# Prevalence of Fluoroquinolone-ResistantCampylobacter Species in Iran: A Systematic Review and Meta-Analysis

Authors: Farzad Khademi; Amirhossein Sahebkar
Journal: International Journal of Microbiology
 (2020)

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## Abstract

Background. Campylobacter species are one of the main causes of bacterial food poisoning worldwide. Recently, WHO reported that the emergence of fluoroquinolone-resistant Campylobacter species is becoming a public health issue around the world. The aim of the present systematic review and meta-analysis was to evaluate the prevalence of the antimicrobial susceptibility patterns of Campylobacter species, especially fluoroquinolone-resistant strains isolated from human and animal origins in Iran. Methods. Using related keywords and without date and language limitations, a comprehensive literature search was conducted in PubMed, Scopus, ISI Web of Knowledge, Google Scholar, and SID to identify relevant studies on the prevalence of the antimicrobial susceptibility patterns of Campylobacter species in Iran. Results. A total of 34 reports (9 in Persian and 25 in English) were selected based on inclusion and exclusion criteria. Disk diffusion, E-test, and agar dilution were common methods used for antimicrobial susceptibility testing. The antibiotic resistance profiles of Campylobacter species against fluoroquinolones were as follows: 53.6%, 41.8%, and 0% to ciprofloxacin for C. jejuni, C. coli, and C. lari, respectively, 24.3% and 25.1% to enrofloxacin for C. jejuni and C. coli, respectively, 59.6% and 49.2% to nalidixic acid for C. jejuni and C. coli, respectively, and 87.3% and 64.7% to ofloxacin for C. jejuni and C. coli, respectively. Conclusion. Our findings revealed a high prevalence of fluoroquinolone-resistant Campylobacter species in Iran. This calls for the use of more effective antibiotics with low resistance rates including aminoglycosides, chloramphenicol, and imipenem.


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## Body

## 1. Introduction

The genusCampylobacter includes small, motile, and curved Gram-negative bacteria [1–3]. These rod-shaped bacteria are thermophilic, 30°C to 46°C, and microaerophilic, 5% O2, and belong to the family Campylobacteraceae [4]. Campylobacter is a zoonotic pathogen that is colonized in the intestinal tract of domestic and wild animals and birds and can infect human through consumption of contaminated water, different foods such as raw or uncooked meat, unpasteurized milk, and contact with infected animals or (rarely) human [4, 5]. Poultry, cattle, sheep, pigs, birds, dogs, and cats are common reservoir hosts for human infections [2]. This food-borne bacterial pathogen is the major cause of bacterial gastroenteritis and septicemia in humans in both developing and developed countries [1, 2]. In developed countries, Campylobacter bacteria are the most important causative agents for gastrointestinal infection [6]. It is estimated that between 400 and 500 million individuals become infected with Campylobacter species in the world annually [4, 5]. The most common species associated with bacterial gastroenteritis in human are Campylobacter jejuni and Campylobacter coli as well as Campylobacter fetus associated with systemic infections [2, 4]. Additionally, in some cases, these enteric pathogens are associated with two immune-related late complications, i.e., Guillain-Barré syndrome and reactive arthritis [1, 2]. The severity of Campylobacter infections varies from a mild and self-limiting illness to severe infections [5]. For the treatment of self-limiting intestinal infections, the replacement of fluids and electrolytes is enough, while severe extraintestinal Campylobacter infections such as septicemia, endocarditis, and septic thrombophlebitis should be treated with appropriate antibiotics [2, 7]. Macrolides, including erythromycin and azithromycin, and fluoroquinolones are considered as the drugs of choice for infected patients [2, 4, 5]. Alternative treatments are tetracyclines and gentamicin [2, 4, 5]. Additionally, Campylobacter strains are susceptible to amoxicillin/clavulanic acid, imipenem, aminoglycosides, chloramphenicol, and clindamycin [2]. However, in recent years, antimicrobial resistance of Campylobacter species has been increased in both developing and developed countries and is becoming a global problem [8]. It is noteworthy that resistance to penicillins, cephalosporins, and sulfonamides has emerged [2]. On the other hand, in February 2017, the World Health Organization (WHO) announced that fluoroquinolone-resistant Campylobacter species are growing globally, calling for a priority to find effective antibiotics [9]. Therefore, the aim of the present systematic review and meta-analysis was to evaluate the antimicrobial susceptibility patterns of Campylobacter species, especially fluoroquinolone-resistant strains, isolated from human and animal origins in Iran.


## 2. Methods

### 2.1. Literature Search and Selection Criteria

We started at 1 August 2018 for a comprehensive literature search in international search engines including PubMed (https://www.ncbi.nlm.nih.gov), Scopus (https://www.scopus.com), ISI Web of Knowledge (https://www.isiwebofknowledge.com), Google Scholar (http://scholar.google.com), and Scientific Information Database (SID) (http://www.sid.ir), a national database, on each report about the prevalence of the antimicrobial susceptibility patterns of Campylobacter species in Iran. There was no date and language limitation for searching, and related keywords used were antibiotic resistance, Campylobacter species (C. jejuni, C. coli, and C. lari), and Iran. A number of missed studies were obtained by reviewing the list of references and searching for journals. The meta-analysis was performed step by step based on the PRISMA recommendations [10].Inclusion or exclusion criteria for assessing eligibility in the study were all types of Persian- and English-language articles which had enough data on the prevalence of the resistance patterns of campylobacters, in species level, to different antibiotics in Iran. Review articles, case reports, abstracts of articles, and duplicates were excluded. Articles evaluating the resistance patterns of campylobacters only at the genus level or the resistance genes and those studies with unclear results were excluded.


### 2.2. Data Extraction of Articles

After completely reviewing all included studies by two authors, needed information was extracted and placed in Tables1–3 based on organism species type. The quality of data was evaluated based on the Newcastle-Ottawa scale adapted for cross-sectional studies (data has not been shown). The checklist of items was based on three criteria including selection (representativeness of the sample, sample size, nonrespondents, and ascertainment of the exposure) (maximum 5 stars), comparability (comparability of outcome groups) (maximum 2 stars), and outcome (assessment of the outcome and statistical test) (maximum 3 stars).Table 1
The antibiotic resistance profiles ofC. jejuni.
YearCityStrains (n)OriginASTAntibiotic resistance (n)AMPAMXCSTNFXSPTNEOSTRCHLTETTMP-SMXCTXERYCIPIPMGENMEMCEFNALCAZLEX2007-2008Ahvaz177AnimalDisk diffusion3314ND85NDND111141NDND3119ND0NDND105NDND2007-2008Ahvaz9HumanDisk diffusion E-test9NDNDNDNDNDNDND6ND654ND0ND976ND2009-2010Ahvaz-Shahrekord24AnimalDisk diffusion41ND6NDND2218NDND07ND1NDND9NDND2016Hamadan53AnimalDisk diffusion232243NDNDND1131044ND315ND0ND400NDND2013-2014Hamadan6HumanDisk diffusionNDNDNDNDNDNDND15NDND46ND33ND2NDND2014-2015Isfahan22AnimalDisk diffusion14ND5NDND2118NDND116ND0NDND12NDND2006–2008Isfahan13AnimalDisk diffusion13ND3NDND105NDND09ND0NDND7NDND2011-2012Isfahan-Shahrekord10AnimalDisk diffusion10ND0NDND104NDND03ND0NDND5NDND2008-2009Isfahan-Yazd42AnimalDisk diffusion51ND10NDND3028NDND021ND0NDND18NDND2007–2009Kerman190AnimalDisk diffusion103NDNDNDNDNDNDND103173NDNDNDNDNDNDNDNDNDND2015-2016Kurdistan50AnimalDisk diffusion agar dilution510NDNDNDNDNDND34NDND131ND00NDNDNDND2013Mashhad200AnimalDisk diffusion1326ND60ND42ND9181NDND76168ND7NDND132NDND2012Mashhad122AnimalDisk diffusion2042511186688NDND1107ND0NDND91NDND2014-2015Mazandaran-Golestan79AnimalDisk diffusion2640ND28NDND15ND59NDND563ND1NDND59NDND2010Rafsanjan19AnimalDisk diffusionNDNDNDNDNDNDNDNDND19ND00ND19NDND0NDND2014Shahrekord2AnimalDisk diffusion11ND1NDND100NDND01ND0NDND1NDND2009-2010Shahrekord172AnimalDisk diffusion293ND20NDND34125NDND289ND0NDND96NDNDNDShahrekord35AnimalDisk diffusion26ND14NDND3128NDND123ND0NDND18NDND2007Semnan27HumanDisk diffusionNDNDNDNDNDNDNDND912ND24ND1NDNDNDNDND2007Semnan38HumanDisk diffusionNDNDNDNDNDNDNDND1120ND25ND1NDNDNDNDND2014-2015Shiraz7HumanDisk diffusion5NDNDNDNDNDNDND7NDNDND7ND00ND7NDND2011–2013Shiraz48AnimalDisk diffusion22ND08ND0ND413ND13330ND4ND447NDNDNDShiraz15AnimalDisk diffusion E-test2NDNDNDNDNDND412410ND2NDNDNDND8NDShiraz15AnimalDisk diffusion E-test2NDNDNDNDNDND41ND710ND2NDNDNDND82011-2012Tehran93AnimalDisk diffusion122632ND485433NDND448ND3NDND66NDND2011Tehran9HumanDisk diffusionNDNDNDNDNDNDNDND35ND21ND0NDNDNDNDND2010Tehran19AnimalDisk diffusion19NDNDNDND11NDND5NDNDND16NDNDNDND18NDND2008–2010Tehran138AnimalDisk diffusion154432NDND336109NDND5118ND0NDND103NDND2008-2009Tehran34HumanDisk diffusion6ND5NDND43312ND1942902NDND2721ND2006-2007Tehran70AnimalDisk diffusion51822ND122122NDND134ND0NDND47NDND2004-2005Tehran29HumanDisk diffusion3ND0NDND1017ND311700ND28221227NDTonekabon12AnimalDisk diffusion E-test12NDNDNDNDNDND22ND930ND4NDNDNDND10NDTonekabon16AnimalDisk diffusion1616NDNDNDND111NDND20ND1NDNDNDND142011–2013Zahedan19HumanDisk diffusionNDNDNDNDNDNDNDNDNDNDND0NDNDNDNDNDNDNDNDAbbreviations: AMP: ampicillin; AMX: amoxicillin; CST: colistin; NFX: enrofloxacin; SPT: spectinomycin; NEO: neomycin; STR: streptomycin; CHL: chloramphenicol; TET: tetracycline; TMP/SMX: trimethoprim/sulfamethoxazole; CTX: cefotaxime; ERY: erythromycin\; CIP: ciprofloxacin; IPM: imipenem; GEN: gentamicin; MEM: meropenem; CEF: cephalothin; NAL: nalidixic acid; CAZ: ceftazidime; LEX: cephalexin; AST: antimicrobial susceptibility testing; ND: not determined.Table 2
Antibiotic resistance profiles ofC. coli.
YearCityStrains (n)OriginASTAntibiotic resistance (n)AMPAMXCSTNFXSPTNEOSTRCHLTETTMP-SMXCTXERYCIPIPMGENMEMCEFNALCAZLEX2007-2008Ahvaz21AnimalDisk diffusion40ND3NDND1014NDND04ND0NDND11NDND2007-2008Ahvaz5HumanDisk diffusionE-test5NDNDNDNDNDNDND3ND341ND1ND524ND2009-2010Ahvaz-Shahrekord7AnimalDisk diffusion01ND0NDND103NDND13ND0NDND1NDND2016Hamadan19AnimalDisk diffusion10812NDNDND41513ND27ND0ND121NDND2013-2014Hamadan3HumanDisk diffusionNDNDNDNDNDNDND02NDND32ND12ND1NDND2014-2015Isfahan6AnimalDisk diffusion00ND0NDND003NDND00ND0NDND2NDND2006–2008Isfahan4AnimalDisk diffusion01ND2NDND002NDND01ND0NDND1NDND2011-2012Isfahan-Shahrekord3AnimalDisk diffusion00ND1NDND001NDND11ND0NDND1NDND2008-2009Isfahan-Yazd8AnimalDisk diffusion00ND1NDND006NDND02ND0NDND2NDND2015-2016Kurdistan8AnimalDisk diffusion agar dilution56NDNDNDNDNDND7NDND06ND00NDNDNDND2013Mashhad27AnimalDisk diffusion36ND4ND5ND317NDND912ND1NDND13NDND2012Mashhad27AnimalDisk diffusion2197102113NDND015ND0NDND18NDND2014-2015Mazandaran-Golestan41AnimalDisk diffusion1715ND16NDND15ND36NDND236ND2NDND32NDND2010Rafsanjan12AnimalDisk diffusionNDNDNDNDNDNDNDNDND12ND00ND12NDND0NDND2014Shahrekord13AnimalDisk diffusion03ND4NDND007NDND05ND0NDND4NDND2009-2010Shahrekord15AnimalDisk diffusion20ND2NDND107NDND04ND0NDND5NDNDNDShahrekord4AnimalDisk diffusion00ND1NDND002NDND00ND0NDND2NDND2011–2013Shiraz17AnimalDisk diffusion5ND03ND0ND12ND4514ND1ND108NDNDNDShiraz10AnimalDisk diffusion E-test1NDNDNDNDNDND211610ND1NDNDNDND4NDShiraz10AnimalDisk diffusionE-test1NDNDNDNDNDND21ND610ND1NDNDNDND42011-2012Tehran28AnimalDisk diffusion154ND22116NDND113ND1NDND24NDND2012Tehran39AnimalDisk diffusion3230NDNDNDND35273831ND3334ND0NDND36NDND2010Tehran33AnimalDisk diffusion25NDNDNDND0NDND31NDNDND10NDNDNDND0NDND2008–2010Tehran23AnimalDisk diffusion138NDND11015NDND115ND0NDND18NDND2008-2009Tehran12HumanDisk diffusion2ND2NDND1113ND61600NDND65ND2006-2007Tehran22AnimalDisk diffusion032ND11004NDND09ND0NDND18NDND2004-2005Tehran5HumanDisk diffusion1ND0NDND0000ND20400ND5545NDTonekabon8AnimalDisk diffusionE-test8NDNDNDNDNDND21ND720ND1NDNDNDND8NDTonekabon9AnimalDisk diffusion99NDNDNDND121NDND10ND0NDNDNDND9Abbreviations: AMP: ampicillin; AMX: amoxicillin; CST: colistin; NFX: enrofloxacin; SPT: spectinomycin; NEO: neomycin; STR: streptomycin; CHL: chloramphenicol; TET: tetracycline; TMP/SMX: trimethoprim/sulfamethoxazole; CTX: cefotaxime; ERY: erythromycin; CIP: ciprofloxacin; IPM: imipenem; GEN: gentamicin; MEM: meropenem; CEF: cephalothin; NAL: nalidixic acid; CAZ: ceftazidime; LEX: cephalexin; AST: antimicrobial susceptibility testing; ND: not determined.Table 3
Antibiotic resistance profiles ofC. lari.
YearCityStrains (n)OriginASTAntibiotic resistance (n)AMPAMXCSTNFXSPTNEOSTRCHLTETTMP-SMXCTXERYCIPIPMGENMEMCEFNALCAZLEXNDShiraz12AnimalDisk diffusionE-test3NDNDNDNDNDND212810ND1NDNDNDND5NDShiraz12NDDisk diffusionE-test3NDNDNDNDNDND21ND810ND1NDNDNDND5NDTonekabon8NDDisk diffusionE-test8NDNDNDNDNDND21ND800ND2NDNDNDND7NDTonekabon7AnimalDisk diffusion77NDNDNDND121NDND00ND0NDNDNDND7Data obtained from eligible studies include publishing year, location of the study, number of strains, origin of samples, methods used for antimicrobial susceptibility testing, and antibiotic resistance profiles ofC. jejuni, C. coli, and C. lari.


### 2.3. Meta-Analysis

The data for the quantitative data synthesis were transferred to the Comprehensive Meta-Analysis (CMA) software (Biostat, Englewood, NJ). Resistance rates ofC. jejuni, C. coli, and C. lari were calculated for each antibiotic as a percentage and expressed as 95% confidence intervals (95% CIs). I2 statistic was used to evaluate the existed heterogeneity, and considering the percent of inconsistency among studies, pooling of data was performed using fixed-or random-effects models. The assessment of publication bias was done using funnel plots.


## 2.1. Literature Search and Selection Criteria

We started at 1 August 2018 for a comprehensive literature search in international search engines including PubMed (https://www.ncbi.nlm.nih.gov), Scopus (https://www.scopus.com), ISI Web of Knowledge (https://www.isiwebofknowledge.com), Google Scholar (http://scholar.google.com), and Scientific Information Database (SID) (http://www.sid.ir), a national database, on each report about the prevalence of the antimicrobial susceptibility patterns of Campylobacter species in Iran. There was no date and language limitation for searching, and related keywords used were antibiotic resistance, Campylobacter species (C. jejuni, C. coli, and C. lari), and Iran. A number of missed studies were obtained by reviewing the list of references and searching for journals. The meta-analysis was performed step by step based on the PRISMA recommendations [10].Inclusion or exclusion criteria for assessing eligibility in the study were all types of Persian- and English-language articles which had enough data on the prevalence of the resistance patterns of campylobacters, in species level, to different antibiotics in Iran. Review articles, case reports, abstracts of articles, and duplicates were excluded. Articles evaluating the resistance patterns of campylobacters only at the genus level or the resistance genes and those studies with unclear results were excluded.


## 2.2. Data Extraction of Articles

After completely reviewing all included studies by two authors, needed information was extracted and placed in Tables1–3 based on organism species type. The quality of data was evaluated based on the Newcastle-Ottawa scale adapted for cross-sectional studies (data has not been shown). The checklist of items was based on three criteria including selection (representativeness of the sample, sample size, nonrespondents, and ascertainment of the exposure) (maximum 5 stars), comparability (comparability of outcome groups) (maximum 2 stars), and outcome (assessment of the outcome and statistical test) (maximum 3 stars).Table 1
The antibiotic resistance profiles ofC. jejuni.
YearCityStrains (n)OriginASTAntibiotic resistance (n)AMPAMXCSTNFXSPTNEOSTRCHLTETTMP-SMXCTXERYCIPIPMGENMEMCEFNALCAZLEX2007-2008Ahvaz177AnimalDisk diffusion3314ND85NDND111141NDND3119ND0NDND105NDND2007-2008Ahvaz9HumanDisk diffusion E-test9NDNDNDNDNDNDND6ND654ND0ND976ND2009-2010Ahvaz-Shahrekord24AnimalDisk diffusion41ND6NDND2218NDND07ND1NDND9NDND2016Hamadan53AnimalDisk diffusion232243NDNDND1131044ND315ND0ND400NDND2013-2014Hamadan6HumanDisk diffusionNDNDNDNDNDNDND15NDND46ND33ND2NDND2014-2015Isfahan22AnimalDisk diffusion14ND5NDND2118NDND116ND0NDND12NDND2006–2008Isfahan13AnimalDisk diffusion13ND3NDND105NDND09ND0NDND7NDND2011-2012Isfahan-Shahrekord10AnimalDisk diffusion10ND0NDND104NDND03ND0NDND5NDND2008-2009Isfahan-Yazd42AnimalDisk diffusion51ND10NDND3028NDND021ND0NDND18NDND2007–2009Kerman190AnimalDisk diffusion103NDNDNDNDNDNDND103173NDNDNDNDNDNDNDNDNDND2015-2016Kurdistan50AnimalDisk diffusion agar dilution510NDNDNDNDNDND34NDND131ND00NDNDNDND2013Mashhad200AnimalDisk diffusion1326ND60ND42ND9181NDND76168ND7NDND132NDND2012Mashhad122AnimalDisk diffusion2042511186688NDND1107ND0NDND91NDND2014-2015Mazandaran-Golestan79AnimalDisk diffusion2640ND28NDND15ND59NDND563ND1NDND59NDND2010Rafsanjan19AnimalDisk diffusionNDNDNDNDNDNDNDNDND19ND00ND19NDND0NDND2014Shahrekord2AnimalDisk diffusion11ND1NDND100NDND01ND0NDND1NDND2009-2010Shahrekord172AnimalDisk diffusion293ND20NDND34125NDND289ND0NDND96NDNDNDShahrekord35AnimalDisk diffusion26ND14NDND3128NDND123ND0NDND18NDND2007Semnan27HumanDisk diffusionNDNDNDNDNDNDNDND912ND24ND1NDNDNDNDND2007Semnan38HumanDisk diffusionNDNDNDNDNDNDNDND1120ND25ND1NDNDNDNDND2014-2015Shiraz7HumanDisk diffusion5NDNDNDNDNDNDND7NDNDND7ND00ND7NDND2011–2013Shiraz48AnimalDisk diffusion22ND08ND0ND413ND13330ND4ND447NDNDNDShiraz15AnimalDisk diffusion E-test2NDNDNDNDNDND412410ND2NDNDNDND8NDShiraz15AnimalDisk diffusion E-test2NDNDNDNDNDND41ND710ND2NDNDNDND82011-2012Tehran93AnimalDisk diffusion122632ND485433NDND448ND3NDND66NDND2011Tehran9HumanDisk diffusionNDNDNDNDNDNDNDND35ND21ND0NDNDNDNDND2010Tehran19AnimalDisk diffusion19NDNDNDND11NDND5NDNDND16NDNDNDND18NDND2008–2010Tehran138AnimalDisk diffusion154432NDND336109NDND5118ND0NDND103NDND2008-2009Tehran34HumanDisk diffusion6ND5NDND43312ND1942902NDND2721ND2006-2007Tehran70AnimalDisk diffusion51822ND122122NDND134ND0NDND47NDND2004-2005Tehran29HumanDisk diffusion3ND0NDND1017ND311700ND28221227NDTonekabon12AnimalDisk diffusion E-test12NDNDNDNDNDND22ND930ND4NDNDNDND10NDTonekabon16AnimalDisk diffusion1616NDNDNDND111NDND20ND1NDNDNDND142011–2013Zahedan19HumanDisk diffusionNDNDNDNDNDNDNDNDNDNDND0NDNDNDNDNDNDNDNDAbbreviations: AMP: ampicillin; AMX: amoxicillin; CST: colistin; NFX: enrofloxacin; SPT: spectinomycin; NEO: neomycin; STR: streptomycin; CHL: chloramphenicol; TET: tetracycline; TMP/SMX: trimethoprim/sulfamethoxazole; CTX: cefotaxime; ERY: erythromycin\; CIP: ciprofloxacin; IPM: imipenem; GEN: gentamicin; MEM: meropenem; CEF: cephalothin; NAL: nalidixic acid; CAZ: ceftazidime; LEX: cephalexin; AST: antimicrobial susceptibility testing; ND: not determined.Table 2
Antibiotic resistance profiles ofC. coli.
YearCityStrains (n)OriginASTAntibiotic resistance (n)AMPAMXCSTNFXSPTNEOSTRCHLTETTMP-SMXCTXERYCIPIPMGENMEMCEFNALCAZLEX2007-2008Ahvaz21AnimalDisk diffusion40ND3NDND1014NDND04ND0NDND11NDND2007-2008Ahvaz5HumanDisk diffusionE-test5NDNDNDNDNDNDND3ND341ND1ND524ND2009-2010Ahvaz-Shahrekord7AnimalDisk diffusion01ND0NDND103NDND13ND0NDND1NDND2016Hamadan19AnimalDisk diffusion10812NDNDND41513ND27ND0ND121NDND2013-2014Hamadan3HumanDisk diffusionNDNDNDNDNDNDND02NDND32ND12ND1NDND2014-2015Isfahan6AnimalDisk diffusion00ND0NDND003NDND00ND0NDND2NDND2006–2008Isfahan4AnimalDisk diffusion01ND2NDND002NDND01ND0NDND1NDND2011-2012Isfahan-Shahrekord3AnimalDisk diffusion00ND1NDND001NDND11ND0NDND1NDND2008-2009Isfahan-Yazd8AnimalDisk diffusion00ND1NDND006NDND02ND0NDND2NDND2015-2016Kurdistan8AnimalDisk diffusion agar dilution56NDNDNDNDNDND7NDND06ND00NDNDNDND2013Mashhad27AnimalDisk diffusion36ND4ND5ND317NDND912ND1NDND13NDND2012Mashhad27AnimalDisk diffusion2197102113NDND015ND0NDND18NDND2014-2015Mazandaran-Golestan41AnimalDisk diffusion1715ND16NDND15ND36NDND236ND2NDND32NDND2010Rafsanjan12AnimalDisk diffusionNDNDNDNDNDNDNDNDND12ND00ND12NDND0NDND2014Shahrekord13AnimalDisk diffusion03ND4NDND007NDND05ND0NDND4NDND2009-2010Shahrekord15AnimalDisk diffusion20ND2NDND107NDND04ND0NDND5NDNDNDShahrekord4AnimalDisk diffusion00ND1NDND002NDND00ND0NDND2NDND2011–2013Shiraz17AnimalDisk diffusion5ND03ND0ND12ND4514ND1ND108NDNDNDShiraz10AnimalDisk diffusion E-test1NDNDNDNDNDND211610ND1NDNDNDND4NDShiraz10AnimalDisk diffusionE-test1NDNDNDNDNDND21ND610ND1NDNDNDND42011-2012Tehran28AnimalDisk diffusion154ND22116NDND113ND1NDND24NDND2012Tehran39AnimalDisk diffusion3230NDNDNDND35273831ND3334ND0NDND36NDND2010Tehran33AnimalDisk diffusion25NDNDNDND0NDND31NDNDND10NDNDNDND0NDND2008–2010Tehran23AnimalDisk diffusion138NDND11015NDND115ND0NDND18NDND2008-2009Tehran12HumanDisk diffusion2ND2NDND1113ND61600NDND65ND2006-2007Tehran22AnimalDisk diffusion032ND11004NDND09ND0NDND18NDND2004-2005Tehran5HumanDisk diffusion1ND0NDND0000ND20400ND5545NDTonekabon8AnimalDisk diffusionE-test8NDNDNDNDNDND21ND720ND1NDNDNDND8NDTonekabon9AnimalDisk diffusion99NDNDNDND121NDND10ND0NDNDNDND9Abbreviations: AMP: ampicillin; AMX: amoxicillin; CST: colistin; NFX: enrofloxacin; SPT: spectinomycin; NEO: neomycin; STR: streptomycin; CHL: chloramphenicol; TET: tetracycline; TMP/SMX: trimethoprim/sulfamethoxazole; CTX: cefotaxime; ERY: erythromycin; CIP: ciprofloxacin; IPM: imipenem; GEN: gentamicin; MEM: meropenem; CEF: cephalothin; NAL: nalidixic acid; CAZ: ceftazidime; LEX: cephalexin; AST: antimicrobial susceptibility testing; ND: not determined.Table 3
Antibiotic resistance profiles ofC. lari.
YearCityStrains (n)OriginASTAntibiotic resistance (n)AMPAMXCSTNFXSPTNEOSTRCHLTETTMP-SMXCTXERYCIPIPMGENMEMCEFNALCAZLEXNDShiraz12AnimalDisk diffusionE-test3NDNDNDNDNDND212810ND1NDNDNDND5NDShiraz12NDDisk diffusionE-test3NDNDNDNDNDND21ND810ND1NDNDNDND5NDTonekabon8NDDisk diffusionE-test8NDNDNDNDNDND21ND800ND2NDNDNDND7NDTonekabon7AnimalDisk diffusion77NDNDNDND121NDND00ND0NDNDNDND7Data obtained from eligible studies include publishing year, location of the study, number of strains, origin of samples, methods used for antimicrobial susceptibility testing, and antibiotic resistance profiles ofC. jejuni, C. coli, and C. lari.


## 2.3. Meta-Analysis

The data for the quantitative data synthesis were transferred to the Comprehensive Meta-Analysis (CMA) software (Biostat, Englewood, NJ). Resistance rates ofC. jejuni, C. coli, and C. lari were calculated for each antibiotic as a percentage and expressed as 95% confidence intervals (95% CIs). I2 statistic was used to evaluate the existed heterogeneity, and considering the percent of inconsistency among studies, pooling of data was performed using fixed-or random-effects models. The assessment of publication bias was done using funnel plots.


## 3. Results

### 3.1. Characteristics of Included Studies

As shown in Figure1, a total of 1299 articles were obtained from five databases (PubMed, Scopus, ISI Web of Knowledge, Google Scholar, and SID). According to the presented inclusion or exclusion criteria in Figure 1, 1249 articles were removed and the eligibility of 50 remained articles was evaluated. Among them, 16 studies did not meet inclusion criteria because of reporting the resistance patterns of campylobacters only in the genus level or had inadequate information, while 34 articles (9 in Persian and 25 in English) had complete data and were included in our meta-analysis.Figure 1
A summary of the study selection processes.The characteristics of the 34 included studies are summarized in Tables1–3. The main data was extracted from 3 studies from Ahvaz [11–13], 2 studies from Hamadan [14, 15], 4 studies from Isfahan [16–19], 1 study from Kerman [20], 1 study from Kurdistan [21], 2 studies from Mashhad [22, 23], 1 study from Mazandaran and Golestan [24], 1 study from Rafsanjan [25], 5 studies from Shahrekord [13, 18, 26–28], 2 studies from Semnan [29, 30], 4 studies from Shiraz [31–34], 8 studies from Tehran [35–42], 2 studies from Tonekabon [34, 43], 1 study from Yazd [19], and 1 study from Zahedan [44]. Disk diffusion, E-test, and agar dilution were the most common methods used to evaluate antibiotic-resistant Campylobacter species in Iran (Tables 1–3). Additionally, the most common Campylobacter species for which their antibiotic resistance has been evaluated were C. jejuni, C. coli, and C. lari. The origins of Campylobacter species were human and animal fecal samples as well as food samples with animal origin including milk, dairy products, and animal meats like poultry, cattle, sheep, camels, beef, water buffalo, ducks, and geese. A random-effects model was used for pooling data on the prevalence of antibiotic resistance of Campylobacter species due to the presence of high heterogeneity (I2 > 25%). There was some evidence of publication bias (Figures 2 and 3).Figure 2
Funnel plot of the meta-analysis of the prevalence ofC. jejuni resistant to ciprofloxacin in Iran.Figure 3
Funnel plot of the meta-analysis of the prevalence ofC. coli resistant to ciprofloxacin in Iran.


### 3.2. Characteristics ofC. jejuni Antibiotic Resistance

In our presented meta-analysis, a total of 34 studies determined the prevalence ofC. jejuni antibiotic resistance (Table 1). Antimicrobial resistance patterns of C. jejuni in Iran were as follows: 22.8% (95% CI: 15.9–31.6) to ampicillin, 17.7% (95% CI: 11.4–26.5) to amoxicillin, 25.8% (95% CI: 14.5–41.7) to colistin, 24.3% (95% CI: 16.8–33.7) to enrofloxacin, 2.3% (95% CI: 0.8–6.4) to spectinomycin, 8.6% (95% CI: 3.9–17.7) to neomycin, 7.1% (95% CI: 4.7–10.7) to streptomycin, 6% (95% CI: 4.1–8.6) to chloramphenicol, 50.7% (95% CI: 41.1–60.4) to tetracycline, 66.9% (95% CI: 40.5–85.8) to trimethoprim/sulfamethoxazole, 41.2% (95% CI: 25.1–59.5) to cefotaxime, 6.4% (95% CI: 3.6–11.1) to erythromycin, 53.6% (95% CI: 43.9–62.9) to ciprofloxacin (Figure 4), 0% to imipenem, 4.5% (95% CI: 2.5–7.7) to gentamicin, 9.5% (95% CI: 0.6–65.5) to meropenem, 89.4% (95% CI: 73.8–96.2) to cephalothin, 59.6% (95% CI: 52.1–66.7) to nalidixic acid, 54.6% (95% CI: 38.9–69.4) to ceftazidime and 76.5% (95% CI: 54.5–89.8) to cephalexin. Additionally, other antibiotic resistance patterns were as follows: clindamycin 4 (66.6%), tylosin 15 (31.2%), oxacillin 9 (100%), amikacin 4 (5.1%), azithromycin 0 (0%), ceftriaxone 9 (56.2%), amoxi-clave 16 (100%), penicillin 16 (100%), vancomycin 16 (100%), tobramycin 4 (25%), ofloxacin 55 (87.3%), and carbenicillin 25 (39.6%).Figure 4
Forest plot of the meta-analysis of the prevalence ofC. jejuni resistant to ciprofloxacin in Iran.


### 3.3. Characteristics ofC. coli Antibiotic Resistance

The characteristics of the 29 studies that determined the prevalence ofC. coli antibiotic resistance are summarized in Table 2. The prevalence of resistance of C. coli to different antibiotics was as follows: 24.5% (95% CI: 14.5–38.4) to ampicillin, 23.5% (95% CI: 13.7–37.2) to amoxicillin, 23.1% (95% CI: 12.1–39.5) to colistin, 25.1% (95% CI: 19.2–32.1) to enrofloxacin, 5.4% (95% CI: 2–13.5) to spectinomycin, 8.3% (95% CI: 4.7–14.1) to neomycin, 11.6% (95% CI: 5.4–23.3) to streptomycin, 9.6% (95% CI: 4.9–17.8) to chloramphenicol, 47.7% (95% CI: 35.6–60.1) to tetracycline, 67.2% (95% CI: 33.6–89.3) to trimethoprim/sulfamethoxazole, 51.5% (95% CI: 35.8–66.9) to cefotaxime, 13% (95% CI: 6.9–23) to erythromycin, 41.8% (95% CI: 31.4–53.1) to ciprofloxacin (Figure 5), 0% to imipenem, 6.8% (95% CI: 4.3–10.5) to gentamicin, 27.2% (95% CI: 1.2–92.2) to meropenem, 65.5% (95% CI: 50.1–78.2) to cephalothin, 49.2% (95% CI: 36.6–61.9) to nalidixic acid, 62.2% (95% CI: 31.8–85.2) to ceftazidime, and 73% (95% CI: 38.6–92.1) to cephalexin. Additionally, other antibiotic resistance patterns were as follows: clindamycin 2 (66.6%), tylosin 2 (11.7%), oxacillin 5 (100%), amikacin 3 (7.3%), ceftriaxone 9 (100%), amoxi-clave 9 (100%), penicillin 9 (100%), vancomycin 9 (100%), tobramycin 0 (0%), ofloxacin 11 (64.7%), and carbenicillin 7 (41.1%).Figure 5
Forest plot of the meta-analysis of the prevalence ofC. coli resistant to ciprofloxacin in Iran.


### 3.4. Characteristics ofC. lari Antibiotic Resistance

A total of 4 studies investigating the prevalence ofC. lari antibiotic resistance were included in the meta-analysis (Table 3). Antimicrobial resistance patterns of C. lari in Iran were as follows: 60% (95% CI: 19–90.5) to ampicillin, 93.7% (95% CI: 46.1–99.6) to amoxicillin, 14.3% (95% CI: 2–58.1) to streptomycin, 20.9% (95% CI: 10.8–36.7) to chloramphenicol, 10.5% (95% CI: 4–24.9) to tetracycline, 16.7% (95% CI: 4.2–47.7) to trimethoprim/sulfamethoxazole, 70.4% (95% CI: 51.3–84.3) to cefotaxime, 7.4% (95% CI: 2.4–20.6) to erythromycin, 0% to ciprofloxacin, 12.7% (95% CI: 5.1–28.5) to gentamicin, and 63.2% (95% CI: 32.7–85.9) to cephalexin. Additionally, other antibiotic resistance patterns were as follows: ceftriaxone 7 (100%), amikacin 0 (0%), amoxi-clave 7 (100%), penicillin 7 (100%), vancomycin 7 (100%) and tobramycin 2 (29%).Abbreviations: AMP: ampicillin; AMX: amoxicillin; CST: colistin; NFX: enrofloxacin; SPT: spectinomycin; NEO: neomycin; STR: streptomycin; CHL: chloramphenicol; TET: tetracycline; TMP/SMX: trimethoprim/sulfamethoxazole; CTX: cefotaxime; ERY: erythromycin; CIP: ciprofloxacin; IPM: imipenem; GEN: gentamicin; MEM: meropenem; CEF: cephalothin; NAL: nalidixic acid; CAZ: ceftazidime; LEX: cephalexin; AST: antimicrobial susceptibility testing; ND: not determined.


## 3.1. Characteristics of Included Studies

As shown in Figure1, a total of 1299 articles were obtained from five databases (PubMed, Scopus, ISI Web of Knowledge, Google Scholar, and SID). According to the presented inclusion or exclusion criteria in Figure 1, 1249 articles were removed and the eligibility of 50 remained articles was evaluated. Among them, 16 studies did not meet inclusion criteria because of reporting the resistance patterns of campylobacters only in the genus level or had inadequate information, while 34 articles (9 in Persian and 25 in English) had complete data and were included in our meta-analysis.Figure 1
A summary of the study selection processes.The characteristics of the 34 included studies are summarized in Tables1–3. The main data was extracted from 3 studies from Ahvaz [11–13], 2 studies from Hamadan [14, 15], 4 studies from Isfahan [16–19], 1 study from Kerman [20], 1 study from Kurdistan [21], 2 studies from Mashhad [22, 23], 1 study from Mazandaran and Golestan [24], 1 study from Rafsanjan [25], 5 studies from Shahrekord [13, 18, 26–28], 2 studies from Semnan [29, 30], 4 studies from Shiraz [31–34], 8 studies from Tehran [35–42], 2 studies from Tonekabon [34, 43], 1 study from Yazd [19], and 1 study from Zahedan [44]. Disk diffusion, E-test, and agar dilution were the most common methods used to evaluate antibiotic-resistant Campylobacter species in Iran (Tables 1–3). Additionally, the most common Campylobacter species for which their antibiotic resistance has been evaluated were C. jejuni, C. coli, and C. lari. The origins of Campylobacter species were human and animal fecal samples as well as food samples with animal origin including milk, dairy products, and animal meats like poultry, cattle, sheep, camels, beef, water buffalo, ducks, and geese. A random-effects model was used for pooling data on the prevalence of antibiotic resistance of Campylobacter species due to the presence of high heterogeneity (I2 > 25%). There was some evidence of publication bias (Figures 2 and 3).Figure 2
Funnel plot of the meta-analysis of the prevalence ofC. jejuni resistant to ciprofloxacin in Iran.Figure 3
Funnel plot of the meta-analysis of the prevalence ofC. coli resistant to ciprofloxacin in Iran.


## 3.2. Characteristics ofC. jejuni Antibiotic Resistance

In our presented meta-analysis, a total of 34 studies determined the prevalence ofC. jejuni antibiotic resistance (Table 1). Antimicrobial resistance patterns of C. jejuni in Iran were as follows: 22.8% (95% CI: 15.9–31.6) to ampicillin, 17.7% (95% CI: 11.4–26.5) to amoxicillin, 25.8% (95% CI: 14.5–41.7) to colistin, 24.3% (95% CI: 16.8–33.7) to enrofloxacin, 2.3% (95% CI: 0.8–6.4) to spectinomycin, 8.6% (95% CI: 3.9–17.7) to neomycin, 7.1% (95% CI: 4.7–10.7) to streptomycin, 6% (95% CI: 4.1–8.6) to chloramphenicol, 50.7% (95% CI: 41.1–60.4) to tetracycline, 66.9% (95% CI: 40.5–85.8) to trimethoprim/sulfamethoxazole, 41.2% (95% CI: 25.1–59.5) to cefotaxime, 6.4% (95% CI: 3.6–11.1) to erythromycin, 53.6% (95% CI: 43.9–62.9) to ciprofloxacin (Figure 4), 0% to imipenem, 4.5% (95% CI: 2.5–7.7) to gentamicin, 9.5% (95% CI: 0.6–65.5) to meropenem, 89.4% (95% CI: 73.8–96.2) to cephalothin, 59.6% (95% CI: 52.1–66.7) to nalidixic acid, 54.6% (95% CI: 38.9–69.4) to ceftazidime and 76.5% (95% CI: 54.5–89.8) to cephalexin. Additionally, other antibiotic resistance patterns were as follows: clindamycin 4 (66.6%), tylosin 15 (31.2%), oxacillin 9 (100%), amikacin 4 (5.1%), azithromycin 0 (0%), ceftriaxone 9 (56.2%), amoxi-clave 16 (100%), penicillin 16 (100%), vancomycin 16 (100%), tobramycin 4 (25%), ofloxacin 55 (87.3%), and carbenicillin 25 (39.6%).Figure 4
Forest plot of the meta-analysis of the prevalence ofC. jejuni resistant to ciprofloxacin in Iran.


## 3.3. Characteristics ofC. coli Antibiotic Resistance

The characteristics of the 29 studies that determined the prevalence ofC. coli antibiotic resistance are summarized in Table 2. The prevalence of resistance of C. coli to different antibiotics was as follows: 24.5% (95% CI: 14.5–38.4) to ampicillin, 23.5% (95% CI: 13.7–37.2) to amoxicillin, 23.1% (95% CI: 12.1–39.5) to colistin, 25.1% (95% CI: 19.2–32.1) to enrofloxacin, 5.4% (95% CI: 2–13.5) to spectinomycin, 8.3% (95% CI: 4.7–14.1) to neomycin, 11.6% (95% CI: 5.4–23.3) to streptomycin, 9.6% (95% CI: 4.9–17.8) to chloramphenicol, 47.7% (95% CI: 35.6–60.1) to tetracycline, 67.2% (95% CI: 33.6–89.3) to trimethoprim/sulfamethoxazole, 51.5% (95% CI: 35.8–66.9) to cefotaxime, 13% (95% CI: 6.9–23) to erythromycin, 41.8% (95% CI: 31.4–53.1) to ciprofloxacin (Figure 5), 0% to imipenem, 6.8% (95% CI: 4.3–10.5) to gentamicin, 27.2% (95% CI: 1.2–92.2) to meropenem, 65.5% (95% CI: 50.1–78.2) to cephalothin, 49.2% (95% CI: 36.6–61.9) to nalidixic acid, 62.2% (95% CI: 31.8–85.2) to ceftazidime, and 73% (95% CI: 38.6–92.1) to cephalexin. Additionally, other antibiotic resistance patterns were as follows: clindamycin 2 (66.6%), tylosin 2 (11.7%), oxacillin 5 (100%), amikacin 3 (7.3%), ceftriaxone 9 (100%), amoxi-clave 9 (100%), penicillin 9 (100%), vancomycin 9 (100%), tobramycin 0 (0%), ofloxacin 11 (64.7%), and carbenicillin 7 (41.1%).Figure 5
Forest plot of the meta-analysis of the prevalence ofC. coli resistant to ciprofloxacin in Iran.


## 3.4. Characteristics ofC. lari Antibiotic Resistance

A total of 4 studies investigating the prevalence ofC. lari antibiotic resistance were included in the meta-analysis (Table 3). Antimicrobial resistance patterns of C. lari in Iran were as follows: 60% (95% CI: 19–90.5) to ampicillin, 93.7% (95% CI: 46.1–99.6) to amoxicillin, 14.3% (95% CI: 2–58.1) to streptomycin, 20.9% (95% CI: 10.8–36.7) to chloramphenicol, 10.5% (95% CI: 4–24.9) to tetracycline, 16.7% (95% CI: 4.2–47.7) to trimethoprim/sulfamethoxazole, 70.4% (95% CI: 51.3–84.3) to cefotaxime, 7.4% (95% CI: 2.4–20.6) to erythromycin, 0% to ciprofloxacin, 12.7% (95% CI: 5.1–28.5) to gentamicin, and 63.2% (95% CI: 32.7–85.9) to cephalexin. Additionally, other antibiotic resistance patterns were as follows: ceftriaxone 7 (100%), amikacin 0 (0%), amoxi-clave 7 (100%), penicillin 7 (100%), vancomycin 7 (100%) and tobramycin 2 (29%).Abbreviations: AMP: ampicillin; AMX: amoxicillin; CST: colistin; NFX: enrofloxacin; SPT: spectinomycin; NEO: neomycin; STR: streptomycin; CHL: chloramphenicol; TET: tetracycline; TMP/SMX: trimethoprim/sulfamethoxazole; CTX: cefotaxime; ERY: erythromycin; CIP: ciprofloxacin; IPM: imipenem; GEN: gentamicin; MEM: meropenem; CEF: cephalothin; NAL: nalidixic acid; CAZ: ceftazidime; LEX: cephalexin; AST: antimicrobial susceptibility testing; ND: not determined.


## 4. Discussion

Food-borne illnesses caused byCampylobacter species as well as other bacteria related to food poisoning can be prevented by avoiding food contamination and growth of bacteria through proper food preparation and proper cooking as well as avoidance of contamination of water sources and consuming pasteurized dairy products [2, 45]. However, the main problem is food contamination with drug-resistant pathogens, which is a major threat to public health [46]. Antibiotic resistance genes can be transferred among food-borne pathogens, and this makes the treatment of severe infections difficult [46]. Today, fluoroquinolone-resistant Campylobacter species have turned into a global concern [9]. Fluoroquinolones are selective drugs in the treatment of campylobacteriosis; however, an increasing trend of resistance in Campylobacter species isolated from human and animal origins has been reported in the USA and Canada (19–47%), European countries (17–99%), and Africa and Asia (>80%) [5]. According to the present study, the resistance of Campylobacter species isolated from human and animal origins to quinolones and fluoroquinolones including ciprofloxacin, nalidixic acid, enrofloxacin, and ofloxacin was also prevalent in Iran and varied from 0% to 87.3% (Tables 1–3). Efflux pumps, CmeABC, and single point mutations in DNA gyrase A (GyrA) such as C257 T mutation, the most frequent mutation, are involved in chromosomally mediated quinolone resistance in Campylobacter species [5].Macrolides are also recommended as another selective antibiotic class for the treatment of campylobacteriosis [2, 5]. The resistance rate to erythromycin in Campylobacter species isolated from human and animal samples in Iran was low (6.4%, 13%, and 7.4% for C. jejuni, C. coli, and C. lari, respectively). The frequency of erythromycin resistance in Iran was higher than that in Turkey [47], Ethiopia [48], Canada [49], Australia [50], and the Czech Republic [51] and lower than that of South Africa [52], Malaysia [53], Italy [54], and China [55]. The target modifications through point mutations in the 23S rRNA gene such as A2074C, A2074G, and A2075G mutations, modifying L4 and L22 ribosomal proteins along with CmeABC efflux pump, are three main mechanisms complicated in macrolide resistance in Campylobacter species [5].Tetracyclines and gentamicin have also importance inCampylobacter infection therapy as second-line antibiotics [2, 4, 5]. The tet(O) gene, which encodes a ribosomal protection protein, and CmeABC multidrug efflux pump are associated with tetracycline resistance in Campylobacter species [5]. Additionally, aminoglycoside-modifying enzymes play an important role in aminoglycoside resistance in Campylobacter species [5]. Based on the results of this study, C. jejuni and C. coli antibiotic resistance rates to tetracycline were much higher than gentamicin. Similar results were observed in the studies reported from Turkey [47], Italy [54], South Korea [56], and Poland [57]. Moreover, similar to our results, high rates of tetracycline resistance were reported in the studies of Turkey [47], Canada [49], South Africa [52], Malaysia [53], Italy [54], China [55], South Korea [56], and Poland [57]. Noteworthy, the determination of Campylobacter species susceptibility patterns against other antibiotics has received less attention. One reason could be attributed to the high sensitivity of bacteria to these antibiotics. For example, in the current study, antibiotic resistance pattern to protein synthesis inhibitors was low. On the other hand, resistance to protein synthesis inhibitors was lower than cell growth inhibitors and folic acid metabolism inhibitors.As shown in other studies, the efficacy of cell growth inhibitor antibiotics againstCampylobacter species is limited [5]. Our study also showed that among the three evaluated Campylobacter species, antibiotic resistance to β-lactam antibiotics, especially penicillins and cephalosporins, was high. On the other hand, the resistance rate to imipenem was lower than meropenem. The intrinsic resistance and β-lactamase enzymes are two main mechanisms of resistance to β-lactam antibiotics in Campylobacter species [5]. The intrinsic resistance is also the main resistance mechanism of Campylobacter species against vancomycin and folic acid metabolism inhibitors [5]. Our results confirmed high resistance rates to these antibiotics probably due to intrinsic resistance.


## 5. Conclusion

In accordance with the WHO report on fluoroquinolone-resistantCampylobacter species in the world and the urgent need to develop new antibiotics, our meta-analysis showed a high prevalence of resistance of Campylobacter species isolated from human and animal origins to quinolones and fluoroquinolones in Iran. On the other hand, compared to penicillins, cephalosporins, and sulfonamides, Campylobacter species were susceptible or showed low resistance rates to aminoglycosides, chloramphenicol, and imipenem. Therefore, these antibiotics could be recommended for the treatment of campylobacteriosis in Iran. We recommend monitoring antibiotic-resistant Campylobacter species through continuous drug sensitivity monitoring and investigating resistance mechanisms, especially against fluoroquinolones, to prevent further expansion of resistant species in Iran.



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