Antimicrobial Susceptibilities of the Ertapenem-non-susceptible Non-carbapenemase-producing Enterobacterales Isolates Causing Intra-abdominal Infections in the Asia-Pacific Region during 2008-2014: Results from the Study for Monitoring the Antimicrobial Resistance Trends (SMART)

Journal Pre-proof Antimicrobial Susceptibilities of the Ertapenem-non-susceptible Non-carbapenemase-producing Enterobacterales Isolates Causing Intra-abdominal Infections in the Asia-Pacific Region during 2008-2014: Results from the Study for Monitoring the Antimicrobial Resistance Trends (SMART) Shio-Shin Jean, Po-Ren Hsueh, on behalf of the SMART Asia-Pacific Group

PII:

S2213-7165(19)30258-9

DOI:

https://doi.org/10.1016/j.jgar.2019.10.004

Reference:

JGAR 1061

To appear in:

Journal of Global Antimicrobial Resistance

Received Date:

13 August 2019

Revised Date:

1 October 2019

Accepted Date:

6 October 2019

Please cite this article as: Jean S-Shin, Hsueh P-Ren, Antimicrobial Susceptibilities of the Ertapenem-non-susceptible Non-carbapenemase-producing Enterobacterales Isolates Causing Intra-abdominal Infections in the Asia-Pacific Region during 2008-2014: Results from the Study for Monitoring the Antimicrobial Resistance Trends (SMART), Journal of Global Antimicrobial Resistance (2019), doi: https://doi.org/10.1016/j.jgar.2019.10.004

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Antimicrobial Susceptibilities of the Ertapenem-non-susceptible Non-carbapenemase-producing Enterobacterales Isolates Causing Intra-abdominal Infections in the Asia-Pacific Region during 2008-2014: Results from the Study for Monitoring the

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Antimicrobial Resistance Trends (SMART)

Running title: Ertapenem-non-susceptible non-carbapenemase-producing

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Enterobacterales

Shio-Shin Jeana,b, Po-Ren Hsuehc* on behalf of the SMART Asia-Pacific

Department of Emergency, School of Medicine, College of Medicine, Taipei Medical

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a

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Group*

University, Taipei, Taiwan; bDepartment of Emergency Medicine, Department of

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Emergency and Critical Care Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; cDepartments of Laboratory Medicine and Internal

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Medicine, National Taiwan University Hospital, National Taiwan University College

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of Medicine, Taipei 100, Taiwan

∗Corresponding author. Present address: Departments of Laboratory Medicine and Internal Medicine, National Taiwan University Hospital, No. 7 Chung-Shan S. Road, Taipei 100, Taiwan. E-mail address: [email protected] (P.-R. Hsueh).

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Highlights  MICs of 404 ETP-NS-non-CPE isolates collected from different intra-abdominal infection (IAI) sites amongst hospitalised patients in the Asia-Pacific region during 2008-2014 were determined. 

The vast majority (>84%) of IAI-ETP-NS-non-CPE isolates, including Escherichia coli (n=83), Klebsiella pneumoniae (n=91), and Enterobacter species (n=210), were susceptible to imipenem and amikacin. A significant fraction of IAI-ETP-NS-non-CP Enterobacter isolates exhibited

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

ciprofloxacin MIC <2 mg/L. 

The hepatobiliary ETP-NS-non-CPE displayed lower cefepime MICs than those

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cultured from the peritoneal space.

ABSTRACT

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Objectives: To investigate the susceptibility profiles amongst ertapenem-nonsusceptible (ETP-NS) non-carbapenemase-producing Enterobacterales (CPE) isolates.

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Methods: Minimum inhibitory concentrations (MICs) of 404 ETP-NS-non-CPE isolates collected from different intra-abdominal infection (IAI) sites amongst patients

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in the Asia-Pacific region during 2008-2014 were determined using the broth microdilution method. The susceptibility results were interpreted according to the

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MIC breakpoints recommended by the Clinical and Laboratory Standards Institute in 2018. The MICs data of several agents were evaluated based on their published pharmacokinetic/pharmacodynamic (PK/PD) profiles. Results: The majority (>84%) of IAI-ETP-NS-non-CPE isolates, including Escherichia coli (n=83), Klebsiella pneumoniae (n=91), and Enterobacter species (n=210), were susceptible to imipenem and amikacin. The 193 hepatobiliary ETP-NS2

non-CPE isolates exhibited a trend of lower cefepime MIC (4 mg/L) distribution than those (n=145) cultured from the peritoneal space (P=0.058). Amongst the ETPNS-non-CP Enterobacter isolates, 65.7% displayed a cefepime MIC 4 mg/L. In addition, compared with E. coli and K. pneumoniae isolates, 82.9% and 72.9% of the ETP-NS-non-CP Enterobacter isolates were susceptible to levofloxacin and ciprofloxacin, respectively. Of note, 74.5% and 70.3% of the ETP-NS-non-CP Enterobacter isolates cultured from the hepatobiliary tract and peritoneal space

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exhibited a ciprofloxacin MIC 2 mg/L and 0.25 mg/L, respectively. In conclusion, imipenem and amikacin show good in vitro susceptibility rates against the IAI-ETP-

NS-non-CPE isolates. The hepatobiliary ETP-NS-non-CPE displayed lower cefepime

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MICs than those cultured from the peritoneal space. Additionally, a significant

fraction of IAI-ETP-NS-non-CP Enterobacter isolates exhibited ciprofloxacin MIC

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<2 mg/L.

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Conclusion: Based upon the PK/PD analyses, ciprofloxacin, imipenem and cefepime

Keywords:

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are probably effective against IAI-ETP-NS-non-CPE isolates.

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Ertapenem-non-susceptible non-carbapenemase-producing Enterobacterales Intra-abdominal infection

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Imipenem Cefepime

Ciprofloxacin

1. Introduction Intra-abdominal infections (IAI) are primarily caused by Enterobacterales 3

species and are usually associated with high fatality risks [1-9]. Throughout this decade, multidrug resistance loading has been gradually worsening [2,6,10-12]. In 2018, resistance to carbapenem agents amongst Enterobacterales isolates is recognised as a critical concern for the global patients in healthcare settings [2,13]. In the study regarding carbapenem-resistant Enterobacterales (CRE) conducted by Tamma et al [14], the values of minimum inhibitory concentrations (MICs) for imipenem and meropenem against the subgroup of non-carbapenemase-producing

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(non-CP) Enterobacterales (non-CPE) isolates were lower than those of the CPE subgroup. This result is partly consistent with that observed by Jean et al [15]. The susceptibility data regarding other antibiotic agents against clinical non-CP-CRE

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isolates in the Asia-Pacific region, however, are lacking. Using our database [10]

documenting the detailed MIC data of IAI Enterobacterales isolates cultured from

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patients hospitalised in the Asia-Pacific region, we investigated the susceptibility

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results against important antibiotics for carbapenem-non-susceptible (NS)-non-CPE isolates recovered from various IAI sites. Additionally, the pharmacokinetic (PK) properties of given antibiotics at different infection sites play decisive roles in success

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of treatment against the implicated pathogens amongst critically-ill patients [16,17]. To precisely prescribe correct antibiotic regimen/dosage in treating the potential IAI

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due to drug-resistant Enterobacterales spp., we also explored the relevant PK profiles

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of intra-abdominal organs (especially hepatobiliary system and peritoneum, accounting for major IAI sources) and pharmacodynamic (PD) parameters of important antibiotics to try to recommend the appropriate choice for treatment of IAI caused by carbapenem-NS-non-CPE isolates.

2. Materials and Methods 4

2.1. Study countries and sources of the IAI isolates under survey Thirty-seven medical centres in 12 Asia-Pacific countries/regions, including Australia (n=5), the Hong Kong Special Administrative Region of China (n=2), Japan (n=3), Kazakhstan (n=1), Malaysia (n=2), New Zealand (n=4), Singapore (n=2), South Korea (n=2), Taiwan (n=8), Thailand (n=2), the Philippines (n=2), and Vietnam (n=4), participated in this IAI survey programme between 2008 and 2014. Consecutive isolates of Enterobacterales cultured from the first clinical specimens of

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respective patients with IAI, as part of the routine laboratory procedures, were obtained (each isolate was from one different patient). Clinical specimens were

recorded from various intra-abdominal sites with relation to IAI. They consisted of

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tissue, fluid, or deep wound cultures obtained intraoperatively, and fluid from

paracentesis or percutaneous aspiration of abscess, and specimens of unspecified

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intra-abdominal etiologies. Duplicate isolates (the same species from the same patient

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within 30 days from the first positive culture) were excluded. Ages of all IAI patients were also recorded. This study was approved by the Institutional Review Boards and Ethical Committees of the participating centres, including the National Taiwan

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University Hospital (Taipei, Taiwan) [NTUH 9561709108].

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2.2. Antimicrobial susceptibility testing, molecular detection of extended-spectrum β-

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lactamases (ESBLs), AmpC β-lactamases, and the definition of ertapenem-NS-nonCPE

Determinations of MICs of the following antibiotics: cefoxitin (2->16 mg/L),

ceftriaxone (1->64 mg/L), piperacillin/tazobactam (2->64 mg/L), cefepime (0.5->32 mg/L), ertapenem (0.03->4 mg/L), imipenem (0.12->8 mg/L), amikacin (4->32 mg/L), ciprofloxacin (0.25->2 mg/L) and levofloxacin (0.5->4 mg/L) by the broth 5

microdilution method and quality control testing for all Enterobacterales isolates were both performed at the Central Laboratory (International Health Management Associates, Inc., Schaumburg, IL, USA). The antimicrobial susceptibility results were interpreted according to the MIC breakpoints recommended by the Clinical and Laboratory Standards Institute in 2018 [18]. As ertapenem (ETP) is most vulnerable to various mechanisms of carbapenem non-susceptibility (carbapenemase production; ESBL or AmpC plus development porin change and/or efflux pump) amongst overall

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carbapenem drugs [10], we used the MICs of ETP to screen CRE. ETP-NS isolates were those showing in vitro non-susceptibility to ertapenem.

Multiplex PCR for detecting the genes encoding ESBL, AmpC β-lactamases,

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and carbapenemases was employed for all isolates exhibiting an ertapenem MIC >0.5

mg/L as previously described [13]. Whole genomic DNA of the isolates was extracted

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using a QIAamp DNA minikit and QIAcube instrument (Qiagen, Valencia, CA, USA)

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from colonies grown overnight on blood agar plate (Remel, Lenexa, KS, USA). Specific primers to detect ESBL alleles (blaCTX-M, blaTEM, blaSHV, blaVEB, blaGES and blaPER), plasmid-mediated AmpC genes (blaACC, blaCMY, blaMOX, blaFOX, blaDHA,

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blaACT, and blaMIR) and carbapenemase genes (blaSPM, blaGIM, blaKPC, blaVIM, blaNDM, blaIMP and blaOXA) were used as previously described [19]. In this study, if the IAI

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ETP-NS Enterobacterales strains were demonstrated to lack carbapenemase-encoding

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genes based upon the multiplex PCR results, they were defined as ETP-NS-non-CPE and were enrolled into the analysis.

2.3. Statistical analysis Continuous variables were presented as the mean ± standard deviation (SD) or median with interquartile range, and they were compared using the Student’s t-test or 6

Wilcoxon rank sum test for two indicated groups depending upon the normality of distributions. Calculations of the susceptibility differences were evaluated using Pearson X2 test or Fisher’s exact test as appropriate. Odds ratios (OR) and 95% confidence interval (CI) were also evaluated. A P value <0.05 was considered statistically significant. All tests were two-tailed, and were performed with statistical package SPSS for Windows (version 17.0, SPSS, Chicago, IL, USA).

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3. Results

3.1. ETP-NS-non-CPE isolates of different species, and production rates of ESBL and

AmpC enzymes amongst the ETP-NS-non-CPE isolates cultured from various IAI sites

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In this Asia-Pacific IAI Enterobacterales survey, 2.59% (484/18689) of

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Enterobacterales isolates were IAI-CRE exhibiting in vitro non-susceptibility to ertapenem. Of these, 404 (83.5%) ETP-NS isolates were non-CPE according to the

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results of the multiplex PCR assay. Isolates of Enterobacter species (n=210), followed by Klebsiella pneumoniae (n=91) and Escherichia coli (n=83) accounted for a

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majority (95.0%) of the enrolled ETP-NS-non-CPE isolates. The remaining 20 ETPNS-non-CPE isolates consisted of Citrobacter species (n=9), Serratia species (n=8),

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Klebsiella oxytoca (n=1), Cronobacter sakazakii (n=1), and Pantoea agglomerans (n=1). The production rates of ESBL alone, plasmidic AmpC alone, and coexistence

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of dual enzymes amongst the ETP-NS-IAI isolates of three leading non-CPE species (E. coli, K. pneumoniae, and Enterobacter spp.) from various IAI sites are illustrated in Table 1. The isolates collected in hepatobiliary system were mostly from the gallbladder and hepatic parenchyma. The rates of ESBL/AmpC production were similar to those of ETP-NS-CPE isolates (data not shown). Amongst the distribution countries of IAI-ETP-NS-non-CPE isolates in this Asia-Pacific study, the isolates 7

submitted by Taiwan, south Korea, Australia followed by Vietnam accounted for a majority (73.8%) of overall isolates. They were significantly different from those regarding the IAI-ETP-NS-CPE isolates.

3.2. Susceptibility data for imipenem, amikacin, and cefepime against the overall ETP-NS-non-CPE isolates cultured from the hepatobiliary system and the peritoneal space

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Amongst the IAI-ETP-NS-non-CPE isolates of three leading species, the fraction of hepatobiliary isolates and that of isolates cultured from the peritoneal

space were 47.0% vs. 32.5% for E. coli, 41.8% vs. 39.6% for K. pneumoniae, and

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50.5% vs. 35.2% for Enterobacter spp. (OR, 1.444, 1.056, and 1.432; 95% CI, 0.983 2.123, 0.743 - 1.500, and 1.141 - 1.798; P values, 0.057, 0.880, and 0.002,

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respectively). Additionally, the mean age (years) of the patient group with

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hepatobiliary ETP-NS-non-CPE IAI (n=193) is significantly higher than that of the peritoneal IAI group (n=145) when evaluated by Student’s t-test (mean ± SD, 66.4 ± 15.9 and 58.7 ± 18.7, respectively; P <0.001).

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The majority (>75%) of the ETP-NS-non-CPE isolates enrolled in this study were NS to ceftriaxone, cefoxitin, and piperacillin-tazobactam. The susceptibility data

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for imipenem, amikacin, and cefepime against the overall ETP-NS-non-CPE IAI

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isolates are illustrated in Fig. 1. The MIC50/MIC90 values for imipenem were 0.5/2.0 mg/L for the overall isolates of ETP-NS-non-CPE cultured from either the hepatobiliary system or from the peritoneal space. Despite this, a significantly lower non-susceptible rate for imipenem was observed amongst the overall hepatobiliary ETP-NS-non-CPE isolates than that for the overall peritoneal isolates (P = 0.034; OR, 0.519; 95% CI, 0.287 – 0.938). The hepatobiliary imipenem-NS-non-CPE group 8

consisted of one S. marcescens isolate and 22 isolates of the three leading species, whilst the peritoneal imipenem-NS-non-CPE group included one Serratia odorifera and one C. freundii isolate in addition to 28 isolates from the three main species. Moreover, a higher proportion of the ETP-NS-non-CPE isolates with a cefepime MIC >4 mg/L was observed from the peritoneal space (69/145) when compared with those from the hepatobiliary system (71/193; P = 0.058; OR, 1.206; 95% CI, 0.999 - 1.457;

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Fig. 2).

3.3. Susceptibility data for amikacin, ciprofloxacin, levofloxacin, and cefepime

against the isolates of ETP-NS-non-CPE of different species cultured from different

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IAI sites

ETP-NS-non-CPE isolates were divided according to the species difference to

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evaluate the antibiotic non-susceptibility profiles for the subgroups of E. coli, K.

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pneumoniae, and isolates of Enterobacter species. We observed that overall isolates of ETP-NS-non-CP Enterobacter species [mainly E. cloacae (n=185; 88.1%)] displayed significantly higher susceptibility rates to levofloxacin and ciprofloxacin, as well as a

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lower cefepime MIC distribution (<4, and <8 mg/L) than those for the subgroups of ETP-NS-non-CP K. pneumoniae and E. coli subgroups (all P values <0.005), as

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illustrated in Fig. 3. Between the subgroups of ETP-NS-non-CP Enterobacter isolates

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with imipenem-susceptible and imipenem-NS phenotypes (n=184 and 26, respectively), the susceptibility rates against amikacin, ciprofloxacin and levofloxacin were not significantly different (P values, 1.000, 0.355 and 0.782, respectively). The hepatobiliary and peritoneal ETP-NS-non-CPE isolates were also divided according to the species difference. For hepatobiliary IAI isolates [including E. coli (n=39), K. pneumoniae (n=38), and Enterobacter species (n=106) mainly], 9

prominently lower non-susceptibility rates to amikacin, ciprofloxacin, levofloxacin, and a distribution of lower cefepime MIC (<4 mg/L) were found amongst isolates of Enterobacter species than those of E. coli isolates (OR, 255, 0.368, 0.226, and 0.518; 95% CI, 0.118 - 0.548, 0.250 - 0.542, 0.137 - 0.374, and 0.346 - 0.777, respectively; all P values <0.005). A similar trend, with the exception of cefepime MIC distribution, was observed between the hepatobiliary Enterobacter spp. and K. pneumoniae isolates (OR, 0.248, 0.358, 0.239, and 0.818; 95% CI, 0.116 - 0.533,

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0.244 - 0.526, 0.143 - 0.399, and 0.608 - 1.102; P values, 0.0004, <0.0001, <0.0001, and 0.162, respectively) (Fig. 4). The peritoneal isolates, cultured from various

quadrants of abdomen, also predominantly included E. coli (n=27), K. pneumoniae

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(n=36), and Enterobacter species (n=74). This statistically significant trend regarding differences in non-susceptibility against the four antibiotics listed above (amikacin,

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ciprofloxacin, levofloxacin, and cefepime) is also observed for the peritoneal ETP-

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NS-non-CPE isolates between Enterobacter spp. and E. coli (OR, 0.243, 0.279, 0.215, and 0.486; 95% CI, 0.096 - 0.619, 0.157 - 0.494, 0.113 - 0.409, and 0.319 - 0.743, respectively; all P values <0.005) and for K. pneumoniae (OR, 0.208, 0.253, 0.270,

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and 0.508; 95% CI, 0.087 - 0.497, 0.148 - 0.434, 0.139 - 0.524, and 0.337 - 0.765, respectively; all P values <0.005), as illustrated in Fig. 5. Additionally, Figure 6

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illustrates the MIC distribution curves of imipenem, cefepime, levofloxacin and

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ciprofloxacin (further separated for hepatobiliary and peritoneal isolates) against isolates of ETP-NS-non-CP Enterobacter species.

4. Discussion To our knowledge, this is the largest study investigating the non-susceptibility data of non-CP-CRE isolates now. This in vitro study regarding the Asia-Pacific IAI10

ETP-NS-non-CPE isolates highlights three important points. Firstly, most (>80%) of the ETP-NS-non-CPE isolates were in vitro susceptible to imipenem and amikacin. Secondly, the overall hepatobiliary ETP-NS-non-CPE isolates exhibited slightly better susceptibility rates to imipenem, amikacin, and a distribution of lower cefepime MICs (4 mg/L) than those cultured from the peritoneal space. Thirdly, from two main IAI sites, significant fractions of the ETP-NS-non-CP Enterobacter isolates displayed cefepime MICs 4 mg/L, and were susceptible in vitro to levofloxacin and

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ciprofloxacin.

As reflected in the age distributions amongst two groups of different IAI

sources of ETP-NS-non-CPE isolates in this study, the hepatobiliary disorder is more

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likely to occur in elderly patients [20]. Despite amikacin exhibiting a high

susceptibility rate for the IAI-ETP-NS-non-CPE isolates, it fails to achieve the PD

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target (at least eight-fold of concentration above the amikacin MIC [21]) for the ETP-

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NS-non-CPE isolates within biliary tracts [21-23] and the peritoneal space [24,25]. Consequently, amikacin is only recommended as an adjuvant option in treating the

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ETP-NS-non-CPE IAI isolates. In this study, amongst the ETP-NS-non-CP Enterobacter isolates, the hyperproduction of AmpC enzymes and/or porin change

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might be the main mechanisms resulting in ertapenem non-susceptibility. Compared to isolates of Enterobacter spp., production of ESBL enzymes in conjunction with

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porin dysfunction and/or development of efflux pump might greatly contribute to the ETP-NS phenotype amongst the enrolled E. coli and K. pneumoniae isolates. The higher non-susceptibility rates to imipenem and cefepime against peritoneal isolates than those cultured from hepatobiliary system might be related to a higher difficulty of antibiotic therapy for deep-seated peritoneal isolates than other sites. Approximately half of the plasma concentration is measured in bile after 11

imipenem intravenous administration [26]. Imipenem displays an optimal bactericidal efficacy when more than 40% of the dosing interval is at a drug concentration above the MIC for the given bacteria [27]. A PK analysis in humans indicates that the halflife (t1/2) of imipenem is 1.24 h in patients with normal creatinine clearance rates, and following an intravenous administration of 1000 mg imipenem, the mean peak concentration in bile is 17.5 mg/L [28]. After two t1/2 (2.5 hours, approximately 40% of the 6-hour interval) of 1000 mg imipenem administration, its mean peak

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concentration within bile is calculated to be 4.4 mg/L, which was above the MIC levels of most [95.3% (184/193), data not shown] hepatobiliary ETP-NS-non-CPE isolates. In addition, the other PK study involving patients with severe peritonitis

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showed that 79% of the dosing time where imipenem concentration is 4 mg/L in

peritoneal fluid is achieved when 1000 mg imipenem is administered intravenously

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[29]. It is also noteworthy that 93.1% and 90.3% (135/145 and 131/145, respectively,

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data not shown) of the 145 peritoneal ETP-NS-non-CPE isolates exhibit imipenem MICs 4 mg/L and 2 mg/L, respectively. Therefore, 1000 mg imipenem

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administered every 6 h is a theoretically effective regimen against the IAI-ETP-NSnon-CPE isolates.

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PK results for levofloxacin are not available in the PubMed database. The PK and PD profile of ciprofloxacin in humans, however, were both published in the

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PubMed database [30,31]. The MIC50/MIC90 values of ciprofloxacin against 193 ETPNS-non-CPE isolates cultured from the hepatobiliary system and 145 ETP-NS-nonCPE isolates from the peritoneal space isolates were 1/>2 mg/L. A PD analysis undergone on humans to investigate ciprofloxacin that was proposed by Forrest et al demonstrated that a 24-h area under the inhibitory curve (AUIC) 125 is required to achieve >80% probability of eradicating effectively the target Gram-negative bacteria 12

(GNB) [30]. In addition, Ball et al developed a PK regression formula used to calculate the concentration and area under the concentration-time curve (AUC) of ciprofloxacin in bile [31]. When the linear extrapolation of this regression formula was applied, under conditions where 400 mg ciprofloxacin is administered intravenously every 8 h, the 24-h AUC of this drug in bile is approximately 280, and the mean peak concentration of ciprofloxacin in bile is 22-24 mg/L. In this IAI study, approximately three-fourths [74.5% (79/106), as shown in Fig. 6] of 106 hepatobiliary

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ETP-NS-non-CP Enterobacter isolates exhibited ciprofloxacin MICs 2 mg/L, indicating that these could be successfully treated with 400 mg ciprofloxacin

intravenously every 8 h. By contrast, a significantly lower AUC was found in ascites

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(20.7 ± 5.0 mg • h/L, 12 h following a single oral 750 mg ciprofloxacin

administration) compared to that in biliary tracts [32]; however, 70.3% (52/74, shown

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in Fig. 6) of the isolates of peritoneal ETP-NS-non-CP Enterobacter spp. exhibited

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ciprofloxacin MICs 0.25 mg/L. As calculated, 400 mg ciprofloxacin administered intravenously every 8 h also likely achieves the PD goal of ciprofloxacin AUIC 125

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against approximately 70% of the peritoneal ETP-NS-non-CP Enterobacter isolates. As compared to other cephalosporins, cefepime possesses a low molecular

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weight (572 Dalton), a zwitterionic nature (thus likely with high peritoneal penetrability), and a low protein-affinity percentage (12%) (MAXIPIME package

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insert; Bristol-Myers-Squibb, NJ, USA). Additionally, cefepime exhibits an average t1/2 of 2.3 h in patients with normal creatinine clearance rates [33]. Compared to isolates of E. coli and K. pneumoniae, cefepime shows a higher in vitro activity against Enterobacter isolates that were intrinsically AmpC hyper-producers and had less ESBL enzyme production. After 1 g cefepime is administered intravenously, its maximal concentration in the blood reaches 96.0 + 19.0 mg/L [34]. Following an 13

intravenous administration of 2 g cefepime, the average cefepime concentration in well-functioning gallbladder can be as high as 45-50 μg/g, and the concentration range is between 15 mg/L and 20 mg/L in bile at 8 h post-dosing [35,36]. In this IAI survey, 84.9% (90/106, data not shown) of the hepatobiliary Enterobacter isolates exhibited cefepime MICs 16 mg/L. Therefore, according to the above PK analyses [33-36] and PD target of cefepime [37], 2 g cefepime administered every 8 h is likely an effective treatment option against the biliary tract infections caused by ETP-NS-

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non-CP Enterobacter isolates.

A two-thirds ratio of plasma-to-peritoneum and plasma-to-intestinal tissue penetration of cefepime was noted [37,38]. Consequently, remarkably high initial

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peak concentrations of cefepime (>50 mg/L) in ascites and the bowel tissue exist

following 1 - 2 g cefepime administration intravenously. In addition, a PD survey of

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cefepime reveals an 85% probability of target attainment is achieved in treating the

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GNB with a cefepime MIC of 8 mg/L when 1 g cefepime intravenously infused over a 3-h duration is administered three times per day [34]. As seen in Fig. 5 and Fig. 6, when compared to the ETP-NS-non-CP E. coli and K. pneumoniae isolates cultured

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from peritoneal space, a 3 g/day with 3-h infusion regimen of cefepime is

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significantly more active against the peritoneal ETP-NS-non-CP Enterobacter isolates. Table 2 summarises the PD parameters of important antibiotics for predicting

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the clinical efficacy in treatment of IAI due to ETP-NS-non-CPE isolates [21,27,30,37].

There are some limitations to this study. Firstly, we did not investigate porin

dysfunction [39,40] and the existence of efflux pumps in these ETP-NS-non-CPE isolates. We also did not investigate the susceptibility data of meropenem and doripenem for the ETP-NS-non-CPE isolates. Secondly, the genetic relatedness, and 14

clones of special sequence types (e.g., ST131 E. coli [41,42], ST11 K. pneumoniae [41]) of these enrolled IAI isolates were not determined. Despite the above-mentioned limitations, these IAI isolates were collected consecutively and randomly from the patients hospitalised amongst 12 Asia-Pacific countries during a 7-year period. Therefore, they were able to be deemed a representative population of IAI isolates. Thirdly, as this study was conducted in 2008, the susceptibility data of some novel anti-Gram-negative antibiotics, including ceftolozane-tazobactam and ceftazidime-

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avibactam against IAI-ETP-NS-non-CPE isolates, are lacking. Fourthly, the accurate sequencing of some ESBL variants (blaTEM and blaSHV) was not determined. Finally, we did not perform further investigation to prove the reality of PD for the antibiotics

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recommended to treat the IAI-ETP-NS-non-CPE isolates in this study. Nevertheless, the appropriate regimens and dosage of antibiotics concluded in this study are

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robustly inferred from the reliable PK evidence well documented in literature

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[21,23,25-32,34-38], and thus have the value of recommendation. The emergence of post-treatment resistance on these isolates of drug-resistant Enterobacterales spp., however, needs to be investigated.

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In conclusion, although the clinical efficacy of above recommended regimens against the IAI-ETP-NS-non-CPE isolates requires validation, a regimen of 1000 mg

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imipenem administered intravenously every 6 h theoretically predicts a good efficacy

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in treatment of the IAI-ETP-NS-non-CPE isolates. Additionally, 400 mg ciprofloxacin administered intravenously every 8 h and a 3 - 6 g/day, with 3-h infusion regimen of cefepime also predict reliable efficacy against approximately 70% of the IAI isolates of ETP-NS-non-CP Enterobacter species.

Declarations 15

Funding: This study was supported by Merck Sharp & Dohme.

Competing interests: The authors declare no competing interests.

Ethical Approval: This study was approved by the Institutional Review Boards and Ethical Committees of the participating centres, including the National Taiwan

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University Hospital (Taipei, Taiwan) [NTUH 9561709108].

Acknowledgments

We acknowledge all of the investigators in the Asia-Pacific region for their

-p

participation in the SMART programme. The investigators included Tony Korman

re

(Monash Medical Centre, Clayton, VIC, Australia), Justin Ellem (Westmead Hospital, Westmead, NSW, Australia), Narelle George (Royal Brisbane Hospital, Brisbane,

lP

QLD, Australia), Geoffrey Coombs (Royal Perth Hospital, Perth, WA, Australia), Thomas Ling (Prince of Wales Hospital, Shatin, New Territories, Hong Kong),

na

Raymond Leung (Queen Mary Hospital, Hong Kong), Hiroshige Mikamo (Aichi Medical University Hospital, Nagakute, Japan), Yoshikazu Ishii (Toho University,

ur

Tokyo, Japan), Yasunao Wada (Hyogo College of Medicine, Hyogo, Japan), Tetsu Mizutani (Osaka Police Hospital, Osaka City, Japan), Wee-Gyo Lee (Ajou University

Jo

Hospital, Suwon, Gyeonggi-do, South Korea), Jacob Lee (Hallym University Kangnam Sacred Heart Hospital, Seoul, South Korea), Min-Ja Kim (Korea University Anam Hospital, Seoul, South Korea), In-Gyu Bae (Kyeongsang University Hospital, Jinju, South Korea), Nurulhuda Binti Umur (Hospital Kuala Lumpur, Kuala Lumpur, Malaysia), Roziana Anis (Hospital Sultanah Aminah Johin Bahru, Johor Bahru, Malaysia), Susan Taylor (Middlemore Hospital at Counties Manukau District, 16

Otahuhu, New Zealand), Sally Roberts (Auckland City Hospital, Grafton, New Zealand), Koen van der Werff (Wellington Hospital, Wellington, New Zealand), Dragana Drinkovic (North Shore Hospital, Auckland, New Zealand), Evelina Lagamayo (St Luke’s Medical Centre, Quezon City, the Philippines), Marissa Alejandria (Philippine General Hospital, Manila, the Philippines), Thean Yen Tan (Changi General Hospital, Singapore), Prabha Krishnan (Tan Tock Seng Hospital, Singapore), Wen-Chien Ko (National Cheng Kung University Hospital, Tainan,

ro of

Taiwan), Po-Liang Lu (Kaohsiung Medical University Hospital, Kaohsiung City, Taiwan), Chun-Eng Liu (Changhua Christian Hospital, Changhua City, Taiwan),

Kenneth Yin-Ching Chuang (Chi-Mei Medical Centre, Tainan City, Taiwan), Fu-Der

-p

Wang (Taipei Veterans General Hospital, Taipei, Taiwan), Jen-Hsien Wang (China

Medical University Hospital, Taichung City, Taiwan), Hsing-ping Chin (Kaohsiung

re

Veteran General Hospital, Kaohsiung City, Taiwan), Min-Chi Lu (Chung Shan

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Medical University Hospital, Taichung City, Taiwan), Siripen Panthuwong (Songklanakarin Hospital, Songkhla Province, Thailand), Pattarachai Kiratisin (Siriraj Hospital, Bangkok-Noi, Thailand), Phan Thi Thu Hong (Binh Dan Hospital, Ho Chi

na

Minh City, Vietnam), Pham Hong Nhung (Bach Mai Hospital, Hanoi, Vietnam), Nguyen Thi Van (Benh Vien Viet Duc Hospital, Hanoi, Vietnam) and Tran Thi Thanh

Jo

ur

Nga (Choray Hospital, Ho Chi Minh City, Vietnam).

17

References 1.

Sartelli M, Catena F, Ansaloni L, Lazzareschi DV, Taviloglu K, Van Goor H, et al. Complicated intra-abdominal infections observational European study (CIAO Study). World J Emerg Surg 2011;6:40.

2.

Jean SS, Lee NY, Tang HJ, Lu MC, Ko WC, Hsueh PR. Carbapenem-resistant Enterobacteriaceae infections: Taiwan aspects. Front Microbiol 2018;9:2888.

3.

Jayaraman R, Varghese R, Kumar JL, Neeravi A, Shanmugasundaram D, Ralph

ro of

R, et al. Invasive pneumococcal disease in Indian adults: 11 years' experience. J Microbiol Immunol Infect 2018 May 22. pii: S1684-1182(18)30113-0. http://doi.org/10.1016/j.jmii.2018.03.004. [Epub ahead of print].

Chen WC, Chen YW, Ko HK, Yu WK, Yang KY. Comparisons of clinical

-p

4.

re

features and outcomes between Elizabethkingia meningoseptica and other glucose non-fermenting Gram-negative bacilli bacteremia in adult ICU patients.

lP

J Microbiol Immunol Infect 2018 Sep 19. pii: S1684-1182(18)30396-7. http://doi.org/10.1016/j.jmii.2018.08.016. [Epub ahead of print]. Lin WT, Tang HJ, Lai CC, Chao CM. Clinical manifestations and bacteriological

na

5.

features of culture-proven Gram-negative bacterial arthritis. J Microbiol

6.

ur

Immunol Infect 2017;50:527-31. Ting SW, Lee CH, Liu JW. Risk factors and outcomes for the acquisition of

Jo

carbapenem-resistant Gram-negative bacillus bacteremia: A retrospective propensity-matched case control study. J Microbiol Immunol Infect 2018;51:6218.

7.

Tago S, Hirai Y, Ainoda Y, Fujita T, Kikuchi K. Gram-negative rod bacteremia after cardiovascular surgery: Clinical features and prognostic factors. J Microbiol Immunol Infect 2017;50:333-8. 18

8.

Kuo SH, Lin WR, Lin JY, Huang CH, Jao YT, Yang PW, et al. The epidemiology, antibiograms and predictors of mortality among critically-ill patients with central line-associated bloodstream infections. J Microbiol Immunol Infect 2018;51:401-10.

9.

Ko WC, Hsueh PR. Increasing extended-spectrum β-lactamase production and quinolone resistance among Gram-negative bacilli causing intra-abdominal infections in the Asia/Pacific region: data from the SMART Study 2002-2006. J

ro of

Infect 2009;59:95-103. 10. Jean SS, Hsueh PR. Distribution of ESBLs, AmpC β-lactamases and

carbapenemases among Enterobacteriaceae isolates causing intra-abdominal and

-p

urinary tract infections in the Asia-Pacific region during 2008-14: results from the Study for Monitoring Antimicrobial Resistance Trends (SMART). J

re

Antimicrob Chemother 2017;72:166-71.

lP

11. Tseng SP, Wang SF, Ma L, Wang TY, Yang TY, Siu LK, et al. The plasmidmediated fosfomycin resistance determinants and synergy of fosfomycin and meropenem in carbapenem-resistant Klebsiella pneumoniae isolates in Taiwan. J

na

Microbiol Immunol Infect 2017;50:653-61. 12. Ismail B, Shafei MN, Harun A, Ali S, Omar M, Deris ZZ. Predictors of

ur

polymyxin B treatment failure in Gram-negative healthcare-associated infections

Jo

among critically ill patients. J Microbiol Immunol Infect 2018;51:763-9. 13. Tacconelli E, Carrara E, Savoldi A, Harbarth S, Mendelson M, Monnet DL, et al; WHO Pathogens Priority List Working Group. WHO Pathogens Priority List Working Group. Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect Dis 2018;18:318-27. 19

14. Tamma PD, Goodman KE, Harris AD, Tekle T, Roberts A, Taiwo A, et al. Comparing the outcomes of patients with carbapenemase-producing and noncarbapenemase-producing carbapenem-resistant Enterobacteriaceae bacteremia. Clin Infect Dis 2017;64:257-64. 15. Jean SS, Lee WS, Hsueh PR; SMART Asia-Pacific Group. Ertapenem nonsusceptibility and independent predictors of the carbapenemase production among the Enterobacteriaceae isolates causing intra-abdominal infections in the

ro of

Asia-Pacific region: results from the Study for Monitoring Antimicrobial Resistance Trends (SMART). Infect Drug Resist 2018;11:1881-91.

16. Roberts JA, Lipman J. Pharmacokinetic issues for antibiotics in the critically ill

-p

patient. Crit Care Med 2009;37:840-51.

17. Onufrak NJ, Forrest A, Gonzalez D. Pharmacokinetic and pharmacodynamic

re

principles of anti-infective dosing. Clin Ther 2016;38:1930-47.

lP

18. Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing: Twenty-seventh Informational Supplement M100-S28. CLSI, Wayne, PA, USA, 2018.

na

19. Lob SH, Kazmierczak KM, Badal RE, Hackel MA, Bouchillon SK, Biedenbach DJ, et al. Trends in susceptibility of Escherichia coli from intra-abdominal

ur

infections to ertapenem and comparators in the United States according to data

Jo

from the SMART program, 2009 to 2013. Antimicrob Agents Chemother 2015;59:3606-10.

20. da Rocha MC, Marinho RT, Rodrigues T. Mortality associated with hepatobiliary disease in Portugal between 2006 and 2012. GE Port J Gastroenterol 2018;25:123-31.

20

21. Kato H, Hagihara M, Hirai J, Sakanashi D, Suematsu H, Nishiyama N, et al. Evaluation of amikacin pharmacokinetics and pharmacodynamics for optimal initial dosing regimen. Drugs R D 2017;17:177-87. 22. LeFrock JL, Schell RF, Siskind S, Carr BB. Amikacin levels in the human biliary tract. J Clin Pharmacol 1984;24:247-54. 23. Bermúdez RH, Lugo A, Ramírez-Ronda CH, Amadeo JA, Morales J. Amikacin sulfate levels in human serum and bile. Antimicrob Agents Chemother

ro of

1981;19:352-4. 24. Smithivas T, Hyams PJ, Matalon R, Simberkoff MS, Rahal JJ Jr. The use of gentamicin in peritoneal dialysis. I. Pharmacologic results. J Infect Dis

-p

1971;124:S77-S83.

25. MacGregor RR. Comparative penetration of amikacin, gentamicin, and penicillin

lP

Chemother 1977;11:110-3.

re

G into exudate fluid in experimental sterile peritonitis. Antimicrob Agents

26. Buckley MM, Brogden RN, Barradell LB, Goa KL. Imipenem/cilastatin: a reappraisal of its antibacterial activity, pharmacokinetic properties and

na

therapeutic efficacy. Drugs 1992;44:408-44. 27. Zhanel GG, Wiebe R, Dilay L, Thomson K, Rubinstein E, Hoban DJ, et al.

ur

Comparative review of the carbapenems. Drugs 2007;67:1027-52.

Jo

28. Mayer M, Tophof C, Opferkuch W. Bile levels of imipenem in patients with Tdrain following the administration of imipenem/cilastatin. Infection 1988;16:225-8.

29. Dahyot-Fizelier C, Lefeuvre S, Laksiri L, Marchand S, Sawchuk RJ, Couet W, et al. Kinetics of imipenem distribution into the peritoneal fluid of patients with severe peritonitis studied by microdialysis. Clin Pharmacokinet 2010;49:323-34. 21

30. Forrest A, Nix DE, Ballow CH, Goss TF, Birmingham MC, Schentag JJ. Pharmacodynamics of intravenous ciprofloxacin in seriously ill patients. Antimicrob Agents Chemother 1993;37:1073-81. 31. Ball CS, Manson JM, Reid F, Tweedle DE. The pharmacokinetics of the biliary excretion of ciprofloxacin. HPB Surg 1989;1:319-26. 32. Dan M, Zuabi T, Quassem C, Rotmensch HH. Distribution of ciprofloxacin in ascitic fluid following administration of a single oral dose of 750 milligrams.

ro of

Antimicrob Agents Chemother 1992;36:677-8. 33. Barbhaiya RH, Knupp CA, Forgue ST, Matzke GR, Guay DR, Pittman KA. Pharmacokinetics of cefepime in subjects with renal insufficiency. Clin

-p

Pharmacol Ther 1990;48:268-76.

34. Higuchi K, Ikawa K, Ikeda K, Ohge H, Sueda T, Houchi H, et al. Peritoneal

re

pharmacokinetics of cefepime in laparotomy patients with inflammatory bowel

lP

disease, and dosage considerations for surgical intra-abdominal infections based on pharmacodynamic assessment. J Infect Chemother 2008;14:110-6. 35. Petrikkos G, Kastanakis M, Markogiannakis A, Kastanakis S, Bastounis E,

na

Antonios P, et al. Pharmacokinetics of cefepime in bile and gall bladder tissue after prophylactic administration in patients with extrahepatic biliary diseases.

ur

Int J Antimicrob Agents 2006;27:331-4.

Jo

36. Okamoto MP, Gill MA, Nakahiro RK, Chin A, Yellin AE, Berne TV, et al. Tissue concentrations of cefepime in acute cholecystitis patients. Ther Drug Monit 1992;14:220-5.

37. Ikawa K, Morikawa N, Hayato S, Ikeda K, Ohge H, Sueda T. Pharmacokinetic and pharmacodynamic profiling of cefepime in plasma and peritoneal fluid of abdominal surgery patients. Int J Antimicrob Agents 2007;30:270-3. 22

38. Okamoto MP, Chin A, Gill MA, Yellin AE, Berne TV, Heseltine PN, et al. Analysis of cefepime tissue penetration into human appendix. Pharmacotherapy 1991;11:353-8. 39. Wozniak A, Villagra NA, Undabarrena A, Gallardo N, Keller N, Moraga M, et al. Porin alterations present in non-carbapenemase-producing Enterobacteriaceae with high and intermediate levels of carbapenem resistance in Chile. J Med Microbiol 2012;61:1270-9.

ro of

40. Senchyna F, Gaur RL, Sandlund J, Truong C, Tremintin G, Kültz D, et al. Diversity of resistance mechanisms in carbapenem-resistant Enterobacteriaceae at a health care system in Northern California, from 2013 to 2016. Diagn

-p

Microbiol Infect Dis 2019;93:250-7.

41. Jean SS, Lee WS, Lam C, Hsu CW, Chen RJ, Hsueh PR. Carbapenemase-

re

producing Gram-negative bacteria: current epidemics, antimicrobial

lP

susceptibility and treatment options. Future Microbiol 2015;10:407-25. 42. Johnson JR, Johnston B, Clabots C, Kuskowski MA, Castanheira M. Escherichia coli sequence type ST131 as the major cause of serious multidrug-resistant E.

Jo

ur

na

coli infections in the United States. Clin Infect Dis 2010;51:286-9.

23

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Fig. 1. In vitro susceptibility data of overall ertapenem-non-susceptible non-

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carbapenemase-producing Enterobacterales isolates (n=404) to three different

Jo

ur

na

lP

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antimicrobial agents (imipenem, amikacin, and cefepime)

24

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Fig. 2. Non-susceptibility data to different antibiotics for the overall ertapenem-non-

re

system (n=193) and peritoneal space (n=145)

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susceptible non-carbapenemase-producing isolates cultured from the hepatobiliary

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Non-CPE, non-carbapenemase-producing Enterobacterales. The 23 hepatobiliary imipenem/ertapenem-non-susceptible non-carbapenemase-producing Enterobacterales isolates cultured from hepatobiliary system consisted of one Serratia marcescens

na

isolate, 4 Escherichia coli isolates, 7 Klebsiella pneumoniae isolates, and 11 isolates of Enterobacter species. In addition, 30 peritoneal imipenem/ertapenem-non-

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susceptible non-carbapenemase-producing Enterobacterales isolates consisted of one

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S. odorifera, one Citrobacter freundii isolate, 6 E. coli isolates, 11 K. pneumoniae isolates, and 11 isolates of Enterobacter species.

25

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Fig. 3. Non-susceptibility data to different antibiotics for the overall ertapenem-non-

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susceptible non-carbapenemase-producing isolates of Escherichia coli (n=83),

Jo

ur

na

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Non-CP, non-carbapenemase-producing

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Klebsiella pneumoniae (n=91), and Enterobacter species (n=210)

26

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Fig. 4. Non-susceptibility data to different antibiotics for the ertapenem-non-

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susceptible non-carbapenemase-producing isolates of Escherichia coli (n=39),

Klebsiella pneumoniae (n=38), and Enterobacter species (n=106) cultured from the

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hepatobiliary system

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ur

na

Non-CP, non-carbapenemase-producing

27

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Fig. 5. Non-susceptibility data to different antibiotics for the ertapenem-non-

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susceptible non-carbapenemase-producing isolates of Escherichia coli (n=27),

Klebsiella pneumoniae (n=36), and Enterobacter species (n=74) cultured from the

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peritoneal space

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na

Non-CP, non-carbapenemase-producing

28

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Fig. 6. Distributions of curves of minimum inhibitory concentrations to imipenem,

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cefepime, and levofloxacin against all 210 ertapenem-non-susceptible non-

carbapenemase-producing isolates of Enterobacter species, and that to ciprofloxacin

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na

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recovered from peritoneal space)

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against certain isolates (including 106 recovered from hepatobiliary system vs. 74

29

Table 1 Percentages of ESBL, plasmidic AmpC production, or coexistence of above dual βlactamase enzymes amongst the isolates of ertapenem-non-susceptible noncarbapenemase-producing Enterobacterales including Escherichia coli, Klebsiella pneumoniae, and Enterobacter species, causing intra-abdominal infections amongst patients hospitalised in the Asia-Pacific region during 2008-2014 E. colia

Culture

Overa

Hepato-

Peritoneal

Overall

Hepato-

Peritoneal

Overall

Hepato-

Peritoneal

sites

ll (83)

biliary

space (27)

(91)

biliary

space (36)

(210)

biliary

space (74)

(number)

K. pneumoniaeb

(39)

(38)

Enterobacter speciesc

ro of

Species

(106)

72.3

69.2

66.7

86.8

84.2

86.1

15.7

14.2

12.2

Main

TEM

TEM

TEM

SHV

SHV

SHV

TEM

TEM

TEM (9.5),

ESBL

(47),

(48.7),

(40.7),

(79.1),

(73.7),

(77.8),

(11.4),

(10.4),

CTX-M-1

types (%)

CTX-

CTX-

CTX-M-9

TEM

TEM

TEM

CTX-

CTX-

(6.8)

M-1

M-1

(25.9)

(40.7)

(38.9)

M-1

M-1

(25.3)

(28.2)

(7.1)

(5.7)

60.2

53.8

AmpC

re (44.7)

59.3

68.4

61.1

69.0

66.0

73.0

ACT (50)

CMY

CMY-2

CMY-2

DHA-1

DHA-1

DHA-1

ACT

ACT

AmpC

-2

(43.6)

(55.6)

(46.2)

(44.7)

(61.1)

(43.8)

(36.8)

types (%)

(48.2)

37.0

50.5

57.9

52.8

12.9

10.4

ur

Main

66.7

na

(%)

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Plasmidic

-p

ESBL (%)

Coexistenc

28.2

10.8

Jo

e of

36.1

ESBL plus

plasmidic AmpC (%)

UGI, upper gastrointestinal tract. LGI, lower gastrointestinal tract. 30

a

Includes 17 E. coli isolates recovered from other intra-abdominal sources.

b

Includes 17 K. pneumoniae isolates recovered from other intra-abdominal sources.

c

Includes 30 isolates of Enterobacter spp. recovered from other intra-abdominal

Jo

ur

na

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re

-p

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sources.

31

f oo

Table 2

The pharmacodynamic parameters of selected antibiotics for predicting clinical efficacy in treatment of intra-abdominal infections due to

PD parameters [reference]

Susceptible

MIC value (mg/L) with >80%

MIC50/MIC90 (mg/L) of

breakpoints

probability of target attainment

main ETP-NS-non-CPE

(CLSI 2018)

(dosage)

isolates (this study)

<2 mg/L (1000 mg every 6 h)

0.5/2 mg/L

Pr

e-

Agent

pr

ertapenem-non-susceptible non-carbapenemase-producing Enterobacterales isolates

>40% of the dosing interval is at a drug concentration above the MIC for the given bacteria [27]

Cefepime

About 60-70% of the dosing interval <2 mg/L when the free-drug concentration is above the MIC for the indicated bacteria [37] At least eight-fold of concentrations <16 mg/L above the amikacin MIC for the given bacteria [21]

<8 mg/L (>3 g/day with 3-h infusion regimen)

4/>32 mg/L

For bloodstream bacterial isolates, <8 mg/L (25 mg/kg intravenously once daily)

4/16 mg/L

A 24-h area under the inhibitory curve 125 [30]

For isolates of ETP-NS-non-CP Enterobacter species, <2 and <0.25 mg/L for isolates cultured from the hepatobiliary system and from the peritoneal space, respectively (400 mg intravenously every 8 h)

0.25/>2 mg/L

Jo ur

Amikacin

Ciprofloxacin

<1 mg/L

na l

Imipenem

<1 mg/L

32

f oo

PD, pharmacodynamic. MIC, minimum inhibitory concentration. CLSI, Clinical and Laboratory Standards Institute. ETP-NS-non-CPE,

Jo ur

na l

Pr

e-

pr

ertapenem-non-susceptible non-carbapenemase-producing Enterobacterales.

33