# Reply to Shapiro, “Cefepime/Enmetazobactam Is a Clinically Effective Combination Targeting Extended-Spectrum $\beta$-Lactamase-Producing Enterobacterales”

Juan Carlos Vázquez-Ucha, Cristina Lasarte-Monterrubio, Paula Guijarro-Sánchez, Marina Oviaño, Laura Álvarez-Fraga, Isaac Alonso-García, Jorge Arca-Suárez, German Bou, Alejandro Beceiro

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Juan Carlos Vázquez-Ucha, Cristina Lasarte-Monterrubio, Paula Guijarro-Sánchez, Marina Oviaño, Laura Álvarez-Fraga, et al.. Reply to Shapiro, “Cefepime/Enmetazobactam Is a Clinically Effective Combination Targeting Extended-Spectrum $\beta$-Lactamase-Producing Enterobacterales”. Antimicrobial Agents and Chemotherapy, 2022, 66, 10.1128/aac.00353-22. hal-04959180

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Submitted on 23 Apr 2025

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Reply to Shapiro, “Cefepime/Enmetazobactam Is a Clinically Effective Combination
Targeting Extended-Spectrum β-Lactamase-Producing Enterobacterales”

Juan Carlos Vázquez-Ucha a, Cristina Lasarte-Monerrubio a, Paula Guijarro-Sánchez a, Marina Oviaño a, Laura Álvarez-Fraga a, Isaac Alonso-García a, Jorge Arca-Suárez a, German Bou a, Alejandro Beceiro a,*

ªServicio de Microbiología do Complejo Hospitalario Universitario da Coruña (CHUAC),
Instituto de Investigación Biomédica da Coruña (INIBIC), Coruña, CIBER de Enfermedades
Infecciosas, Spain

* Corresponding author

**Reply**

The emergence of bacterial resistance, mainly due to the widespread presence of β-lactamase enzymes, is an important health concern. The use of β-lactamase inhibitors is probably the main strategy available for restoring the effectiveness of β-lactam antibiotics. However, the emergence of new β-lactamases, such as extended-spectrum β-lactamases (ESBLs) and carbapenemases, is a new worldwide problem.

Fortunately, new extended-spectrum inhibitors have emerged in recent years in the fight against multidrug resistance in bacteria. Thus, the efficacy of the novel β-lactamase inhibitors enmetazobactam, zidebactam, and taniborbactam is being evaluated, and promising results for these inhibitors in combination with cefepime have been obtained in phase III clinical trials.
As S. Shapiro indicates in his letter (1) in response to our study (2), the prevalence of ESBLs in *Enterobacterales* is higher than that of carbapenemases; however, we must not forget that carbapenemases are the main challenge when treating an infection with β-lactam antibiotics and, regardless of their prevalence, are associated with high rates of mortality (3). Most of the carbapenemases, such as KPC (class A), VIM, IMP, and NDM (class B), and OXA-48 (class D), are not inhibited by the majority of inhibitors approved by clinical agencies. Therefore, the objective of our study (2) was to evaluate the efficacy of the novel combinations of cefepime and these inhibitors against a collection of 400 carbapenemase-producing isolates of *Enterobacterales*. It is essential to test the new inhibitors against these worrisome carbapenemases in order to identify the best therapeutic options in the near future.

Cefepime/enmetazobactam is known to be a potential carbapenem-sparing agent with activity against ESBLs, as is also, e.g., cefepime/tazobactam (4, 5). This aspect is neither questioned nor evaluated in our study. However, we consider that the evaluation of enmetazobactam (along with other novel inhibitors) against a broad collection of carbapenemase-producing *Enterobacterales* is of interest to readers of *Antimicrobial Agents and Chemotherapy* and to clinical microbiologists in general.

Regarding S. Shapiro’s opinion about the cefepime breakpoints used in the study, we would like to point out that breakpoints have not yet been defined for these new combinations of β-lactamase inhibitors with cefepime. Thus, in order to facilitate interpretation of the results obtained, we, following CLSI criteria, used cefepime MIC values of ≤2 and ≥16 mg/L as breakpoints to define “susceptible” and “resistant” categories, respectively (6).

Finally, concerning the last comment in the letter, about KPC-carrying isolates, we point out that previous studies have also observed that cefepime/enmetazobactam presented moderate activity against KPC-producing *Klebsiella pneumoniae* isolates (7–9). As indicated in the text and Table
2 in our report and in Table S2 in its supplemental material, the MICs of cefepime and cefepime/enmetazobactam for KPC-carrying isolates are determined by the clonality of the isolates. The non-ESBL-producing *K. pneumoniae* isolates mostly belong to sequence type 512 (ST512), whereas the KPC- and ESBL-producing isolates mostly belong to ST307. The non-ESBL-producing isolates were cefepime/enmetazobactam resistant; however, as indicated in the report, this was probably due to inactivating mutations identified in OmpK35 and OmpK36, which do not appear in ST307 (cefepime/enmetazobactam susceptible) (Table S2) (2). We consider very unlikely the hypothesis of downregulation of KPC gene expression in the presence of ESBL suggested by S. Shapiro.

## Acknowledgment

We declare no competing financial interests.

## References

1. Shapiro S. 2022. Cefepime/enmetazobactam is a clinically effective combination targeting extended-spectrum β-lactamase-producing *Enterobacterales*. Antimicrob Agents Chemother 66:e00298-22. doi: 10.1128/AAC.00298-22.

2. Vázquez-Ucha JC, Lasarte-Monterrubio C, Guijarro-Sánchez P, Oviaño M, Álvarez-Fraga L, Alonso-García I, Arca-Suárez J, Bou G, Beceiro A, GEMARA-SEIMC/REIPI *Enterobacterales* Study Group. 2022. Assessment of activity and resistance mechanisms to cefepime in combination with the novel β-lactamase inhibitors zidebactam, taniborbactam, and enmetazobactam against a multicenter collection of carbapenemase-producing *Enterobacterales*. Antimicrob Agents Chemother 66:e01676-21. doi: 10.1128/AAC.01676-21.
3. Falagas ME, Tansarli GS, Karageorgopoulos DE, Vardakas KZ. 2014. Deaths attributable to carbapenem-resistant *Enterobacteriaceae* infections. Emerg Infect Dis 20:1170–1175. doi: 10.3201/eid2007.121004.

4. Papp-Wallace KM, Bethel CR, Caillon J, Barnes MD, Potel G, Bajaksouzian S, Rutter JD, Reghal A, Shapiro S, Taracila MA, Jacobs MR, Bonomo RA, Jacqueline C. 2019. C. Beyond piperacillin-tazobactam: cefepime and AAI101 as a potent β-lactam-β-lactamase inhibitor combination. Antimicrob Agents Chemother 63:e00105-19. doi: 10.1128/AAC.00105-19.

5. Isler B, Harris P, Stewart AG, Paterson DL. 2021. An update on cefepime and its future role in combination with novel β-lactamase inhibitors for MDR *Enterobacterales* and *Pseudomonas aeruginosa*. J Antimicrob Chemother 76:550–560. doi: 10.1093/jac/dkaa511.

6. Clinical and Laboratory Standards Institute. 2021. Performance standards for antimicrobial susceptibility testing, 31st ed. CLSI supplement M100. Clinical and Laboratory Standards Institute, Wayne, PA.

7. Lee Y-L, Ko W-C, Lee W-S, Lu P-L, Chen Y-H, Cheng S-H, Lu M-C, Lin C-Y, Wu T-S, Yen M-Y, Wang L-S, Liu C-P, Shao P-L, Shi Z-Y, Chen Y-S, Wang F-D, Tseng S-H, Lin C-N, Chen Y-H, Sheng W-H, Lee C-M, Tang H-J, Hsueh P-R. 2021. In-vitro activity of cefiderocol, cefepime/zidebactam, cefepime/enmetazobactam, omadacycline, eravacycline and other comparative agents against carbapenem-nonsusceptible *Enterobacterales*: results from the Surveillance of Multicenter Antimicrobial Resistance in Taiwan (SMART) in 2017–2020. Int J Antimicrob Agents 58:106377. doi: 10.1016/j.ijantimicag.2021.106377.
8. Morrissey I, Magnet S, Hawser S, Shapiro S, Knechtle P. 2019. In vitro activity of cefepime-enmetazobactam against Gram-negative isolates collected from U.S. and European hospitals during 2014–2015. Antimicrob Agents Chemother 63:e00514-19. doi: 10.1128/AAC.00514-19.

9. Tselepis L, Langley GW, Aboklaish AF, Widlake E, Jackson DE, Walsh TR, Schofield CJ, Brem J, Tyrrell JM. 2020. In vitro efficacy of imipenem-relebactam and cefepime-AAI101 against a global collection of ESBL-positive and carbapenemase-producing *Enterobacteriaceae*. Int J Antimicrob Agents 56:105925. doi: 10.1016/j.ijantimicag.2020.105925.