China Antimicrobial Surveillance Network (CHINET) in 2019. Microbiol. Spectr. 2022; 10(4): e0185422. https://doi.org/10.1128/spectrum.01854-22

18. Durand-Réville T.F., Comita-Prevoir J., Zhang J., et al. Discovery of an orally available diazabicyclooctane inhibitor (ETX0282) of class A, C, and D serine β-lactamases. J. Med. Chem. 2020; 63(21): 12511–25. https://doi.org/10.1021/acs.jmedchem.0c00579

19. Miller A.A., Shapiro A.B., McLeod S.M., et al. In Vitro characterization of ETX1317, a broad-spectrum β-lactamase inhibitor that restores and enhances β-lactam activity against multi-drug-resistant Enterobacteriales, including carbapenem-resistant strains. ACS Infect. Dis. 2020; 6(6): 1389–97. https://doi.org/10.1021/acsinfecdis.0c00020

20. Duncan L.R., Rhomberg P.R., Mendes R.E., et al. Ceftibuten-avibactam activity against β-lactam-resistant Enterobacterales clinical isolates. ASM Microbe; 2019. Available at: https://jmilabs.com/data/posters/ASM-Microbe19-ceftibuten-avibactam.pdf

21. Karlowsky J.A., Hackel M.A., Sahm D.F. In vitro activity of ceftibuten/VNRX-5236 against urinary tract infection isolates of antimicrobial-resistant Enterobacterales. Antimicrob. Agents Chemother. 2022; 66(1): e0130421. https://doi.org/10.1128/aac.01304-21

22. Chatwin C.L., Hamrick J.C., Trout R.E.L., et al. Microbiological characterization of VNRX5236, a broad-spectrum β-lactamase inhibitor for rescue of the orally bioavailable cephalosporin ceftibuten as a carbapenemsparing agent against strains of Enterobacterales expressing extended-spectrum β-lactamases and serine carbapenemases. Antimicrob. Agents Chemother. 2021; 65(8): e0055221. https://doi.org/10.1128/AAC.00552-21

23. Karlowsky J.A., Wisek M.G., Hackel M.A., et al. Ceftibuten-ledaborbactam activity against multidrugresistant and extended-spectrum-β-lactamase-positive clinical isolates of Enterobacterales from a 2018–2020 global surveillance collection. Antimicrob. Agents Chemother. 2022; 66(11): e0093422. https://doi.org/10.1128/aac.00934-22

24. Sun D., Tsivkovski R., Pogliano J., et al. Intrinsic antibacterial activity of xeruborbactam in vitro: assessing spectrum and mode of action. Antimicrob. Agents Chemother. 2022; 66(10): e0087922. https://doi.org/10.1128/aac.00879-22

25. Reddy K.R., Parkinson J., Sabet M., et al. Selection of QPX7831, an orally bioavailable prodrug of boronic acid β-lactamase inhibitor QPX7728. J. Med. Chem. 2021; 64(23): 17523–9. https://doi.org/10.1021/acs.jmedchem.1c01722

26. Lomovskaya O., Sun D., Rubio-Aparicio D., et al. Vaborbactam: spectrum of beta-lactamase inhibition and impact of resistance mechanisms on activity in Enterobacterales. Antimicrob. Agents Chemother. 2017; 61(11): e01443-17. https://doi.org/10.1128/aac.01443-17

27. Hillyer T., Shin W.S. Meropenem/Vaborbactam – a mechanistic review for insight into future development of combinational therapies. Antibiotics (Basel). 2024; 13(6): 472. https://doi.org/10.3390/antibiotics13060472

28. Zhanel G.G., Lawrence C.K., Adam H., et al. Imipenem–relebactam and meropenem–vaborbactam: two novel carbapenem-β-lactamase inhibitor combinations. Drugs. 2018; 78(1): 65–98. https://doi.org/10.1007/s40265-017-0851-9

29. Melinta Therapeutics granted European Commission Marketing Authorization for Vabomere® (meropenem and vaborbactam). Press Release; 2018. Available at: https://malinplc.com/wp-content/uploads/2018/11/27.11.2018-Melinta-Therapeutics-Granted-European-Commission-Marketing-Authorization-for-Vabomere.pdf

30. Papp-Wallace K.M., Barnes M.D., Alsop J., et al. Relebactam is a potent inhibitor of the KPC-2 β-lactamase and restores imipenem susceptibility in KPC-producing Enterobacterales. Antimicrob. Agents Chemother. 2018; 62(6): e00174-18. https://doi.org/10.1128/aac.00174-18

31. Mushtaq S., Garello P., Vickers A., et al. Activity of ertapenem/zidebactam (WCK 6777) against problem Enterobacterales. J. Antimicrob. Chemother. 2022; 77(10): 2772–8. https://doi.org/10.1093/jac/dkac280

32. Asempa T.E., Motos A., Abdelraouf K., et al. Efficacy of Human-simulated epithelial lining fluid exposure of meropenem-nacubactam combination against class a serineβ-lactamase-producing Enterobacterales in the neutropenic murine lung infection model. Antimicrob. Agents Chemother. 2019; 63(4): e02382-18. https://doi.org/10.1128/aac.02382-18

33. Livermore D.M., Warner M., Mushtaq S., Woodford N. Interactions of OP0595, a novel triple-action diazabicyclooctane, with β-lactams against OP0595-resistant Enterobacterales mutants. Antimicrob. Agents Chemother. 2016; 60(1): 554–60. https://doi.org/10.1128/AAC.02184-15

34. Ma Z., Lynch A.S. Development of a dual-acting antibacterial agent (TNP-2092) for the treatment of persistent bacterial infections. J. Med. Chem. 2016; 59(14): 6645–57. https://doi.org/10.1021/acs.jmedchem.6b00485

35. Robertson G.T., Bonventre E.J., Doyle T.B., et al. In vitro evaluation of CBR-2092, a novel rifamycin-quinolone hybrid antibiotic: microbiology profiling studies with staphylococci and streptococci. Antimicrob. Agents Chemother. 2008; 52(7): 2324–34. https://doi.org/10.1128/AAC.01651-07