
==== Front
J Antimicrob Chemother
J Antimicrob Chemother
jac
Journal of Antimicrobial Chemotherapy
0305-7453
1460-2091
Oxford University Press UK

39011845
10.1093/jac/dkae220
dkae220
Original Research
AcademicSubjects/MED00740
AcademicSubjects/MED00290
AcademicSubjects/MED00230
Establishment of epidemiological cut-off values for eravacycline, against Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Acinetobacter baumannii and Staphylococcus aureus
Jing Ran Department of Laboratory Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
Beijing Key Laboratory for Mechanisms Research and Precision Diagnosis of Invasive Fungal Diseases, Beijing, China

Yi Qiao-Lian Department of Laboratory Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
Beijing Key Laboratory for Mechanisms Research and Precision Diagnosis of Invasive Fungal Diseases, Beijing, China

Zhuo Chao Department of Clinical Infectious Diseases, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, China

Kang Wei Department of Laboratory Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
Beijing Key Laboratory for Mechanisms Research and Precision Diagnosis of Invasive Fungal Diseases, Beijing, China

https://orcid.org/0000-0001-7272-3900
Yang Qi-Wen Department of Laboratory Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
Beijing Key Laboratory for Mechanisms Research and Precision Diagnosis of Invasive Fungal Diseases, Beijing, China

Yu Yun-Song Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, China

Zheng Bo Institute of Clinical Pharmacology, Peking University First Hospital, Beijing 100191, China

Li Yun Institute of Clinical Pharmacology, Peking University First Hospital, Beijing 100191, China

Hu Fu-Pin Institute of Antibiotics, Huashan Hospital, Fudan University, and Key Laboratory of Clinical Pharmacology of Antibiotics, Shanghai, China

Yang Yang Institute of Antibiotics, Huashan Hospital, Fudan University, and Key Laboratory of Clinical Pharmacology of Antibiotics, Shanghai, China

Lin Jie Department of Laboratory Medicine, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China

Zhang Ge Department of Laboratory Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
Beijing Key Laboratory for Mechanisms Research and Precision Diagnosis of Invasive Fungal Diseases, Beijing, China

Zhang Jing-Jia Department of Laboratory Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
Beijing Key Laboratory for Mechanisms Research and Precision Diagnosis of Invasive Fungal Diseases, Beijing, China

Wang Tong Department of Laboratory Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
Beijing Key Laboratory for Mechanisms Research and Precision Diagnosis of Invasive Fungal Diseases, Beijing, China

Li Jin Department of Laboratory Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
Beijing Key Laboratory for Mechanisms Research and Precision Diagnosis of Invasive Fungal Diseases, Beijing, China

Zhuo Chu-Yue Department of Clinical Infectious Diseases, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, China

Li Xue Department of Laboratory Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
Beijing Key Laboratory for Mechanisms Research and Precision Diagnosis of Invasive Fungal Diseases, Beijing, China

Zhu Yun-Fan Everest Medicines (China) Co., Ltd., Shanghai, China

Xu Ying-Chun Department of Laboratory Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
Beijing Key Laboratory for Mechanisms Research and Precision Diagnosis of Invasive Fungal Diseases, Beijing, China
on behalf of Expert Committee of the National Health Commission on Antimicrobial Susceptibility Testing and Standard Research (ECAST)

Corresponding author. E-mail: xycpumch@139.com
Ran Jing, Qiao-Lian Yi and Chao Zhuo contributed equally to this study.

9 2024
16 7 2024
16 7 2024
79 9 22462250
27 1 2024
14 6 2024
© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.

Abstract

Objectives

To establish the epidemiology cut-off (ECOFF) values of eravacycline against Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Acinetobacter baumannii and Staphylococcus aureus, from a multi-centre study in China.

Methods

We collected 2500 clinical isolates from five hospitals in China from 2017 to 2020. The MICs of eravacycline were determined using broth microdilution. The ECOFF values of eravacycline against the five species commonly causing cIAIs were calculated using visual estimation and ECOFFinder following the EUCAST guideline.

Results

The MICs of eravacycline against all the strains were in the range of 0.004–16 mg/L. The ECOFF values of eravacycline were 0.5 mg/L for E. coli, 2 mg/L for K. pneumonia and E. cloacae, and 0.25 mg/L for A. baumannii and S. aureus, consistent with the newest EUCAST publication of eravacycline ECOFF values for the populations. No discrepancy was found between the visually estimated and 99.00% ECOFF values calculated using ECOFFinder.

Conclusions

The determined ECOFF values of eravacycline against the five species can assist in distinguishing wild-type from non-wild-type strains. Given its promising activity, eravacycline may represent a member of the tetracycline class in treating cIAIs caused by commonly encountered Gram-negative and Gram-positive pathogens.

National High Level Hospital 2022-PUMCH-B-074
==== Body
pmcIntroduction

Eravacycline, a novel fully synthetic fluorocycline belonging to the tetracycline class, first approved in 2018 by the FDA, has been developed for the treatment of serious infections, such as complex intra-abdominal infections (cIAIs).

Before a study on the therapeutic effect of eravacycline on cIAI patients in China, we first performed a multi-centre antimicrobial susceptibility testing (AST) of eravacyline against 2500 isolates of common pathogens causing cIAIs. Also, this study was mainly to establish epidemiological cut-off (ECOFF) values of eravacycline against a series of common Gram-negative Enterobacteriaceae causing cIAIs, so Escherichia coli, Klebsiella pneumoniae and Enterobacter cloacae were selected as the representative species.1Acinetobacter baumannii was selected on behalf of the non-fermentative bacteria, but not Pseudomonas aeruginosa due to its intrinsic resistance to tetracycline (https://mic.eucast.org/search/). Although A. baumannii is less common in cIAIs, it has been flagged as a growing cause of postoperative abdominal infections in hospital settings.2–4 For Gram-positive bacteria, Staphylococcus aureus was selected as a representative because it was one of the most common causative pathogens of hospital-acquired IAIs.5

Notably, EUCAST has established the MIC breakpoints of eravacycline against E. coli and S. aureus (EUCAST Breakpoint tables version 13.1) and ECOFFs of eravacycline against E. coli, E. cloacae, K. pneumonia and S. aureus (https://mic.eucast.org/search/). As MIC breakpoints were specific to the country of origin of the bacteria, and separating Chinese breakpoints were not the major work, so this was not established in this study. Meanwhile, there was a lack of studies on ECOFF establishment of eravacycline against commonly encountered pathogens causing cIAIs in China. In particular, the ECOFF value of eravacycline against A. baumannii was unavailable from the newest EUCAST publication (https://mic.eucast.org/search/). Therefore, it is inconvenient and difficult to interpret an AST result. To more comprehensively determine the ECOFF values of eravacycline against the pathogens causing cIAIs, this study not only included the common populations, such as E. coli, E. cloacae, K. pneumonia and S. aureus, bus also A. baumannii as one of the non-fermentative bacteria. The establishment of ECOFF against the population is expected to assist in differentiating wild-type (WT) from non-wild-type (NWT) isolates without MIC breakpoints available for eravacyline.

Materials and methods

Ethics approval

The study was approved by the Ethics Committee of Peking Union Medical College Hospital (no. S-K1253).

Isolate collection and quality control (QC) strains

We collected 2500 non-repetitive strains from five hospitals in four regions of China from 2017 to 2020. Notably, the strains we collected were isolated for the first time after the patient admission. Homologous strains were avoided to be collected during the outbreak; that meant not collecting the same isolates from the same period in the same ward. The isolates were accurately identified to be E. coli (n = 500), K. pneumoniae (n = 500), E. cloacae (n = 500), A. baumannii (n = 500) and S. aureus (n = 500) through MALDI-TOF MS.

E. coli ATCC 25922, P. aeruginosa ATCC 27853 and S. aureus ATCC 29213 were used as the QC strains in this experiment.6

Antimicrobial susceptibility testing (AST)

The MICs of eravacycline against all the tested isolates were determined by each participating hospital through broth microdilution following the EUCAST guideline (ISO: 20776-1).7 Antimicrobial panels containing eravacycline at the concentration of 0.004–512 mg/L were previously prepared by the central laboratory (Peking Union Medical College Hospital) using standard powders of eravacycline (IHMA, Europe Sarl). Cation-adjusted Mueller–Hinton broth (Lot: BD220100, BD Biosciences, CA, USA) was used as the media for dissolving the antimicrobial agents.

All QC and external quality control strains were tested by each participating hospital on three different days. The variation was considered acceptable if at least two of the three results were within the ±1 dilution range when compared with the central laboratory results. The concentration ranges of eravacycline against the QC strains should be referred to CLSI M100-S33 document.6

Data analysis

The isolates with MICs of the antimicrobial agent less than or equal to the ECOFF value (MICs ≤ ECOFF) were considered WT. By contrast, the NWT isolates are those with MIC values greater than the ECOFF value (MICs > ECOFF).8

The ECOFF values of eravacycline against E. coli, K. pneumoniae, E. cloacae, A. baumannii and S. aureus were calculated using ECOFFinder (downloaded from: https://www.eucast.org/mic_and_zone_distributions_and_ecoffs). WT upper limits were determined statistically at 95.00%, 97.50%, 99.00%, 99.50% and 99.90% of the modelled population. The MIC results captured 99.00% of the modelled WT population to increase the specificity for the WT population. Thus, 99.00% endpoints were chosen as the defined ECOFF values. These values were also confirmed using the ‘visual estimation’ method. Visually estimated ECOFF values were read by the log-normal distribution of the nonlinear regression fitting curve where 99.00% of WT isolates were included.

Results

MIC distributions of eravacycline

A total of 2500 isolates were tested (Table 1). The MICs of eravacycline against the three Enterobacteriaceae species (E. coli, K. pneumonia and E. cloacae) ranged from 0.03 to 16 mg/L. Eravacycline exhibited a similar activity against K. pneumonia and E. cloacae, with the same mode of 0.5 mg/L and MIC50/90 of 0.5/2 mg/L. Meanwhile, the overall MIC distributions for E. coli were a little smaller than those for K. pneumonia and E. cloacae, ranging from 0.03 to 2 mg/L with the mode of 0.12 mg/L and MIC50/90 of 0.12/5 mg/L. For A. baumannii and S. aureus, the MIC distributions ranged from 0.004 to 4 mg/L, with the modes of 0.03 and 0.016 mg/L as well as MIC50/90 of 0.06/0.5 and 0.03/0.12 mg/L, respectively.

Table 1. MIC distributions and epidemiological cut-off values of eravacycline against E. coli, K. pneumoniae, E. cloacae, A. baumannii and S. aureus

Species/hospitals	Number of isolates with MIC (mg/L) of		MIC (mg/L)	ECOFFs
(mg/L)	NWT isolate	
≤0.004	0.008	0.016	0.03	0.06	0.12	0.25	0.5	1	2	4	8	16	32	Total number	Range	Mode	MIC50	MIC90	99% Calculation	Visual estimation	N (%)	
E. coli																							
Hospital 1	0	0	0	0	2	17	49	24	6	2	0	0	0	0	100	0.06–2	0.25	0.25	0.5				
Hospital 2	0	0	0	0	3	35	43	12	5	2	0	0	0	0	100	0.06–2	0.25	0.25	0.5				
Hospital 3	0	0	0	4	32	51	10	2	1	0	0	0	0	0	100	0.03–1	0.12	0.12	0.25				
Hospital 4	0	0	0	1	11	62	24	1	0	1	0	0	0	0	100	0.03–2	0.12	0.12	0.25				
Hospital 5	0	0	0	4	19	58	16	2	0	1	0	0	0	0	100	0.03–2	0.12	0.12	0.25				
Total	0	0	0	9	67	223	142	41	12	6	0	0	0	0	500	0.03–2	0.12	0.12	0.5	0.5	0.5	18 (3.6)	
K. pneumoniae																							
Hospital 1	0	0	0	0	0	0	43	44	5	4	2	2	0	0	100	0.25–8	0.5	0.5	1				
Hospital 2	0	0	0	0	0	0	11	54	20	7	4	3	1	0	100	0.25–16	0.5	0.5	2				
Hospital 3	0	0	0	0	0	22	34	18	9	13	4	0	0	0	100	0.12–4	0.25	0.25	2				
Hospital 4	0	0	0	1	7	42	43	7	0	0	0	0	0	0	100	0.03–0.5	0.25	0.12	0.25				
Hospital 5	0	0	0	0	1	2	26	42	10	14	4	1	0	0	100	0.06–8	0.5	0.5	2				
Total	0	0	0	1	8	66	157	165	44	38	14	6	1	0	500	0.03–16	0.5	0.5	2	2	2	21 (4.2)	
E. cloacae																							
Hospital 1	0	0	0	1	0	0	13	52	15	8	2	7	2	0	100	0.03–16	0.5	0.5	4				
Hospital 2	0	0	0	0	0	1	18	51	18	7	3	2	0	0	100	0.12–8	0.5	0.5	2				
Hospital 3	0	0	0	0	1	7	62	14	5	5	3	3	0	0	100	0.06–8	0.25	0.25	2				
Hospital 4	0	0	0	0	0	4	36	46	11	3	0	0	0	0	100	0.12–2	0.5	0.5	1				
Hospital 5	0	0	0	0	0	0	16	49	29	5	0	0	1	0	100	0.25–16	0.5	0.5	1				
Total	0	0	0	1	1	12	145	212	78	28	8	12	3	0	500	0.03–16	0.5	0.5	2	2	2	23 (4.6)	
A. baumannii																							
Hospital 1	0	1	4	20	23	6	1	31	11	2	1	0	0	0	100	0.008–4	0.06	0.12	1				
Hospital 2	23	4	8	10	7	25	14	8	1	0	0	0	0	0	100	0.004–1	0.12	0.06	0.25				
Hospital 3	0	2	5	23	14	6	8	32	6	2	2	0	0	0	100	0.008–4	0.03	0.12	0.5				
Hospital 4	0	3	9	47	23	6	3	3	2	3	1	0	0	0	100	0.008–4	0.03	0.03	0.25				
Hospital 5	0	4	37	34	5	4	3	10	2	1	0	0	0	0	100	0.008–2	0.016	0.03	0.5				
Total	23	14	63	134	72	47	29	84	22	8	4	0	0	0	500	0.004–4	0.03	0.06	0.5	0.25	0.25	118 (23.6)	
S. aureus																							
Hospital 1	0	0	0	16	46	16	0	10	12	0	0	0	0	0	100	0.03–1	0.06	0.06	1				
Hospital 2	0	0	1	27	51	8	8	5	0	0	0	0	0	0	100	0.016–0.5	0.06	0.06	0.25				
Hospital 3	0	16	50	16	5	5	4	4	0	0	0	0	0	0	100	0.008–0.5	0.016	0.016	0.12				
Hospital 4	1	36	35	24	2	2	0	0	0	0	0	0	0	0	100	0.004–0.12	0.008	0.016	0.03				
Hospital 5	0	0	48	37	10	3	2	0	0	0	0	0	0	0	100	0.016–0.25	0.016	0.03	0.06				
Total	1	52	134	120	114	34	14	19	12	0	0	0	0	0	500	0.004–1	0.016	0.03	0.12	0.25	0.25	31 (6.2)	
Hospital 1: Peking University First Hospital, Hospital 2: Guangzhou Institute of Respiratory Health, Hospital 3: Huashan Hospital of Fudan University, Hospital 4: Peking Union Medical College Hospital, Hospital 5: Sir Run Run Shaw Hospital of Zhejiang University; MIC50 and MIC90 are defined as the MICs required to inhibit 50% and 90% of the total population, respectively; NWT isolate: the non-wild-type isolates (MICs > ECOFF) were the population of isolates possibly carrying detectable acquired resistance mechanisms (potentially reduced susceptibility to the agent).

Establishment of ECOFF values

Eravacycline had the same calculated 99.90% ECOFF values against K. pneumonia/E. cloacae and A. baumannii/S. aureus at 2 and 0.25 mg/L, respectively. Also, the calculated 99.90% ECOFFs was 0.5 mg/L against E. coli. Notably, no discrepancy was found between the visually estimated and calculated 99.00% ECOFF values (Figure 1, Table 1). Thus, based on the calculated data, the ECOFF values of eravacycline were established to be 0.5 mg/L for E. coli, 2 mg/L for K. pneumonia and E. cloacae, and 0.25 mg/L for A. baumannii and S. aureus.

Nonlinear regression fitting MIC distributions of eravacycline for E. coli, K. pneumoniae, E. cloacae, A. baumannii and S. aureus are shown in Figure 1. Among the populations of Enterobaterales and S. aureus, the fitted count curve representing the simulated MIC data corresponded to the raw count curve representing the measured MIC data. However, a lower coincidence occurred in both curves of A. baumannii. The MICs of eravacycline against K. pneumonia and E. cloacae were widely distributed and showed atypical bimodal distribution. The MIC distributions of eravacycline against E. coli and S. aureus were narrow, with unimodal and atypical bimodal distributions, respectively. The atypical bimodal MIC distribution with one large (left) and small (right) peaks was observed in S. aureus. Eravacycline had atypical bimodal MIC distribution against A. baumannii.

Figure 1. Nonlinear regression fitting MIC distribution of eravacycline to E. coli, K. pneumoniae, E. cloacae, A. baumannii and S. aureus (red ‘Raw Count or %’ represents measured MIC data, green ‘Fitted Count or %’ represents simulated MIC data). The dotted lines represent estimated ECOFFs using ECOFFinder for these species. For E. coli and S. aureus, the dotted lines also represent the available MIC breakpoints from the newest EUCAST publication (https://mic.eucast.org/search/).

Discussion

Whether from the isolate collection or the data analysis, this study met the criteria for accurately establishing the ECOFF values of eravacycline against the populations as outlined in the EUCAST guideline.8 Therefore, our results must be accurate and reliable. They were consistent with the newest EUCAST publication of eravacycline ECOFF values for the populations (https://mic.eucast.org/search/). According to the EUCAST guideline,8 the ECOFF values should be determined when the results of ECOFFinder calculation and visual estimation agree or have no more than one dilution of discrepancy. In the present study, the visually estimated ECOFF values were consistent with the 99.00% ECOFF values calculated using ECOFFinder (Table 1).

A previous multi-centre study evaluated the in vitro activities of eravacycline against Gram-positive and Enterobacteriaceae bacteria, including S. aureus (MIC50/90, 0.06/0.12 mg/L), K. pneumonia (MIC50/90, 0.25/1 mg/L) and E. coli (MIC50/90, 0.12/0.5 mg/L),9,10 which were similar to the values obtained in this study. Huang et al. reported that eravacycline exerts similar activities against K. pneumonia and E. coli, and their results have an approximately one-dilution MIC discrepancy compared with the results of this study, with MIC50/90 values of 0.5/4 and 0.5/1 mg/L, respectively.11 In the present study, eravacycline had an MIC50/90 of 0.5/2 mg/L against E. cloacae, which was similar to the MIC50/90 values of 0.25/2 and 0.5/2 mg/L reported by studies in the USA and Taiwan, respectively.11,12

For a typical bimodal distribution diagram, the right and left peaks generally represent the MIC distributions of the NWT and WT strains to the agent, respectively.13 In the present study, eravacycline had a typical bimodal MIC distribution against A. baumannii, and the right peak possibly indicated a higher proportion of NWT isolates of eravacycline (Figure 1). Other research also indicated the lower activity of eravacycline against A. baumannii, with the MIC distribution around 4-fold higher than this study.9 The species with unimodal or atypical bimodal MIC distributions had a lower proportion of NWT isolates of eravacycline, with 3.6% accounting for E. coli, 4.2% for K. pneumonia, 4.6% for E. cloacae and 6.2% for S. aureus, compared with 23.6% for A. baumannii, which had typical bimodal MIC distributions (Figure 1, Table 1). Devid M et al. reported that MIC90s of eravacycline were 2- to 4-fold higher for carbapenem-resistant Enterobacteriaceae and A. baumannii isolates than for the carbapenem-susceptible controls.14 The likely explanation is that a subset of carbapenem-resistant isolates have upregulated endogenous efflux or reduced permeability.15 This possibly explains the typical bimodal and atypical bimodal MIC distributions (right peaks) of eravacycline against A. baumannii and Enterobacteriaceae, respectively. In addition, the susceptibility of S. aureus to eravacycline could be affected by genetic mutation of the MepRAB efflux pump and 30S ribosome subunits.16

This also explains another atypical bimodal MIC distribution on the right peak occurred in S. aureus section, possibly in association with NWT isolates. Not all antimicrobial agents against all bacterial pathogens have available MIC breakpoints, so the ECOFF values are the effective method to screen NWT isolates with potentially reduced susceptibility to the agent.

Acknowledgements

We appreciate the support of all the members of the Chinese Committee on Antimicrobial Susceptibility Testing (ChiCAST), and technique support from Everest Medicines (China) Co., Ltd.

Funding

This work was funded by the National High Level Hospital Clinical Research Funding [2022-PUMCH-B-074, 2022-PUMCH-B-028 and 2022-PUMCH-C-060]. Sponsors have no role in any of the stages from study design to submission of the paper for publication.

Transparency declarations

None to declare.
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