# Prevalence of ESBL-ProducingEnterobacter Species Resistant to Carbapenems in Iran: A Systematic Review and Meta-Analysis

Authors: Farzad Khademi; Hamid Vaez; Zohreh Neyestani; Amirhossein Sahebkar
Journal: International Journal of Microbiology
 (2022)

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## Abstract

Background. Carbapenems are the last-line therapy for multidrug-resistant (MDR) infections caused by Enterobacterales, including those caused by Enterobacter species. However, the recent emergence of carbapenem-resistant (CR) and extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae pathogens, which are resistant to nearly all antibiotics, has raised concerns among international healthcare organizations. Hence, because there is no comprehensive data in Iran, the current study aimed to evaluate the prevalence of antibiotic resistance among Enterobacter species, especially CR and ESBL-producing strains, in Iran. Methods. The literature search was performed up to June 21, 2021, in national and international databases using MeSH-extracted keywords, i.e., Enterobacter, antibiotic resistance, carbapenem, ESBL, and Iran. Study selection was done based on the predefined inclusion and exclusion criteria, and data analysis was carried out using the Comprehensive Meta-Analysis (CMA) software. Results. The pooled prevalence of Enterobacter species resistant to various antibiotics is as follows: imipenem 16.6%, meropenem 16.2%, aztreonam 40.9%, ciprofloxacin 35.3%, norfloxacin 31%, levofloxacin 48%, gentamicin 42.1%, amikacin 30.3%, tobramycin 37.2%, tetracycline 50.1%, chloramphenicol 25.7%, trimethoprim/sulfamethoxazole 52%, nalidixic acid 49.1%, nitrofurantoin 43%, ceftriaxone 49.3%, cefixime 52.4%, cefotaxime 52.7%, ceftazidime 47.9%, cefepime 43.6%, and ceftizoxime 45.5%. The prevalence rates of MDR and ESBL-producing Enterobacter species in Iran were 63.1% and 32.8%, respectively. Conclusion. In accordance with the warning of international organizations, our results revealed a high prevalence of ESBL-producing Enterobacter species in Iran, which is probably associated with the high prevalence of Enterobacter species resistant to most of the assessed antibiotics, especially MDR strains. However, the resistance rate to carbapenems was relatively low, and these drugs can still be considered as drugs of choice for the treatment of Enterobacter infections in Iran. Nevertheless, continuous monitoring of drug resistance along with antibiotic therapy based on the local data and evaluation of the therapeutic efficacy of new antibiotics or combination therapeutic strategies, such as ceftazidime/avibactam, meropenem/vaborbactam, plazomicin, and eravacycline, is recommended.


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## Body

## 1. Introduction

The genusEnterobacter includes three medically important species, i.e., Enterobacter cloacae complex, Enterobacter aerogenes complex, and Enterobacter sakazakii [1, 2]. These enteric Gram-negative rods belong to the Enterobacteriaceae family and rarely cause infection in immunocompetent patients, but they are commonly associated with nosocomial infections, especially by the Enterobacter cloacae complex, in neonates and immunocompromised patients [1–6]. The most common nosocomial infections associated with these lactose-fermenting Enterobacter species include pneumonia, urinary tract infection, septicemia, and wound infection, as well as device-associated infections [1, 2]. Like many bacterial infections, in which an increasing trend of antibiotic resistance has led to the emergence of public health problems and imposed economic costs on healthcare, such an increasing trend of antibiotic resistance has also been reported for Enterobacter species [3, 6]. Among different mechanisms of resistance to various antibiotics in these Gram-negative rods, the intrinsic or acquired production of antibiotic-inactivating enzymes such as β-lactamases is very important [1]. Enterobacter species producing AmpC chromosomal cephalosporins are intrinsically resistant to ampicillin as well as first- and second-generation cephalosporins [2]. Plasmid-encoded extended-spectrum β-lactamase (ESBL) genes are involved in Enterobacter species’ resistance to most β-lactam antibiotics, including second- and third-generation cephalosporins and aztreonam [6]. On the other hand, acquired resistance to quinolones, aminoglycosides, and carbapenems has been identified in hospital-acquired strains, which is highly important because these antibiotics are the last line of treatment [2, 4].Recently, based on the World Health Organization (WHO) report, CR and ESBL-producingEnterobacteriaceae have been identified as one of the greatest threats to human health [5]. Although Escherichia and Klebsiella species are two main threats among CR and ESBL-producing Enterobacteriaceae [3], in the United States, CR Enterobacter species are considered the second most common CR Enterobacteriaceae [6].However, there is no comprehensive data on antibiotic resistance patterns ofEnterobacter species, especially CR strains, and ESBL-mediated resistance mechanisms in Iran. Therefore, the current systematic review and meta-analysis were designed to determine the prevalence of antibiotic resistance patterns of Enterobacter species, especially carbapenem-resistant strains, along with the frequency of ESBL-producing strains in Iran.


## 2. Methods

### 2.1. Literature Search and Study Selection

International databases including PubMed, Scopus, and Google Scholar, along with national databases including Scientific Information Database (https://www.sid.ir/) and Magiran (https://www.magiran.com/), were searched independently by two investigators to find studies conducted on the prevalence of antibiotic resistance and ESBL-producing Enterobacter species in Iran. The search was performed from 1996 to June 21, 2021. The most common Medical Subject Headings (MeSH)-extracted keywords used for the literature search were as follows: Enterobacter, antibiotic resistance, carbapenem, ESBL, and Iran. We defined the inclusion and exclusion criteria for the studies retrieved in the search and selected studies that met our criteria after a review of the titles, abstracts, and full text of the articles. The following studies were removed from the meta-analysis: studies reporting antibiotic resistance and ESBL-positive isolates published in languages other than English or Persian, studies conducted in other countries, studies reporting other bacteria in the Enterobacteriaceae family, studies with a small sample size (less than 10 bacterial isolates), studies with insufficient data, and nonoriginal articles, abstracts, and duplicates. Reference lists of the included articles were checked in order to find any possible missed studies. The current systematic review and meta-analysis were designed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines [7].


### 2.2. Data Extraction

Two different investigators extracted the data, and a third investigator tabulated the required information in Table1 after resolving possible disagreements in the results of the search and reaching a consensus. Required data were as follows: first author’s surname, study location, study enrollment date, the number of isolates, antibiotic susceptibility testing methods, the prevalence of Enterobacter species resistance to different drugs, the prevalence of multidrug-resistant (MDR) Enterobacter species, and the frequency of ESBL-positive isolates. It is noteworthy that Enterobacter species have intrinsic resistance to β-lactam antibiotics including ampicillin, amoxicillin-clavulanate, ampicillin-sulbactam, cephalosporins I (cefazolin and cephalothin), cephamycins (cefoxitin and cefotetan), and cephalosporin II (cefuroxime). According to the Clinical and Laboratory Standards Institute (CLSI) guideline, susceptibility testing is unnecessary for the above-mentioned antibiotics [8]. For this reason, these antibiotics are not included in Table 1.Table 1
Required data were extracted from included articles in the meta-analysis.
Author (Ref)CityYearIsolate (n)ASTResistance rate (n)ESBL-positive (n)IPMMEMATMCIPNORLVXGENAMKTOBTETCHLSXTNALNITCROCFMCTXCAZCEPZOXMDRAmin et al. [9]Ahvaz2015-2016152Disk diffusion8053ND847063NDNDNDNDNDNDNDNDNDNDNDNDNDNDNDNDAfrugh et al. [10]Ahvaz2013-201417Disk diffusion1515ND15NDND1416ND17ND12161316ND17151416NDNDMousavian et al. [11]Ahvaz201265Disk diffusion0NDND6NDND53NDNDNDNDNDND10ND119ND11ND27Khosravi et al. [12]Ahvaz2009–2012156Disk diffusion98NDND91NDND10260ND64ND1089475121110NDNDNDNDNDNDKhosravi et al. [13]Ahvaz2009-2010209Disk diffusion124NDND88NDND143117ND124ND146119117143148NDNDNDNDNDNDDidgar [14]Arak2010–201247Disk diffusion6NDND19NDND1918NDNDND20NDND29NDND402519NDNDGhasemi et al. [15]Babol202030Disk diffusion6NDND6NDND46NDNDNDNDND9NDND10ND28ND28NDBayani et al. [16]Babol2011-201230Disk diffusion2NDND2NDNDND2NDNDNDNDNDNDNDNDND54ND0NDGhafouri et al. [17]Bojnurd201312Disk diffusion35ND8NDND82ND306ND16001NDNDNDNDPeymani et al. [18]Different cities201449Disk diffusion222716NDND2011NDNDND25NDND28ND3427NDND26NDPeymani et al. [19]Different cities2011-2012137Disk diffusion21672216ND59NDNDNDND83NDND78ND8071NDND83NDPoorabbas et al. [20]Different cities2008-200938Disk diffusion38NDND33ND3524260NDND22ND221813192024NDNDNDMolazade et al. [21]Fasa2012-201328Disk diffusionNDNDND11NDND80ND11ND14111111110NDNDNDNDNDEsmaeili et al. [22]Hamadan201115Disk diffusionNDNDND13NDND13ND13NDND106411NDNDNDNDNDNDNDYasemi et al. [23]Ilam2007–200920Disk diffusionNDNDNDNDNDND3NDNDNDND9ND6NDNDNDNDNDNDNDNDFatemi et al. [24]Isfahan2014-2015135Disk diffusion13169358NDND544653962623NDNDNDND898790ND98NDShokri et al. [25]Isfahan2012-201335Disk diffusion33ND21NDND2210NDNDNDNDND6NDND242212ND35NDKargar et al. [26]Jahrom2011-201225Disk diffusionNDNDNDNDNDND1771124ND2024NDNDND1010NDNDND1Shajari et al. [27]Kashan2005-200635Disk diffusion10NDND13NDND141211NDND2128NDND182222NDNDNDNDSepehri et al. [28]Kerman1996, 200072Disk diffusionNDNDNDNDNDND43NDNDNDND461228NDNDNDNDNDNDNDNDMortazavi et al. [29]Kermanshah2016-201772Disk diffusion7ND293530ND3635NDNDND493116ND403738NDND54NDAmini et al. [30]Kermanshah201518Disk diffusionNDNDND7NDND89NDNDND137566ND10NDNDNDNDKarambin and Zarkesh [31]Rasht2008–201050Disk diffusionNDNDND0NDND1541NDNDND40NDNDNDND43NDNDNDNDNDYaghubi et al. [32]Rasht2013–2015147Disk diffusion7961ND80NDND8166780ND10810510210211910992ND80NDNDRouhi et al. [33]Sanandaj2013-201410Disk diffusion2NDND20ND05ND2NDND003ND54ND5NDNDNikkhoo et al. [34]Sanandaj2009-201011Disk diffusionNDNDND3NDND76ND7ND2NDND655NDNDNDNDNDRamazanzadeh et al. [35]Sanandaj2007-200828Disk diffusionNDNDND1422ND36NDNDND1323ND9ND77ND5NDNDAfkhamzadeh et al. [36]Sanandaj2007-200815Disk diffusionNDNDND10NDND117ND10ND10NDND13ND134NDNDNDNDJazayeri [37]Semnan199911Disk diffusionNDNDND5NDND5NDNDNDND101010ND8NDNDNDNDNDNDKhashei et al. [38]Shiraz2016-201796Disk diffusion21NDND31NDND3922NDNDND45ND68NDNDND70NDND9335Malekzadegan et al. [39]Shiraz2015-201661Disk diffusion26NDND30NDND4661NDNDND2134NDNDND55NDND56NDNematolahi et al. [40]Shiraz2005–201490Disk diffusion414414NDND3327NDND30NDNDND5262554734ND1014Mardaneh et al. [41]Shiraz201333Disk diffusion27145NDND117142489NDND1419151313NDND13Rezaee and Abdinia [42]Tabriz2010–201440Disk diffusionNDNDND0NDND200NDNDND40404020ND40NDND1040NDHamishehkar et al. [43]Tabriz2010–2012282Disk diffusion61NDND89NDND8461NDND78109ND2579ND4155ND49NDNDAzimi et al. [44]Tehran2013–201845Disk diffusion823119ND726153645ND2094530ND3831323912NDAkhavizadegan et al. [45]Tehran2016-201718Disk diffusion0NDND7ND7ND0NDNDND86257ND42NDNDNDSohrabi fard et al. [46]Tehran2014-201512Disk diffusionNDNDNDNDNDNDNDNDND4NDNDNDND5NDNDNDNDNDNDNDGhanavati et al. [47]Tehran2013-201457Disk diffusion8NDNDNDNDNDNDNDNDNDNDNDNDNDNDND2821NDND1030Salimian rizi et al. [48]Tehran2012-201345Disk diffusion0ND146NDND1061026828NDNDNDND13157ND45NDMahmoudi et al. [49]Tehran2011–2016100Disk diffusion4NDNDNDNDND2730NDNDND20NDNDNDND69ND36ND46NDRajabi et al. [50]Tehran2011–201217Disk diffusionNDNDND2NDNDNDNDND2ND2ND9NDNDNDNDNDNDNDNDAfsharpaiman et al. [51]Tehran201133Disk diffusion50NDNDNDND1714NDND1618113014143022ND9NDNDRahbar et al. [52]Tehran2010-2011101Disk diffusion2ND14NDNDND15319191920NDNDNDND20235NDND33Ranjbar et al. [53]Tehran2006-200783Disk diffusionNDNDND32NDND414944ND224747604550ND54ND53NDNDTaheri et al. [54]Tehran2004–201214Disk diffusionNDNDNDND0ND94NDNDND6152NDND0ND2NDNDHaghi et al. [55]Tehran2003-200439Disk diffusionNDNDNDNDNDND13511NDND1723231316ND16ND12NDNDNavidinia et al. [56]TehranNA69Disk diffusion11ND12NDND524NDNDNDNDND39NDNDND43674NDSadeghi bojd et al. [57]Zahedan2013–201532Disk diffusionNDNDND3NDND23NDNDND1492666NDNDNDNDNDIPM-imipenem; MEM-meropenem; ATM-aztreonam; CIP-ciprofloxacin; NOR-norfloxacin; LVX-levofloxacin; GEN-gentamicin; AMK-amikacin; TOB-tobramycin; TET-tetracycline; CHL-chloramphenicol; SXT-trimethoprim/sulfamethoxazole; NAL-nalidixic acid; NIT-nitrofurantoin; CRO-ceftriaxone; CFM-cefixime; CTX-cefotaxime; CAZ-ceftazidime; CEP-cefepime; ZOX-ceftizoxime; MDR-multidrug-resistant; ESBL-extended-spectrumβ-lactamase; AST-antimicrobial susceptibility testing; ND-not determined.


### 2.3. Data Analysis

In the current study, Cochrane’sQ test (chi-squared, χ2) and Higgins I2 statistics were used to assess heterogeneity across the included studies. For this purpose, if the p value was less than 0.1 for the χ2 test and the I2 value was higher than 25%, the presence of heterogeneity was considered and a random-effects model was applied for the meta-analysis. Extracted data on the prevalence of Enterobacter species’ antibiotic resistance and ESBL-producing species in Iran were expressed as a percentage and 95% confidence intervals (95% CIs). Additionally, a subgroup analysis was performed based on the location of the study. A funnel plot-based method was used for reporting the presence or absence of publication bias in the meta-analyses, and it was considered a potential sign of publication bias if the graph showed an asymmetric shape. The Comprehensive Meta-Analysis (CMA) software (Biostat, Englewood, NJ) was used for the meta-analysis.


## 2.1. Literature Search and Study Selection

International databases including PubMed, Scopus, and Google Scholar, along with national databases including Scientific Information Database (https://www.sid.ir/) and Magiran (https://www.magiran.com/), were searched independently by two investigators to find studies conducted on the prevalence of antibiotic resistance and ESBL-producing Enterobacter species in Iran. The search was performed from 1996 to June 21, 2021. The most common Medical Subject Headings (MeSH)-extracted keywords used for the literature search were as follows: Enterobacter, antibiotic resistance, carbapenem, ESBL, and Iran. We defined the inclusion and exclusion criteria for the studies retrieved in the search and selected studies that met our criteria after a review of the titles, abstracts, and full text of the articles. The following studies were removed from the meta-analysis: studies reporting antibiotic resistance and ESBL-positive isolates published in languages other than English or Persian, studies conducted in other countries, studies reporting other bacteria in the Enterobacteriaceae family, studies with a small sample size (less than 10 bacterial isolates), studies with insufficient data, and nonoriginal articles, abstracts, and duplicates. Reference lists of the included articles were checked in order to find any possible missed studies. The current systematic review and meta-analysis were designed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines [7].


## 2.2. Data Extraction

Two different investigators extracted the data, and a third investigator tabulated the required information in Table1 after resolving possible disagreements in the results of the search and reaching a consensus. Required data were as follows: first author’s surname, study location, study enrollment date, the number of isolates, antibiotic susceptibility testing methods, the prevalence of Enterobacter species resistance to different drugs, the prevalence of multidrug-resistant (MDR) Enterobacter species, and the frequency of ESBL-positive isolates. It is noteworthy that Enterobacter species have intrinsic resistance to β-lactam antibiotics including ampicillin, amoxicillin-clavulanate, ampicillin-sulbactam, cephalosporins I (cefazolin and cephalothin), cephamycins (cefoxitin and cefotetan), and cephalosporin II (cefuroxime). According to the Clinical and Laboratory Standards Institute (CLSI) guideline, susceptibility testing is unnecessary for the above-mentioned antibiotics [8]. For this reason, these antibiotics are not included in Table 1.Table 1
Required data were extracted from included articles in the meta-analysis.
Author (Ref)CityYearIsolate (n)ASTResistance rate (n)ESBL-positive (n)IPMMEMATMCIPNORLVXGENAMKTOBTETCHLSXTNALNITCROCFMCTXCAZCEPZOXMDRAmin et al. [9]Ahvaz2015-2016152Disk diffusion8053ND847063NDNDNDNDNDNDNDNDNDNDNDNDNDNDNDNDAfrugh et al. [10]Ahvaz2013-201417Disk diffusion1515ND15NDND1416ND17ND12161316ND17151416NDNDMousavian et al. [11]Ahvaz201265Disk diffusion0NDND6NDND53NDNDNDNDNDND10ND119ND11ND27Khosravi et al. [12]Ahvaz2009–2012156Disk diffusion98NDND91NDND10260ND64ND1089475121110NDNDNDNDNDNDKhosravi et al. [13]Ahvaz2009-2010209Disk diffusion124NDND88NDND143117ND124ND146119117143148NDNDNDNDNDNDDidgar [14]Arak2010–201247Disk diffusion6NDND19NDND1918NDNDND20NDND29NDND402519NDNDGhasemi et al. [15]Babol202030Disk diffusion6NDND6NDND46NDNDNDNDND9NDND10ND28ND28NDBayani et al. [16]Babol2011-201230Disk diffusion2NDND2NDNDND2NDNDNDNDNDNDNDNDND54ND0NDGhafouri et al. [17]Bojnurd201312Disk diffusion35ND8NDND82ND306ND16001NDNDNDNDPeymani et al. [18]Different cities201449Disk diffusion222716NDND2011NDNDND25NDND28ND3427NDND26NDPeymani et al. [19]Different cities2011-2012137Disk diffusion21672216ND59NDNDNDND83NDND78ND8071NDND83NDPoorabbas et al. [20]Different cities2008-200938Disk diffusion38NDND33ND3524260NDND22ND221813192024NDNDNDMolazade et al. [21]Fasa2012-201328Disk diffusionNDNDND11NDND80ND11ND14111111110NDNDNDNDNDEsmaeili et al. [22]Hamadan201115Disk diffusionNDNDND13NDND13ND13NDND106411NDNDNDNDNDNDNDYasemi et al. [23]Ilam2007–200920Disk diffusionNDNDNDNDNDND3NDNDNDND9ND6NDNDNDNDNDNDNDNDFatemi et al. [24]Isfahan2014-2015135Disk diffusion13169358NDND544653962623NDNDNDND898790ND98NDShokri et al. [25]Isfahan2012-201335Disk diffusion33ND21NDND2210NDNDNDNDND6NDND242212ND35NDKargar et al. [26]Jahrom2011-201225Disk diffusionNDNDNDNDNDND1771124ND2024NDNDND1010NDNDND1Shajari et al. [27]Kashan2005-200635Disk diffusion10NDND13NDND141211NDND2128NDND182222NDNDNDNDSepehri et al. [28]Kerman1996, 200072Disk diffusionNDNDNDNDNDND43NDNDNDND461228NDNDNDNDNDNDNDNDMortazavi et al. [29]Kermanshah2016-201772Disk diffusion7ND293530ND3635NDNDND493116ND403738NDND54NDAmini et al. [30]Kermanshah201518Disk diffusionNDNDND7NDND89NDNDND137566ND10NDNDNDNDKarambin and Zarkesh [31]Rasht2008–201050Disk diffusionNDNDND0NDND1541NDNDND40NDNDNDND43NDNDNDNDNDYaghubi et al. [32]Rasht2013–2015147Disk diffusion7961ND80NDND8166780ND10810510210211910992ND80NDNDRouhi et al. [33]Sanandaj2013-201410Disk diffusion2NDND20ND05ND2NDND003ND54ND5NDNDNikkhoo et al. [34]Sanandaj2009-201011Disk diffusionNDNDND3NDND76ND7ND2NDND655NDNDNDNDNDRamazanzadeh et al. [35]Sanandaj2007-200828Disk diffusionNDNDND1422ND36NDNDND1323ND9ND77ND5NDNDAfkhamzadeh et al. [36]Sanandaj2007-200815Disk diffusionNDNDND10NDND117ND10ND10NDND13ND134NDNDNDNDJazayeri [37]Semnan199911Disk diffusionNDNDND5NDND5NDNDNDND101010ND8NDNDNDNDNDNDKhashei et al. [38]Shiraz2016-201796Disk diffusion21NDND31NDND3922NDNDND45ND68NDNDND70NDND9335Malekzadegan et al. [39]Shiraz2015-201661Disk diffusion26NDND30NDND4661NDNDND2134NDNDND55NDND56NDNematolahi et al. [40]Shiraz2005–201490Disk diffusion414414NDND3327NDND30NDNDND5262554734ND1014Mardaneh et al. [41]Shiraz201333Disk diffusion27145NDND117142489NDND1419151313NDND13Rezaee and Abdinia [42]Tabriz2010–201440Disk diffusionNDNDND0NDND200NDNDND40404020ND40NDND1040NDHamishehkar et al. [43]Tabriz2010–2012282Disk diffusion61NDND89NDND8461NDND78109ND2579ND4155ND49NDNDAzimi et al. [44]Tehran2013–201845Disk diffusion823119ND726153645ND2094530ND3831323912NDAkhavizadegan et al. [45]Tehran2016-201718Disk diffusion0NDND7ND7ND0NDNDND86257ND42NDNDNDSohrabi fard et al. [46]Tehran2014-201512Disk diffusionNDNDNDNDNDNDNDNDND4NDNDNDND5NDNDNDNDNDNDNDGhanavati et al. [47]Tehran2013-201457Disk diffusion8NDNDNDNDNDNDNDNDNDNDNDNDNDNDND2821NDND1030Salimian rizi et al. [48]Tehran2012-201345Disk diffusion0ND146NDND1061026828NDNDNDND13157ND45NDMahmoudi et al. [49]Tehran2011–2016100Disk diffusion4NDNDNDNDND2730NDNDND20NDNDNDND69ND36ND46NDRajabi et al. [50]Tehran2011–201217Disk diffusionNDNDND2NDNDNDNDND2ND2ND9NDNDNDNDNDNDNDNDAfsharpaiman et al. [51]Tehran201133Disk diffusion50NDNDNDND1714NDND1618113014143022ND9NDNDRahbar et al. [52]Tehran2010-2011101Disk diffusion2ND14NDNDND15319191920NDNDNDND20235NDND33Ranjbar et al. [53]Tehran2006-200783Disk diffusionNDNDND32NDND414944ND224747604550ND54ND53NDNDTaheri et al. [54]Tehran2004–201214Disk diffusionNDNDNDND0ND94NDNDND6152NDND0ND2NDNDHaghi et al. [55]Tehran2003-200439Disk diffusionNDNDNDNDNDND13511NDND1723231316ND16ND12NDNDNavidinia et al. [56]TehranNA69Disk diffusion11ND12NDND524NDNDNDNDND39NDNDND43674NDSadeghi bojd et al. [57]Zahedan2013–201532Disk diffusionNDNDND3NDND23NDNDND1492666NDNDNDNDNDIPM-imipenem; MEM-meropenem; ATM-aztreonam; CIP-ciprofloxacin; NOR-norfloxacin; LVX-levofloxacin; GEN-gentamicin; AMK-amikacin; TOB-tobramycin; TET-tetracycline; CHL-chloramphenicol; SXT-trimethoprim/sulfamethoxazole; NAL-nalidixic acid; NIT-nitrofurantoin; CRO-ceftriaxone; CFM-cefixime; CTX-cefotaxime; CAZ-ceftazidime; CEP-cefepime; ZOX-ceftizoxime; MDR-multidrug-resistant; ESBL-extended-spectrumβ-lactamase; AST-antimicrobial susceptibility testing; ND-not determined.


## 2.3. Data Analysis

In the current study, Cochrane’sQ test (chi-squared, χ2) and Higgins I2 statistics were used to assess heterogeneity across the included studies. For this purpose, if the p value was less than 0.1 for the χ2 test and the I2 value was higher than 25%, the presence of heterogeneity was considered and a random-effects model was applied for the meta-analysis. Extracted data on the prevalence of Enterobacter species’ antibiotic resistance and ESBL-producing species in Iran were expressed as a percentage and 95% confidence intervals (95% CIs). Additionally, a subgroup analysis was performed based on the location of the study. A funnel plot-based method was used for reporting the presence or absence of publication bias in the meta-analyses, and it was considered a potential sign of publication bias if the graph showed an asymmetric shape. The Comprehensive Meta-Analysis (CMA) software (Biostat, Englewood, NJ) was used for the meta-analysis.


## 3. Results

Among 19,669 eligible studies published from 1996 until June 21, 2021, 49 articles (20 in Persian and 29 in English) met the inclusion criteria and were included in the meta-analysis (Figure1). As shown in Table 1, data were obtained from 19 cities (Ahvaz (n = 5), Arak (n = 1), Babol (n = 2), Bojnurd (n = 1), Fasa (n = 1), Hamadan (n = 1), Ilam (n = 1), Isfahan (n = 2), Jahrom (n = 1), Kashan (n = 1), Kerman (n = 1), Kermanshah (n = 2), Rasht (n = 2), Sanandaj (n = 4), Semnan (n = 1), Shiraz (n = 4), Tabriz (n = 2), Tehran (n = 13), and Zahedan (n = 1)) in Iran. All studies used the disk diffusion method for antimicrobial susceptibility testing. The pooled prevalence of Enterobacter species’ resistance to various antibiotics was as follows: imipenem 16.6% (95% CI: 11–24.1; I2 = 93.1%; Q = 439.9; p≤0.001) (Figure 2), meropenem 16.2% (95% CI: 8.9–27.9; I2 = 89.8%; Q = 117.8; p≤0.001), aztreonam 40.9% (95% CI: 29.6–53.2; I2 = 89.3%; Q = 75; p≤0.001), ciprofloxacin 35.3% (95% CI: 29.5–41.6; I2 = 86.1%; Q = 273.6; p≤0.001), norfloxacin 31% (95% CI: 14.3–54.7; I2 = 91.6%; Q = 59.9; p≤0.001), levofloxacin 48% (95% CI: 21.3–75.9; I2 = 90.7%; Q = 32.4; p≤0.001), gentamicin 42.1% (95% CI: 36.2–48.3; I2 = 87.2%; Q = 328.5; p≤0.001), amikacin 30.3% (95% CI: 24.5–36.8; I2 = 86.9%; Q = 298.8; p≤0.001), tobramycin 37.2% (95% CI: 26.3–49.5; I2 = 88.3%; Q = 103.1; p≤0.001), tetracycline 50.1% (95% CI: 37.3–62.9; I2 = 88%; Q = 134; p≤0.001), chloramphenicol 25.7% (95% CI: 20.5–31.6; I2 = 61.1%; Q = 20.5; p≤0.001), trimethoprim/sulfamethoxazole 52% (95% CI: 45.4–58.6; I2 = 87.5%; Q = 304.9; p≤0.001), nalidixic acid 49.1% (95% CI: 38.8–59.4; I2 = 87.6%; Q = 177.4; p≤0.001), nitrofurantoin 43% (95% CI: 32.4–54.2; I2 = 91.7%; Q = 328.8; p≤0.001), ceftriaxone 49.3% (95% CI: 41.8–56.9; I2 = 87.1%; Q = 226.1; p≤0.001), cefixime 52.4% (95% CI: 43.7–61; I2 = 83.4%; Q = 102.5; p≤0.001), cefotaxime 52.7% (95% CI: 42.4–62.7; I2 = 91.9%; Q = 359.3; p≤0.001), ceftazidime 47.9% (95% CI: 39.8–56.2; I2 = 89.7%; Q = 302; p≤0.001), cefepime 43.6% (95% CI: 31.3–56.8; I2 = 90.1%; Q = 142.2; p≤0.001) and ceftizoxime 45.5% (95% CI: 30.6–61.3; I2 = 92.7%; Q = 178.4; p≤0.001).Figure 1
A schematic view of the study selection process.Figure 2
Forest plots (a) and funnel plots (b) illustrate the prevalence of imipenem-resistantEnterobacter species in Iran.
(a)(b)In addition, Table2 shows the antibiotic resistance profiles of Enterobacter species in different cities of Iran. The rate of MDR Enterobacter species in Iran was 63.1% (95% CI: 45.2–78; I2 = 93.9%; Q = 249.1; p≤0.001).Table 2
Antibiotic resistance profile ofEnterobacter isolates from cities in Iran.
CityPercentage resistance (%)IPMMEMATMCIPNORLVXGENAMKTOBTETCHLSXTNALNITCROCFMCTXCAZCEPZOXAhvaz5864.4NA46.846.141.453.140.9NA56.7NA69.661.255.163.670.768.850.982.461.8Arak12.8NANA40.4NANA40.438.3NANANA42.6NANA61.7NANA85.153.240.4Babol13.2NANA13.2NANA13.313.2NANANANANA30NANA33.316.758.8NABojnurd2541.7NA66.7NANA66.716.7NA253.850NA8.3503.83.88.3NANAFasaNANANA39.3NANA28.61.7NA39.3NA5039.339.339.339.31.7NANANAHamadanNANANA86.7NANA86.7NA86.7NANA66.74026.773.3NANANANANAIlamNANANANANANA15NANANANA45NA30NANANANANANAIsfahan9.411.368.949.9NANA50.33339.371.119.317NA17.1NANA66.564.151.4NAJahromNANANANANANA68284496NA8096NANANA4040NANAKashan28.6NANA37.1NANA4034.331.4NANA6080NANA51.462.962.9NANAKermanNANANANANANA59.7NANANANA63.916.738.9NANANANANANAKermanshah9.7NA40.346.741.7NA48.948.9NANANA68.942.223.433.346.851.453.3NANARasht53.741.5NA11.8NANA42.865.153.10.3NA7571.469.469.48179.462.6NA54.4Sanandaj20NANA43.234.2NA33.540.5NA51.6NA45.236.44.550.745.551.228.6NA30.7SemnanNANANA45.5NANA45.5NANANANA90.990.990.9NA72.7NANANANAShiraz15.15.947.226.9NANA46.834.742.472.731.137.54.929.951.765.154.866.538.2NATabriz21.6NANA9.1NANA38.37.5NANA27.785.398.870.837.4NA75.919.5NA19Tehran6.36.72222.93.32533.118.931.242.826.439.436.363.145.347.658.641.828.859.2ZahedanNANANA9.4NANA6.39.4NANANA43.828.16.318.818.818.8NANANANA-not available.In addition, the prevalence of ESBL-producingEnterobacter species was 32.8% (95% CI: 23.3–44; I2 = 79.4%; Q = 29.1; p≤0.001) in Iran.It should be noted that a random-effects model was applied for the meta-analysis due to the existence of high heterogeneity across the included studies in this study.


## 4. Discussion

The emergence of MDR- and ESBL-producingEnterobacteriaceae, including Enterobacter species, has increased the necessity to deal with these organisms [5, 6]. The Centers for Disease Control and Prevention (CDC) estimated 197,400 cases of ESBL-producing Enterobacteriaceae along with 9,100 deaths among hospitalized patients in the United States in 2017 [58]. The antibiotic of choice to treat infections caused by MDR and ESBL-producing Enterobacteriaceae is carbapenem [3, 58, 59]. However, the widespread use of carbapenem antibiotics has led to the emergence of CR bacteria [3, 59]. According to the CDC report for 2019, increased prevalence of CR Enterobacteriaceae, especially CR Enterobacter cloacae complex, has become a public health issue in the United States [58].In Iran, the prevalence of MDR (63.1%) and ESBL-producingEnterobacter species (32.8%) was high. This is an alarming rate despite the relatively low frequency of imipenem- and meropenem-resistant Enterobacter species in Iran. The results suggest that carbapenems are still the drugs of choice for the treatment of infections caused by MDR and ESBL-producing Enterobacter species in Iran. The distribution of ESBL-producing Enterobacter species in other countries was as follows: Pakistan 14.9%, Nigeria 37.5%, and Ethiopia 50% [60, 61].The CDC has reported that CREnterobacteriaceae-associated infections frequently occur in patients using medical devices, including catheters (intravenous and urinary) and ventilators, and some of these microorganisms are resistant to all available antibiotics, hence their infections are difficult to treat [58]. Currently, the available antimicrobial agents for the treatment of CR Enterobacteriaceae are limited [62]. Historically, aminoglycosides, tigecycline, polymyxins, and fosfomycin have been used as therapeutic options for this purpose [62]. However, according to the included articles in this study, there is insufficient data on the prevalence of tigecycline-, polymyxins-, and fosfomycin-resistant Enterobacter species in Iran. Hence, the evaluation of Enterobacter species resistance rates to these antibiotics is recommended. In the present study, the rate of tetracycline-resistant Enterobacter species was high (50.1%).On the other hand, aminoglycosides, including gentamicin, amikacin, and tobramycin, are also recommended as anti-CREnterobacteriaceae therapies [62]. However, based on the present study, the prevalence of gentamicin-, amikacin-, and tobramycin-resistant Enterobacter species was high in Iran. It is recommended that older antibiotics such as trimethoprim/sulfamethoxazole and chloramphenicol may be effective for the treatment of infections caused by CR Enterobacteriaceae pathogens [62]. Our results showed that the prevalence of Enterobacter species resistant to chloramphenicol was higher than those resistant to trimethoprim/sulfamethoxazole (25.7% vs. 52%). Other treatment options for infections caused by CR Enterobacteriaceae include combination strategies (high-dose tigecycline, high-dose carbapenem, and double-carbapenem therapy), new antibiotics (ceftazidime/avibactam, meropenem/vaborbactam, plazomicin, and eravacycline), and new antibiotics in development (imipenem/cilastatin, relebactam, and cefiderocol) [62]. However, information on the therapeutic efficacy of these drugs against CR Enterobacter species is not available in Iran (according to the included articles in this study). Based on the current study, the frequency of meropenem and ceftazidime-resistant Enterobacter species was 16.2% and 47.9%, respectively. Enterobacter species’ drug resistance rates to the third-generation cephalosporins and aztreonam were high in Iran. Considering the prevalence of ESBL-producing Enterobacter species in this study (32.8%), it seems that these ESBLs are involved in resistance to third-generation cephalosporins and aztreonam in Iran. The CDC estimated the rate of quinolone-resistant Enterobacter species as 30% [3]; however, the prevalence of Enterobacter species resistant to quinolones was higher in this study.Such a high antibiotic resistance ofEnterobacter species, especially MDR, in this study can be attributed to the indiscriminate use of antibiotics and easy, without a prescription, access to antibiotics and self-medication in Iran [63, 64]. On the other hand, since Enterobacter species are responsible for nosocomial infections, using appropriate infection control programs and practices of hygiene such as hand decontamination, glove use, sterilization, and disinfection practices can play an important role in preventing the spread of resistant strains in healthcare settings.One of the limitations of the current study was the inability to compare the obtained results with other countries, particularly adjacent countries, which needs to be addressed in future multicenter and international studies.


## 5. Conclusion

This study is the first systematic review and meta-analysis reportingEnterobacter species antibiotic resistance in Iran. The results of this meta-analysis indicated the high prevalence of Enterobacter species resistant to the majority of assessed antibiotics in the included studies, i.e., quinolones, aminoglycosides, third- and fourth-generation cephalosporins, aztreonam, tetracycline, chloramphenicol, trimethoprim/sulfamethoxazole, and nitrofurantoin. In addition, the prevalence rates of ESBL-producing Enterobacter species (32.8%) and MDR (63.1%) strains were high in Iran. Such an increasing trend of antibiotic resistance in Enterobacter species can impose more economic costs on healthcare systems in Iran due to prolonged periods of hospitalization, increased drug consumption, poor patient outcomes, and higher mortality and morbidity. In total, we suggest the management of antibiotic prescription, launching and developing health education and infection control programs, continuous monitoring of drug resistance, and evaluation of the therapeutic efficacy of new antimicrobial agents (herbal medicine and new antimicrobial peptides) or combination therapeutic strategies are required to control Enterobacter species-associated infections and antibiotic resistance in Iran. Finally, in comparison with the above-mentioned antibiotics, the prevalence of CR Enterobacter species was relatively low in Iran, and it seems that carbapenems can still be considered as drugs of choice for the treatment of MDR and ESBL-producing Enterobacter species.



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