REPLY
We would like to thank Kaye and Belley (1) for highlighting the importance of developing new antibacterial agents to treat infections caused by third-generation cephalosporin (3GC)-resistant Enterobacterales, which predominantly produce extended-spectrum β-lactamases (ESBLs). 3GC-resistant Enterobacterales have been classified by the World Health Organization (WHO) as critical priority pathogens (2), and we agree that the number of patients and the burden on health care systems is greater for ESBLs than for carbapenem-resistant Gram-negative infections (3).
As discussed by Kaye and Belley (1) and in the antibacterial pipeline review (4) published in Antimicrobial Agents and Chemotherapy, there are two carbapenems (benapenem and tebipenem), and one penem (sulopenem) currently being evaluated in late-stage clinical development against ESBL-containing infections. In addition, three β-lactamase inhibitor (BLI) + β-lactam combinations (durlobactam + sulbactam, taniborbactam + cefepime, and enmetazobactam + cefepime) are in phase 3 development to treat the growing numbers of ESBL Enterobacterales infections that could spare the use of carbapenems.
Increasing numbers of patients with complicated urinary tract infections (UTIs) due to ESBLs have been reported from the clinical practice even without health care exposure, as well as pregnant women with bacteriuria and simple UTIs. In a hospital, ESBL bacteremia is usually resistant to current oral medicines but can be treated with intravenous (i.v.) antibacterial drugs. Having new oral and i.v./oral switch options would allow patients to be discharged without the need for home i.v. therapy. Gepotidacin, which is in a new class of topoisomerase II inhibitors that can be administered i.v. and orally, has activity against ESBL Enterobacterales infections (5, 6). There are also orally administered BLI + β-lactam combinations in phase 1 that may have activity against ESBLs as follows: ETX0282 + cefpodoxime proxetil, ARX-1796 + undisclosed, VNRX-7145 + ceftibuten, and QPX7728 + QPX2015. However, we need to ensure that new antibacterial drugs to treat ESBL infections do not increase carbapenem resistance. New antibacterial agents with activity against ESBLs are discussed in more detail in the upcoming WHO report 2021 Antibacterial Agents in Clinical and Preclinical Development: an Overview and Analysis.
ACKNOWLEDGMENTS
This contribution has been prepared strictly in a personal capacity and reflects the view of the authors. The views expressed must not be attributed to the WHO, its Secretariat, or its Member States.
Footnotes
This is a response to a letter by Kaye and Belley https://doi.org/10.1128/AAC.00213-22.
Contributor Information
Mark S. Butler, Email: mark@msbchem.com.
Peter Beyer, Email: beyerp@who.int.
REFERENCES
- 1.Kaye KS, Belley A. 2022. Third-generation cephalosporin-resistant Enterobacterales are critical priority pathogens, too! Antimicrob Agents Chemother. doi: 10.1128/AAC.00213-22. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Tacconelli E, Carrara E, Savoldi A, Harbarth S, Mendelson M, Monnet DL, Pulcini C, Kahlmeter G, Kluytmans J, Carmeli Y, Ouellette M, Outterson K, Patel J, Cavaleri M, Cox EM, Houchens CR, Grayson ML, Hansen P, Singh N, Theuretzbacher U, Magrini N, Aboderin AO, Al ASS, Awang JN, Benzonana N, Bhattacharya S, Brink AJ, Burkert FR, Cars O, Cornaglia G, Dyar OJ, Friedrich AW, Gales AC, Gandra S, Giske CG, Goff DA, Goossens H, Gottlieb T, Guzman BM, Hryniewicz W, Kattula D, Jinks T, Kanj SS, Kerr L, Kieny M-P, Kim YS, Kozlov RS, Labarca J, Laxminarayan R, Leder K, WHO Pathogens Priority List Working Group. 2018. Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect Dis 18:318–327. doi: 10.1016/S1473-3099(17)30753-3. [DOI] [PubMed] [Google Scholar]
- 3.Murray CJL, Ikuta KS, Sharara F, Swetschinski L, Robles Aguilar G, Gray A, Han C, Bisignano C, Rao P, Wool E, Johnson SC, Browne AJ, Chipeta MG, Fell F, Hackett S, Haines-Woodhouse G, Kashef Hamadani BH, Kumaran EAP, McManigal B, Agarwal R, Akech S, Albertson S, Amuasi J, Andrews J, Aravkin A, Ashley E, Bailey F, Baker S, Basnyat B, Bekker A, Bender R, Bethou A, Bielicki J, Boonkasidecha S, Bukosia J, Carvalheiro C, Castañeda-Orjuela C, Chansamouth V, Chaurasia S, Chiurchiù S, Chowdhury F, Cook AJ, Cooper B, Cressey TR, Criollo-Mora E, Cunningham M, Darboe S, Day NPJ, De Luca M, Dokova K, et al. 2022. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet 399:629–655. doi: 10.1016/S0140-6736(21)02724-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Butler MS, Gigante V, Sati H, Paulin S, Al-Sulaiman L, Rex JH, Fernandes P, Arias CA, Paul M, Thwaites GE, Czaplewski L, Alm RA, Lienhardt C, Spigelman M, Silver LL, Ohmagari N, Kozlov R, Harbarth S, Beyer P. 2022. Analysis of the clinical pipeline of treatments for drug resistant bacterial infections: despite progress, more action is needed. Antimicrob Agents Chemother 66:e01991-21. doi: 10.1128/AAC.01991-21. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Flamm RK, Farrell DJ, Rhomberg PR, Scangarella-Oman NE, Sader HS. 2017. Gepotidacin (GSK2140944) in vitro activity against Gram-positive and Gram-negative bacteria. Antimicrob Agents Chemother 61:e00468-17. doi: 10.1128/AAC.00468-17. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Scangarella-Oman NE, Hossain M, Hoover JL, Perry CR, Tiffany C, Barth A, Dumont EF. 2022. Dose selection for phase III clinical evaluation of gepotidacin (GSK2140944) in the treatment of uncomplicated urinary tract infections. Antimicrob Agents Chemother 66:e01492-21. doi: 10.1128/AAC.01492-21. [DOI] [PMC free article] [PubMed] [Google Scholar]