# Is Penicillin-NonsusceptibleStreptococcus pneumoniae a Significant Challenge to Healthcare System? A Systematic Review and Meta-Analysis

Authors: Farzad Khademi; Amirhossein Sahebkar
Journal: Scientifica
 (2021)

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## Abstract

Background. In recent years, antibiotic-resistant pathogens including penicillin-nonsusceptible Streptococcus pneumoniae (PNSP) have posed serious threats against human health. The aim of this meta-analysis was to investigate the prevalence of Streptococcus pneumoniae drug resistance particularly the incidence of PNSP strains in Iran. Methods. A systematic search was done in national and international electronic databases using Persian and English keywords. Up until May 20, 2020, a total of 58 publications were detected as eligible articles based on the inclusion and exclusion criteria, and then the selected studies were enrolled for data extraction and meta-analysis according to the PRISMA guidelines. Results. A high rate of PNSP (46.9%) and multidrug-resistant (MDR) S. pneumoniae (45.3%) in our isolates were evident. Furthermore, total frequency resistance to other drugs in S. pneumoniae was as follows: erythromycin 41.1%, azithromycin 53.2%, tetracycline 39.9%, levofloxacin 1.7%, rifampin 1.2%, clindamycin 31.7%, vancomycin 1.7%, trimethoprim/sulfamethoxazole 63.9%, chloramphenicol 20%, ceftriaxone 10.9%, amoxicillin 30.5%, ciprofloxacin 8.3%, imipenem 6.1%, linezolid 0%, and cefotaxime 8.3%. Conclusion. Although the overall prevalence of cephalosporin- and carbapenem-resistant Streptococcus pneumoniae was low, penicillin-resistant strains, especially PNSP, could become a significant challenge to the healthcare system in Iran. Hence, the prescription of penicillin as the first-choice antibiotic in the treatment of S. pneumoniae infections should be avoided.


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## Body

## 1. Introduction

Streptococcus pneumoniae (S. pneumoniae) (pneumococcus) is a Gram-positive diplococcus that is an exclusively normal inhabitant in the oropharynx and nasopharynx of healthy individuals [1, 2]. Colonization rates are higher in the extreme of age (children under 5 and adults older than 65 years old) and immunocompromised patients especially in developing countries [3]. The bacterium enters the body through droplets and aerosols by person-to-person transmission. It then disseminates into other sites including circulation, brain, lungs, paranasal sinuses, and middle ears and causes severe diseases such as pneumonia, sinusitis, otitis media, bacteremia, and meningitis [1–3]. Pneumonia of any cause is an important disease affecting children under the age of five. In 2017, the World Health Organization (WHO) announced 808,694 pneumonia-related child deaths which accounts for 15% of total mortality in children younger than five years old [4]. The two most common bacterial causes of pneumonia in children are S. pneumoniae and Haemophilus influenzae type b, respectively [3]. Recently, a plan released by the WHO/UNICEF named the Integrated Global Action Plan for the Prevention and Control of Pneumonia and Diarrhea (GAPPD) with the aim of reducing the death rate to less than 3 children per 1000 live births by 2025 [4]. The main strategies to protect, prevent, and treat children with pneumococcal pneumonia include exclusive breastfeeding, adequate complementary feeding, hand washing, reducing household air pollution, prevention of HIV, oxygen therapy, vaccinations, and also the administration of appropriate antibiotics [4]. Potent anticapsular pneumococcal vaccines (PPSV23, PCV13, and PCV7) were developed based on the prevalent serotypes of S. pneumoniae; however, they are less effective in developing countries due to different distribution patterns of serotypes by geographic locations [1], and hence, they are not part of the childhood immunization plan in Iran. Over the last several decades, penicillin was the drug of choice for the treatment of pneumococcal diseases [1, 2]. However, up to 40% of these bacteria are found to be penicillin-resistant [5]. A list of antibiotic-resistant pathogens was released by WHO in February 2017 that urgently requires effective antibiotics [6]. Penicillin-nonsusceptible S. pneumoniae (PNSP) strains are priority 3 (medium) on the list and known as increasingly drug-resistant pathogens which require further research and development of new antibiotics [6]. Given the distinct geographical distributions, which can affect bacterial phenotypic and genetic characteristics such as drug susceptibility, and self-medication of antibiotics in Iran, the current systematic review and meta-analysis was performed to follow four objectives: (1) to estimate the overall prevalence of S. pneumoniae strains resistant to different antibiotics among all age groups in Iran, (2) to determine S. pneumoniae drug resistance in Iranian children, (3) to assess the prevalence of PNSP strains, and (4) to investigate antimicrobial resistance profiles in different provinces of Iran.


## 2. Methods

### 2.1. Search Strategies

The current systematic review and meta-analysis is designed based on the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines [7]. A comprehensive search was performed on studies published from October 1993 to May 2020. English keywords in the ISI Web of Knowledge, PubMed, Scopus, and Google Scholar databases and Persian keywords in national search engines including Scientific Information Database (http://www.sid.ir) and Magiran (http://www.Magiran.com) were used to find original articles addressing S. pneumoniae antibiotic resistance in Iran. For this purpose, the search terms (i.e., S. pneumoniae, antibiotic resistance, and Iran) were extracted from Medical Subject Headings (MeSH) and combined with connectors (AND/OR).


### 2.2. Inclusion and Exclusion Criteria

The articles were selected based on the title, abstract, and full text. First, the titles of cross-sectional studies on the prevalence of drug resistance were evaluated according to the author, bacterium, and country names, and then, abstracts and full texts were further assessed. Inclusion criteria were original articles assessing the prevalence of pneumococcus drug resistance, full-text availability, publication in English or Persian languages, and studies with sufficient data and limited to Iran. Exclusion criteria were studies reporting drug resistance patterns only at the level ofStreptococcus genus or other than S. pneumoniae, evaluating the prevalence of S. pneumoniae resistance with low sample size, repetitive publications, nonoriginal articles, and articles available only in abstract form or abstracts from conferences.


### 2.3. Quality Assessment and Data Extraction

Included articles were further assessed in terms of quality using the Joanna Briggs Institute (JBI) critical appraisal checklist, and then, necessary data were extracted and tabulated in Table1 [66]. The main data included the first author’s surname, study location, publication date, study enrollment date, age group, sample size, antibiotic susceptibility testing methods, the prevalence of S. pneumoniae resistance to different drugs, and the prevalence of multidrug-resistant (MDR) pneumococci.Table 1
Extracted information from eligible studies included in the meta-analysis.
Author (ref)ProvincePublished timeEnrollment timeAge groupStrain (n)ASTAntibiotic resistance (n)PNSPERYAZMTETLVXRIFCLIVANSXTCHLCROAMXCIPIPMLZDCTXMDRGharibani et al. [8]Ardabil20192015Children43Disk diffusion4132311800120357NDNDNDNDNDND32Khoshdel et al. [9]Chaharmahal and Bakhtiari20092007Children38Disk diffusion11NDNDNDNDNDNDNDNDNDNDNDNDNDNDNDNDImani et al. [10]Chaharmahal and Bakhtiari20072005ND17Broth microdilution1610NDNDNDNDNDNDNDND1ND2NDNDNDNDAbdinia et al. [11]East Azerbaijan20142003–2013Children37Disk diffusion146NDNDND1ND01224ND3NDND3NDHadi and Bagheri [12]Fars20192011–2016Children10Disk diffusion73NDNDNDND30914NDNDNDNDNDNDKargar et al. [13]Fars20152011–2012Children/adult45Disk diffusionNDNDNDND31NDNDNDNDNDNDND40NDNDNDNDKargar et al. [14]Fars20122010–2011Children/adult50Disk diffusion30282252NDNDND240NDNDNDNDND2530Shishegar et al. [15]Fars20112007–2008Children10Disk diffusionND1NDNDNDNDNDND10ND240NDND2NDJaponi et al. [16]Fars20102005–2006ND13Disk diffusion53NDNDNDND1061NDND1NDNDNDNDKohanteb and Sadeghi [17]Fars2007NDChildren/adult115Broth microdilution39211528NDNDND0ND97ND9NDND5NDGhaemi et al. [18]Golestan20021998–1999Children63Disk diffusion355ND23NDND13NDNDNDNDNDNDNDNDNDNDKhademi et al. [19]Hamadan20162013–2014Children/adult6Disk diffusionNDNDNDNDNDNDND03ND0ND1NDND0NDYousefi Mashouf et al. [20]Hamadan20142009–2013Children35Disk diffusionNDNDNDNDNDNDNDND912ND19NDNDNDNDNDYousefi Mashouf et al. [21]Hamadan20031998–2000Children11Disk diffusionNDNDNDNDNDNDNDND34ND6NDNDNDNDNDMosleh et al. [22, 23]Hamadan2014NDND55E-test521410NDNDNDND0NDNDNDND655NDND12Yeganeh-Moghadam et al. [24]Isfahan20142011–2013Children15Disk diffusionND59NDNDNDNDND15ND990NDND9NDGhazikalayeh et al. [25]Isfahan20142011–2012Children291Disk diffusion4710ND740050NDNDNDNDNDND0NDNDSabory et al. [26]Kermanshah20152012Children83Disk diffusionNDND53NDND34NDND31ND347NDNDNDND34Khosravi et al. [27]Khuzestan20072005–2006Adult6Disk diffusionNDNDND3NDNDNDND0ND3NDNDNDNDNDNDMoafi and Issazadeh [28]Qazvin20162013–2014Children6Disk diffusionNDNDNDNDNDNDNDND44NDNDNDNDNDNDNDMamishi et al. [29]Tehran20192017–2018Children4Disk diffusion14NDNDNDND201NDNDNDNDNDNDNDNDGhahfarokhi et al. [30]Tehran20202015–2019Children/adult80Disk diffusion2949ND31NDND470571513NDNDNDNDND41Azarsa et al. [31]Tehran20192015Children/adult46Disk diffusion12NDNDNDNDNDNDNDNDNDNDNDNDNDNDNDNDMousavi et al. [32]Tehran20172014–2015Children76Disk diffusion7665654ND0NDNDNDNDNDNDNDNDNDND76Ahmadi et al. [33]Tehran20192013–2016Children/adult100Disk diffusion2259ND57NDND49ND9223NDND3NDNDND54Houri et al. [34]Tehran20172013–2016Children53Broth microdilution1115ND130NDND012ND4NDNDND039Talebi et al. [35]Tehran20192013–2015ND161Disk diffusion9396ND121NDND84ND15195NDNDNDNDNDND69Moghadam et al. [36]Tehran20172013–2015Children/adult100Disk diffusion2664ND770ND56096440NDND00ND71Farshad et al. [37]Tehran20162013Adult48Disk diffusion40NDNDNDNDNDNDNDNDNDNDNDNDNDNDNDNDRahbar et al. [38]Tehran20192012–2016Children/adult50E-test153635281ND2603213NDNDNDNDNDNDNDTabatabaei et al. [39]Tehran20172012–2015Children/adult73Broth microdilution1661NDNDNDNDND011ND23NDNDNDND31NDTalebi et al. [40]Tehran20162011–2013Children/adult100Disk diffusion2860ND85NDND780934800ND00050Azadegan et al. [41]Tehran20152011–2013Children/adult186Disk diffusionND88ND186NDNDNDNDNDNDNDNDNDNDNDNDNDAbdollahi et al. [42]Tehran20182011–2012Children102Disk diffusion6124ND110NDND07023NDNDNDNDND0NDAhmadi et al. [43]Tehran20132011Children/adult88Disk diffusionND47ND55NDNDNDNDNDNDNDNDNDNDNDNDNDSoltan Dallal et al. [44]Tehran20132011Children/adult15Disk diffusion1210ND0NDNDND8ND8ND12NDNDNDNDNDSadeghi et al. [45]Tehran20152010–2012Children/adult80E-test36NDNDNDNDNDNDNDNDNDNDNDNDNDNDNDNDAhmadi et al. [46]Tehran20152010–2012Children/adult70Disk diffusion60NDNDNDNDNDNDNDNDNDNDNDNDNDNDNDNDMahmoudi et al. [47]Tehran20132009–2011Children7Disk diffusion5NDNDNDNDNDNDND7ND4NDNDNDNDNDNDKhoramrooz et al. [48]Tehran20122009–2010Children23Disk diffusion61113ND0ND8023ND3ND0ND0NDNDRahimi et al. [49]Tehran20152008–2012Children/adult38NA32ND8NDNDND2294NDND6NDNDNDNDHabibian et al. [50]Tehran20132008–2012ND50Broth microdilution9NDNDNDNDNDND4NDNDNDND2NDNDNDNDDashti et al. [51]Tehran20122008–2009Children573Disk diffusion53ND315377ND0ND9683426239NDND17NDAshtiani et al. [52]Tehran20142001–2011Children194Disk diffusion8999NDNDNDNDND01395823NDNDNDND25NDPourakbari et al. [53]Tehran20122001–2005Children46Disk diffusion1429NDNDNDND3ND388NDNDNDNDNDNDNDAligholi et al. [54]Tehran20092001–2005Children50Agar dilution1529NDNDND0ND0NDND0ND15NDNDNDNDOskoui et al. [55]Tehran20102000–2008ND54Disk diffusion389ND10NDNDNDND28NDNDNDNDNDND29Jahanmehr et al. [56]Tehran20041999–2001ND66Disk diffusion12NDNDNDNDNDND0NDNDND12NDNDNDNDNDOskoui et al. [57]Tehran20031998–2000ND130Disk diffusion11410ND47NDNDND05728NDNDNDNDNDNDNDRezaeizadeh et al. [58]Tehran20121998–2008Children30Disk diffusion176NDNDNDNDND0196NDNDNDNDNDNDNDModarres et al. [59]Tehran19981993–1995Children51Disk diffusion11NDNDNDNDND29342NDNDNDNDNDNDNDGharailoo et al. [60]Sistan and Balouchastan20162013–2014Children42Disk diffusion4223ND260NDND0396ND7NDNDND0NDBokaeian et al. [61]Sistan and Balouchastan20122008–2010Children75Disk diffusion6266ND430NDND047120NDND0NDND43Bokaeian et al. [62]Sistan and Balouchastan20112007–2008Children/adult136Broth microdilution4325ND13NDNDND0ND115ND2NDND318Rahbar et al. [63]West Azerbaijan20051999–2001ND24Disk diffusion8NDNDNDNDND000NDNDND0NDNDNDNDBehnaz et al. [64]Yazd20042002Children72Disk diffusion3645ND22NDNDNDND45NDNDNDNDNDNDNDNDKarami et al. [65]Zanjan20092006–2007Children/adult57Broth macrodilution33NDNDNDNDNDND0NDNDNDNDNDNDNDNDNDPNSP: penicillin-nonsusceptibleS. pneumoniae (intermediately resistant and fully resistant); ERY: erythromycin; AZM: azithromycin; TET: tetracycline; LVX: levofloxacin; RIF: rifampin; CLI: clindamycin; VAN: vancomycin; SXT: trimethoprim/sulfamethoxazole; CHL: chloramphenicol; CRO: ceftriaxone; AMX: amoxicillin; CIP: ciprofloxacin; IPM: imipenem; LZD: linezolid; CTX: cefotaxime; MDR: multidrug-resistant (resistant to ≥3 antibiotic classes); AST: antimicrobial susceptibility testing; ND: not determined.


### 2.4. Meta-Analysis

Meta-analysis of the extracted data on theS. pneumoniae antibiotic resistance was performed using the Comprehensive Meta-Analysis (CMA) software (Biostat, Englewood, NJ), and the frequency of drug resistance was expressed as the percentage and 95% confidence intervals (95% CIs). Further analysis on the location of the study and age groups was also conducted. To evaluate the heterogeneity across the included studies, I2 statistics and the chi-square test (χ2) with the Cochrane Q statistic (Q test) (p value <0.05 was considered statistically significant) were used. A random-effects model (DerSimonian–Laird method) was used to pool the data when heterogeneity was considered high (I2 ≥ 25%). Distribution bias among published studies was calculated quantitatively using Begg’s and Egger’s tests (p value <0.05 indicates a significant bias) and visualized via the funnel plot graphs for each antibiotic.


## 2.1. Search Strategies

The current systematic review and meta-analysis is designed based on the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines [7]. A comprehensive search was performed on studies published from October 1993 to May 2020. English keywords in the ISI Web of Knowledge, PubMed, Scopus, and Google Scholar databases and Persian keywords in national search engines including Scientific Information Database (http://www.sid.ir) and Magiran (http://www.Magiran.com) were used to find original articles addressing S. pneumoniae antibiotic resistance in Iran. For this purpose, the search terms (i.e., S. pneumoniae, antibiotic resistance, and Iran) were extracted from Medical Subject Headings (MeSH) and combined with connectors (AND/OR).


## 2.2. Inclusion and Exclusion Criteria

The articles were selected based on the title, abstract, and full text. First, the titles of cross-sectional studies on the prevalence of drug resistance were evaluated according to the author, bacterium, and country names, and then, abstracts and full texts were further assessed. Inclusion criteria were original articles assessing the prevalence of pneumococcus drug resistance, full-text availability, publication in English or Persian languages, and studies with sufficient data and limited to Iran. Exclusion criteria were studies reporting drug resistance patterns only at the level ofStreptococcus genus or other than S. pneumoniae, evaluating the prevalence of S. pneumoniae resistance with low sample size, repetitive publications, nonoriginal articles, and articles available only in abstract form or abstracts from conferences.


## 2.3. Quality Assessment and Data Extraction

Included articles were further assessed in terms of quality using the Joanna Briggs Institute (JBI) critical appraisal checklist, and then, necessary data were extracted and tabulated in Table1 [66]. The main data included the first author’s surname, study location, publication date, study enrollment date, age group, sample size, antibiotic susceptibility testing methods, the prevalence of S. pneumoniae resistance to different drugs, and the prevalence of multidrug-resistant (MDR) pneumococci.Table 1
Extracted information from eligible studies included in the meta-analysis.
Author (ref)ProvincePublished timeEnrollment timeAge groupStrain (n)ASTAntibiotic resistance (n)PNSPERYAZMTETLVXRIFCLIVANSXTCHLCROAMXCIPIPMLZDCTXMDRGharibani et al. [8]Ardabil20192015Children43Disk diffusion4132311800120357NDNDNDNDNDND32Khoshdel et al. [9]Chaharmahal and Bakhtiari20092007Children38Disk diffusion11NDNDNDNDNDNDNDNDNDNDNDNDNDNDNDNDImani et al. [10]Chaharmahal and Bakhtiari20072005ND17Broth microdilution1610NDNDNDNDNDNDNDND1ND2NDNDNDNDAbdinia et al. [11]East Azerbaijan20142003–2013Children37Disk diffusion146NDNDND1ND01224ND3NDND3NDHadi and Bagheri [12]Fars20192011–2016Children10Disk diffusion73NDNDNDND30914NDNDNDNDNDNDKargar et al. [13]Fars20152011–2012Children/adult45Disk diffusionNDNDNDND31NDNDNDNDNDNDND40NDNDNDNDKargar et al. [14]Fars20122010–2011Children/adult50Disk diffusion30282252NDNDND240NDNDNDNDND2530Shishegar et al. [15]Fars20112007–2008Children10Disk diffusionND1NDNDNDNDNDND10ND240NDND2NDJaponi et al. [16]Fars20102005–2006ND13Disk diffusion53NDNDNDND1061NDND1NDNDNDNDKohanteb and Sadeghi [17]Fars2007NDChildren/adult115Broth microdilution39211528NDNDND0ND97ND9NDND5NDGhaemi et al. [18]Golestan20021998–1999Children63Disk diffusion355ND23NDND13NDNDNDNDNDNDNDNDNDNDKhademi et al. [19]Hamadan20162013–2014Children/adult6Disk diffusionNDNDNDNDNDNDND03ND0ND1NDND0NDYousefi Mashouf et al. [20]Hamadan20142009–2013Children35Disk diffusionNDNDNDNDNDNDNDND912ND19NDNDNDNDNDYousefi Mashouf et al. [21]Hamadan20031998–2000Children11Disk diffusionNDNDNDNDNDNDNDND34ND6NDNDNDNDNDMosleh et al. [22, 23]Hamadan2014NDND55E-test521410NDNDNDND0NDNDNDND655NDND12Yeganeh-Moghadam et al. [24]Isfahan20142011–2013Children15Disk diffusionND59NDNDNDNDND15ND990NDND9NDGhazikalayeh et al. [25]Isfahan20142011–2012Children291Disk diffusion4710ND740050NDNDNDNDNDND0NDNDSabory et al. [26]Kermanshah20152012Children83Disk diffusionNDND53NDND34NDND31ND347NDNDNDND34Khosravi et al. [27]Khuzestan20072005–2006Adult6Disk diffusionNDNDND3NDNDNDND0ND3NDNDNDNDNDNDMoafi and Issazadeh [28]Qazvin20162013–2014Children6Disk diffusionNDNDNDNDNDNDNDND44NDNDNDNDNDNDNDMamishi et al. [29]Tehran20192017–2018Children4Disk diffusion14NDNDNDND201NDNDNDNDNDNDNDNDGhahfarokhi et al. [30]Tehran20202015–2019Children/adult80Disk diffusion2949ND31NDND470571513NDNDNDNDND41Azarsa et al. [31]Tehran20192015Children/adult46Disk diffusion12NDNDNDNDNDNDNDNDNDNDNDNDNDNDNDNDMousavi et al. [32]Tehran20172014–2015Children76Disk diffusion7665654ND0NDNDNDNDNDNDNDNDNDND76Ahmadi et al. [33]Tehran20192013–2016Children/adult100Disk diffusion2259ND57NDND49ND9223NDND3NDNDND54Houri et al. [34]Tehran20172013–2016Children53Broth microdilution1115ND130NDND012ND4NDNDND039Talebi et al. [35]Tehran20192013–2015ND161Disk diffusion9396ND121NDND84ND15195NDNDNDNDNDND69Moghadam et al. [36]Tehran20172013–2015Children/adult100Disk diffusion2664ND770ND56096440NDND00ND71Farshad et al. [37]Tehran20162013Adult48Disk diffusion40NDNDNDNDNDNDNDNDNDNDNDNDNDNDNDNDRahbar et al. [38]Tehran20192012–2016Children/adult50E-test153635281ND2603213NDNDNDNDNDNDNDTabatabaei et al. [39]Tehran20172012–2015Children/adult73Broth microdilution1661NDNDNDNDND011ND23NDNDNDND31NDTalebi et al. [40]Tehran20162011–2013Children/adult100Disk diffusion2860ND85NDND780934800ND00050Azadegan et al. [41]Tehran20152011–2013Children/adult186Disk diffusionND88ND186NDNDNDNDNDNDNDNDNDNDNDNDNDAbdollahi et al. [42]Tehran20182011–2012Children102Disk diffusion6124ND110NDND07023NDNDNDNDND0NDAhmadi et al. [43]Tehran20132011Children/adult88Disk diffusionND47ND55NDNDNDNDNDNDNDNDNDNDNDNDNDSoltan Dallal et al. [44]Tehran20132011Children/adult15Disk diffusion1210ND0NDNDND8ND8ND12NDNDNDNDNDSadeghi et al. [45]Tehran20152010–2012Children/adult80E-test36NDNDNDNDNDNDNDNDNDNDNDNDNDNDNDNDAhmadi et al. [46]Tehran20152010–2012Children/adult70Disk diffusion60NDNDNDNDNDNDNDNDNDNDNDNDNDNDNDNDMahmoudi et al. [47]Tehran20132009–2011Children7Disk diffusion5NDNDNDNDNDNDND7ND4NDNDNDNDNDNDKhoramrooz et al. [48]Tehran20122009–2010Children23Disk diffusion61113ND0ND8023ND3ND0ND0NDNDRahimi et al. [49]Tehran20152008–2012Children/adult38NA32ND8NDNDND2294NDND6NDNDNDNDHabibian et al. [50]Tehran20132008–2012ND50Broth microdilution9NDNDNDNDNDND4NDNDNDND2NDNDNDNDDashti et al. [51]Tehran20122008–2009Children573Disk diffusion53ND315377ND0ND9683426239NDND17NDAshtiani et al. [52]Tehran20142001–2011Children194Disk diffusion8999NDNDNDNDND01395823NDNDNDND25NDPourakbari et al. [53]Tehran20122001–2005Children46Disk diffusion1429NDNDNDND3ND388NDNDNDNDNDNDNDAligholi et al. [54]Tehran20092001–2005Children50Agar dilution1529NDNDND0ND0NDND0ND15NDNDNDNDOskoui et al. [55]Tehran20102000–2008ND54Disk diffusion389ND10NDNDNDND28NDNDNDNDNDND29Jahanmehr et al. [56]Tehran20041999–2001ND66Disk diffusion12NDNDNDNDNDND0NDNDND12NDNDNDNDNDOskoui et al. [57]Tehran20031998–2000ND130Disk diffusion11410ND47NDNDND05728NDNDNDNDNDNDNDRezaeizadeh et al. [58]Tehran20121998–2008Children30Disk diffusion176NDNDNDNDND0196NDNDNDNDNDNDNDModarres et al. [59]Tehran19981993–1995Children51Disk diffusion11NDNDNDNDND29342NDNDNDNDNDNDNDGharailoo et al. [60]Sistan and Balouchastan20162013–2014Children42Disk diffusion4223ND260NDND0396ND7NDNDND0NDBokaeian et al. [61]Sistan and Balouchastan20122008–2010Children75Disk diffusion6266ND430NDND047120NDND0NDND43Bokaeian et al. [62]Sistan and Balouchastan20112007–2008Children/adult136Broth microdilution4325ND13NDNDND0ND115ND2NDND318Rahbar et al. [63]West Azerbaijan20051999–2001ND24Disk diffusion8NDNDNDNDND000NDNDND0NDNDNDNDBehnaz et al. [64]Yazd20042002Children72Disk diffusion3645ND22NDNDNDND45NDNDNDNDNDNDNDNDKarami et al. [65]Zanjan20092006–2007Children/adult57Broth macrodilution33NDNDNDNDNDND0NDNDNDNDNDNDNDNDNDPNSP: penicillin-nonsusceptibleS. pneumoniae (intermediately resistant and fully resistant); ERY: erythromycin; AZM: azithromycin; TET: tetracycline; LVX: levofloxacin; RIF: rifampin; CLI: clindamycin; VAN: vancomycin; SXT: trimethoprim/sulfamethoxazole; CHL: chloramphenicol; CRO: ceftriaxone; AMX: amoxicillin; CIP: ciprofloxacin; IPM: imipenem; LZD: linezolid; CTX: cefotaxime; MDR: multidrug-resistant (resistant to ≥3 antibiotic classes); AST: antimicrobial susceptibility testing; ND: not determined.


## 2.4. Meta-Analysis

Meta-analysis of the extracted data on theS. pneumoniae antibiotic resistance was performed using the Comprehensive Meta-Analysis (CMA) software (Biostat, Englewood, NJ), and the frequency of drug resistance was expressed as the percentage and 95% confidence intervals (95% CIs). Further analysis on the location of the study and age groups was also conducted. To evaluate the heterogeneity across the included studies, I2 statistics and the chi-square test (χ2) with the Cochrane Q statistic (Q test) (p value <0.05 was considered statistically significant) were used. A random-effects model (DerSimonian–Laird method) was used to pool the data when heterogeneity was considered high (I2 ≥ 25%). Distribution bias among published studies was calculated quantitatively using Begg’s and Egger’s tests (p value <0.05 indicates a significant bias) and visualized via the funnel plot graphs for each antibiotic.


## 3. Results

### 3.1. Results of Search and Characteristics of the Included Articles

Data were available from 15 provinces as follows: Ardabil (n = 1), Chaharmahal and Bakhtiari (n = 2), East Azerbaijan (n = 1), Fars (n = 6), Golestan (n = 1), Hamadan (n = 5), Isfahan (n = 2), Kermanshah (n = 1), Khuzestan (n = 1), Qazvin (n = 1), Tehran (n = 31), Sistan and Balouchastan (n = 3), West Azerbaijan (n = 1), Yazd (n = 1), and Zanjan (n = 1). Detailed characteristics of the selected articles are summarized in Table 1. A total of 1249 reports were identified for the analysis of S. pneumoniae antibiotic resistance in Iran. Finally, 58 articles (50 in English and 8 in Persian) were included in the study (Figure 1). Disk diffusion, E-test, and broth micro- and macrodilution were the most common methods used for antimicrobial susceptibility testing in the included articles.Figure 1
Flow diagram of literature search and study selection.


### 3.2. TotalS. pneumoniae Drug Resistance in Iran

The pooled prevalence ofS. pneumoniae resistance to various antibiotics including erythromycin, azithromycin, tetracycline, levofloxacin, rifampin, clindamycin, vancomycin, trimethoprim/sulfamethoxazole, chloramphenicol, ceftriaxone, amoxicillin, ciprofloxacin, imipenem, linezolid, and cefotaxime was 41.1% (95% CI: 32.9–49.7; I2 = 93%; Q = 545.1; p=0.00), 53.2% (95% CI: 38.9–67.1; I2 = 92.4%; Q = 118.4; p=0.00), 39.9% (95% CI: 30.2–50.4; I2 = 95%; Q = 506.8; p=0.00), 1.7% (95% CI: 0.2–11.1; I2 = 90.9%; Q = 110; p=0.00), 1.2% (95% CI: 0.1–13.2; I2 = 91.1%; Q = 67.6; p=0.00), 31.7% (95% CI: 20.7–45.2; I2 = 91.9%; Q = 172.8; p=0.00), 1.7% (95% CI: 0.7–4.1; I2 = 85.8%; Q = 218.4; p=0.00), 63.9% (95% CI: 52.3–74; I2 = 94.6%; Q = 672.5; p=0.00), 20% (95% CI: 14.2–27.3; I2 = 91.4%; Q = 303.5; p=0.00), 10.9% (95% CI: 6.6–17.6; I2 = 84.7%; Q = 130.8; p=0.00), 30.5% (95% CI: 12.8–56.8; I2 = 95.2%; Q = 187.6; p=0.00), 8.3% (95% CI: 3.6–17.7; I2 = 89.6%; Q = 154.3; p=0.00), 6.1% (95% CI: 0.1–89.4; I2 = 91.8%; Q = 36.6; p=0.00), 0%, and 8.3% (95% CI: 3.7–17.4; I2 = 92.5%; Q = 189; p=0.00), respectively. The frequency of MDR S. pneumoniae strains in Iran was 45.3% (95% CI: 34.3–56.8; I2 = 91.3%; Q = 150.7; p=0.00). As illustrated in Figure 2, the prevalence of MDR S. pneumoniae in Iran showed an increasing trend from 16.7% in 2010 to 51.3% in 2020. A random-effects model was used to estimate pooled effect in terms of the heterogeneity among studies.Figure 2
Total trend in the prevalence rate of PNSP and MDR strains in all age groups in Iran over time (based on the year of publication).


### 3.3.S. pneumoniae Drug Resistance in Different Provinces of Iran

The results of the subgroup analysis of the prevalence ofS. pneumoniae antibiotic resistance based on the different geographic locations in Iran are shown in Table 2. A random-effects model was used to combine studies within each subgroup and obtain the overall effect. The highest rates of S. pneumoniae antibiotic resistance among different provinces in Iran were as follows: 74.4% to erythromycin in Ardabil, 72.1% to azithromycin in Ardabil, 50% to tetracycline in Khuzestan, 24.2% to levofloxacin in Fars, 41% to rifampin in Kermanshah, 50.1% to clindamycin in Tehran, 2.5% to vancomycin in Hamadan, 96.9% to trimethoprim/sulfamethoxazole in Isfahan, 66.7% to chloramphenicol in Qazvin, 60% to ceftriaxone in Isfahan, 60% to amoxicillin in Isfahan, 20.1% to ciprofloxacin in Fars, 99.1% to imipenem in Hamadan, and 60% to cefotaxime in Isfahan. In addition, the highest rates of PNSP and MDR S. pneumoniae strains were detected in Ardabil (95.3% and 74.4%, respectively).Table 2
S. pneumoniae antibiotic resistance profiles in different provinces of Iran.
ProvinceAntibiotic resistance (%)PNSPERYAZMTETLVXRIFCLIVANSXTCHLCROAMXCIPIPMLZDCTXMDRArdabil95.374.472.141.91.11.127.91.181.416.3NDNDNDNDNDND74.4Chaharmahal and Bakhtiari69.258.8NDNDNDNDNDNDNDND5.9ND11.8NDNDNDNDEast Azerbaijan37.816.2NDNDND2.7ND1.332.45.410.8ND8.1NDND8.1NDFars48.627.425.51724.2ND18.51.966.27.317.14020.1NDND18.660Golestan55.67.9ND36.5NDND20.6NDNDNDNDNDNDNDNDNDNDHamadan94.525.518.2NDNDNDND2.529.134.87.154.311.699.1ND7.121.8Isfahan16.211.46025.40.20.21.70.296.9ND60603.1ND060NDKermanshahNDND63.9NDND41NDND37.3ND3.656.6NDNDNDND41KhuzestanNDNDND50NDNDNDND7.1ND50NDNDNDNDNDNDQazvinNDNDNDNDNDNDNDND66.766.7NDNDNDNDNDNDNDTehran40.247.368.145.71.10.450.12.269.524.19.812.85.90.505.447Sistan and Balouchastan79.355.4ND38.10.9NDND0.781.312.12.616.71.50.7ND231.2West Azerbaijan33.3NDNDNDNDND20.22NDNDND2NDNDNDNDYazd5062.5ND30.6NDNDNDND62.5NDNDNDNDNDNDNDNDZanjan57.8NDNDNDNDNDND0.9NDNDNDNDNDNDNDNDND


### 3.4.S. pneumoniae Drug Resistance in Iranian Children

The results of subgroup analysis based on the age group indicated that 27 studies investigated the prevalence ofS. pneumoniae antibiotic resistance profiles in Iranian children. Based on the current meta-analysis, S. pneumoniae resistance to different antibiotics was as follows: 38.5% (95% CI: 25.7–53.2; I2 = 93.4%; Q = 290.2; p=0.00) to erythromycin, 66.5% (95% CI: 54.8–76.5; I2 = 81%; Q = 26.4; p=0.00) to azithromycin, 33% (95% CI: 20.2–49; I2 = 95.9%; Q = 223.1; p=0.00) to tetracycline, 0.8% (95% CI: 0.3–2.1; I2 = 0.0%; Q = 1.9; p=0.92) to levofloxacin, 1.2% (95% CI: 0.1–13.2; I2 = 91.1%; Q = 67.6; p=0.00) to rifampin, 17.3% (95% CI: 7.3–35.6; I2 = 86.8%; Q = 45.5; p=0.00) to clindamycin, 1.7% (95% CI: 0.4–7.1; I2 = 90.7%; Q = 151; p=0.00) to vancomycin, 63.7% (95% CI: 48.3–76.7; I2 = 94.8%; Q = 407.2; p=0.00) to trimethoprim/sulfamethoxazole, 17.7% (95% CI: 11.4–26.3; I2 = 86.1%; Q = 93.6; p=0.00) to chloramphenicol, 12.6% (95% CI: 6.5–22.9; I2 = 84.9%; Q = 73; p=0.00) to ceftriaxone, 35.1% (95% CI: 12.3–67.6; I2 = 96.3%; Q = 162.4; p=0.00) to amoxicillin, 5.5% (95% CI: 1.1–22.7; I2 = 90.7%; Q = 53.7; p=0.00) to ciprofloxacin, 0.7% (95% CI: 0.0–9.7; I2 = 0.0%; Q = 0.0; p=1.00) to imipenem, 0% to linezolid, and 8.3% (95% CI: 3.2–19.8; I2 = 88.6%; Q = 61.4; p=0.00) to cefotaxime. Besides, 57.4% (95% CI: 33.1–78.6; I2 = 91%; Q = 44.8; p=0.00) of S. pneumoniae isolated from Iranian children were MDR strains. Random- or fixed-effects models were used to estimate pooled effect.


### 3.5. Penicillin-NonsusceptibleS. pneumoniae in Iran

According to the random-effects model (I2 = 93.6%; Q = 712.6; p=0.00), the total prevalence of PNSP strains in Iran was 46.9% (95% CI: 38.6–55.4). In addition, the rate of PNSP strains isolated from Iranian children was 46.9% (95% CI: 33.4–60.8; I2 = 94.4%; Q = 363.1; p=0.00) as well (Figure 3(a)). As shown in Figure 3(b), publication bias was detected in the current study due to the evidence of asymmetry in the funnel plot whereas the results of Begg’s (z = 0.21, p=0.83) and Egger’s tests (t = 1.86, p=0.07) were not statistically significant. Finally, as presented in Figure 2, we assessed the frequency of PNSP strains from 1998 to 2020. Figure 2 shows an increasing trend of PNSP strains in Iran.Figure 3
Forest plot (a) and funnel plot (b) showing the prevalence of penicillin-nonsusceptibleS. pneumoniae in Iranian children.
(a)(b)


## 3.1. Results of Search and Characteristics of the Included Articles

Data were available from 15 provinces as follows: Ardabil (n = 1), Chaharmahal and Bakhtiari (n = 2), East Azerbaijan (n = 1), Fars (n = 6), Golestan (n = 1), Hamadan (n = 5), Isfahan (n = 2), Kermanshah (n = 1), Khuzestan (n = 1), Qazvin (n = 1), Tehran (n = 31), Sistan and Balouchastan (n = 3), West Azerbaijan (n = 1), Yazd (n = 1), and Zanjan (n = 1). Detailed characteristics of the selected articles are summarized in Table 1. A total of 1249 reports were identified for the analysis of S. pneumoniae antibiotic resistance in Iran. Finally, 58 articles (50 in English and 8 in Persian) were included in the study (Figure 1). Disk diffusion, E-test, and broth micro- and macrodilution were the most common methods used for antimicrobial susceptibility testing in the included articles.Figure 1
Flow diagram of literature search and study selection.


## 3.2. TotalS. pneumoniae Drug Resistance in Iran

The pooled prevalence ofS. pneumoniae resistance to various antibiotics including erythromycin, azithromycin, tetracycline, levofloxacin, rifampin, clindamycin, vancomycin, trimethoprim/sulfamethoxazole, chloramphenicol, ceftriaxone, amoxicillin, ciprofloxacin, imipenem, linezolid, and cefotaxime was 41.1% (95% CI: 32.9–49.7; I2 = 93%; Q = 545.1; p=0.00), 53.2% (95% CI: 38.9–67.1; I2 = 92.4%; Q = 118.4; p=0.00), 39.9% (95% CI: 30.2–50.4; I2 = 95%; Q = 506.8; p=0.00), 1.7% (95% CI: 0.2–11.1; I2 = 90.9%; Q = 110; p=0.00), 1.2% (95% CI: 0.1–13.2; I2 = 91.1%; Q = 67.6; p=0.00), 31.7% (95% CI: 20.7–45.2; I2 = 91.9%; Q = 172.8; p=0.00), 1.7% (95% CI: 0.7–4.1; I2 = 85.8%; Q = 218.4; p=0.00), 63.9% (95% CI: 52.3–74; I2 = 94.6%; Q = 672.5; p=0.00), 20% (95% CI: 14.2–27.3; I2 = 91.4%; Q = 303.5; p=0.00), 10.9% (95% CI: 6.6–17.6; I2 = 84.7%; Q = 130.8; p=0.00), 30.5% (95% CI: 12.8–56.8; I2 = 95.2%; Q = 187.6; p=0.00), 8.3% (95% CI: 3.6–17.7; I2 = 89.6%; Q = 154.3; p=0.00), 6.1% (95% CI: 0.1–89.4; I2 = 91.8%; Q = 36.6; p=0.00), 0%, and 8.3% (95% CI: 3.7–17.4; I2 = 92.5%; Q = 189; p=0.00), respectively. The frequency of MDR S. pneumoniae strains in Iran was 45.3% (95% CI: 34.3–56.8; I2 = 91.3%; Q = 150.7; p=0.00). As illustrated in Figure 2, the prevalence of MDR S. pneumoniae in Iran showed an increasing trend from 16.7% in 2010 to 51.3% in 2020. A random-effects model was used to estimate pooled effect in terms of the heterogeneity among studies.Figure 2
Total trend in the prevalence rate of PNSP and MDR strains in all age groups in Iran over time (based on the year of publication).


## 3.3.S. pneumoniae Drug Resistance in Different Provinces of Iran

The results of the subgroup analysis of the prevalence ofS. pneumoniae antibiotic resistance based on the different geographic locations in Iran are shown in Table 2. A random-effects model was used to combine studies within each subgroup and obtain the overall effect. The highest rates of S. pneumoniae antibiotic resistance among different provinces in Iran were as follows: 74.4% to erythromycin in Ardabil, 72.1% to azithromycin in Ardabil, 50% to tetracycline in Khuzestan, 24.2% to levofloxacin in Fars, 41% to rifampin in Kermanshah, 50.1% to clindamycin in Tehran, 2.5% to vancomycin in Hamadan, 96.9% to trimethoprim/sulfamethoxazole in Isfahan, 66.7% to chloramphenicol in Qazvin, 60% to ceftriaxone in Isfahan, 60% to amoxicillin in Isfahan, 20.1% to ciprofloxacin in Fars, 99.1% to imipenem in Hamadan, and 60% to cefotaxime in Isfahan. In addition, the highest rates of PNSP and MDR S. pneumoniae strains were detected in Ardabil (95.3% and 74.4%, respectively).Table 2
S. pneumoniae antibiotic resistance profiles in different provinces of Iran.
ProvinceAntibiotic resistance (%)PNSPERYAZMTETLVXRIFCLIVANSXTCHLCROAMXCIPIPMLZDCTXMDRArdabil95.374.472.141.91.11.127.91.181.416.3NDNDNDNDNDND74.4Chaharmahal and Bakhtiari69.258.8NDNDNDNDNDNDNDND5.9ND11.8NDNDNDNDEast Azerbaijan37.816.2NDNDND2.7ND1.332.45.410.8ND8.1NDND8.1NDFars48.627.425.51724.2ND18.51.966.27.317.14020.1NDND18.660Golestan55.67.9ND36.5NDND20.6NDNDNDNDNDNDNDNDNDNDHamadan94.525.518.2NDNDNDND2.529.134.87.154.311.699.1ND7.121.8Isfahan16.211.46025.40.20.21.70.296.9ND60603.1ND060NDKermanshahNDND63.9NDND41NDND37.3ND3.656.6NDNDNDND41KhuzestanNDNDND50NDNDNDND7.1ND50NDNDNDNDNDNDQazvinNDNDNDNDNDNDNDND66.766.7NDNDNDNDNDNDNDTehran40.247.368.145.71.10.450.12.269.524.19.812.85.90.505.447Sistan and Balouchastan79.355.4ND38.10.9NDND0.781.312.12.616.71.50.7ND231.2West Azerbaijan33.3NDNDNDNDND20.22NDNDND2NDNDNDNDYazd5062.5ND30.6NDNDNDND62.5NDNDNDNDNDNDNDNDZanjan57.8NDNDNDNDNDND0.9NDNDNDNDNDNDNDNDND


## 3.4.S. pneumoniae Drug Resistance in Iranian Children

The results of subgroup analysis based on the age group indicated that 27 studies investigated the prevalence ofS. pneumoniae antibiotic resistance profiles in Iranian children. Based on the current meta-analysis, S. pneumoniae resistance to different antibiotics was as follows: 38.5% (95% CI: 25.7–53.2; I2 = 93.4%; Q = 290.2; p=0.00) to erythromycin, 66.5% (95% CI: 54.8–76.5; I2 = 81%; Q = 26.4; p=0.00) to azithromycin, 33% (95% CI: 20.2–49; I2 = 95.9%; Q = 223.1; p=0.00) to tetracycline, 0.8% (95% CI: 0.3–2.1; I2 = 0.0%; Q = 1.9; p=0.92) to levofloxacin, 1.2% (95% CI: 0.1–13.2; I2 = 91.1%; Q = 67.6; p=0.00) to rifampin, 17.3% (95% CI: 7.3–35.6; I2 = 86.8%; Q = 45.5; p=0.00) to clindamycin, 1.7% (95% CI: 0.4–7.1; I2 = 90.7%; Q = 151; p=0.00) to vancomycin, 63.7% (95% CI: 48.3–76.7; I2 = 94.8%; Q = 407.2; p=0.00) to trimethoprim/sulfamethoxazole, 17.7% (95% CI: 11.4–26.3; I2 = 86.1%; Q = 93.6; p=0.00) to chloramphenicol, 12.6% (95% CI: 6.5–22.9; I2 = 84.9%; Q = 73; p=0.00) to ceftriaxone, 35.1% (95% CI: 12.3–67.6; I2 = 96.3%; Q = 162.4; p=0.00) to amoxicillin, 5.5% (95% CI: 1.1–22.7; I2 = 90.7%; Q = 53.7; p=0.00) to ciprofloxacin, 0.7% (95% CI: 0.0–9.7; I2 = 0.0%; Q = 0.0; p=1.00) to imipenem, 0% to linezolid, and 8.3% (95% CI: 3.2–19.8; I2 = 88.6%; Q = 61.4; p=0.00) to cefotaxime. Besides, 57.4% (95% CI: 33.1–78.6; I2 = 91%; Q = 44.8; p=0.00) of S. pneumoniae isolated from Iranian children were MDR strains. Random- or fixed-effects models were used to estimate pooled effect.


## 3.5. Penicillin-NonsusceptibleS. pneumoniae in Iran

According to the random-effects model (I2 = 93.6%; Q = 712.6; p=0.00), the total prevalence of PNSP strains in Iran was 46.9% (95% CI: 38.6–55.4). In addition, the rate of PNSP strains isolated from Iranian children was 46.9% (95% CI: 33.4–60.8; I2 = 94.4%; Q = 363.1; p=0.00) as well (Figure 3(a)). As shown in Figure 3(b), publication bias was detected in the current study due to the evidence of asymmetry in the funnel plot whereas the results of Begg’s (z = 0.21, p=0.83) and Egger’s tests (t = 1.86, p=0.07) were not statistically significant. Finally, as presented in Figure 2, we assessed the frequency of PNSP strains from 1998 to 2020. Figure 2 shows an increasing trend of PNSP strains in Iran.Figure 3
Forest plot (a) and funnel plot (b) showing the prevalence of penicillin-nonsusceptibleS. pneumoniae in Iranian children.
(a)(b)


## 4. Discussion

Antibiotic resistance is consistently growing and has become a global public health crisis. According to the European Center for Disease Prevention and Control (ECDC) and the Center for Disease Control and Prevention (CDC), antibiotic-resistant bacteria in Europe and the USA are associated with an annual mortality rate of 25,000 and 23,000, respectively. Also, nearly 700,000 deaths worldwide are due to antibiotic resistance [5, 67]. It is estimated that antimicrobial resistance will lead to 10 million deaths a year by 2050 [5, 67]. Factors such as antibiotic overuse/misuse in humans and also in the food/veterinary industry along with reduced development of new antibiotics play key roles in the incidence of both Gram-positive and Gram-negative resistant bacteria [5]. Penicillin-resistant S. pneumonia was first detected in Australia in 1967. PNSP strains are listed as one of the most serious emerging bacterial threats as of 2017 [3, 6]. The current rate of penicillin-resistant S. pneumoniae in Iran is 46.9%, whereas it is found to be 1–5% in the UK, Germany, Austria, Norway, and Sweden, 5–10% in Italy, 10–25% in Portugal, Ireland, Finland, and Turkey, 25–50% in Spain, France, Greece, and Israel, 20% in Brazil, and 66.4% in China [68–70]. The results of subgroup analysis based on the age group showed a similarly high rate of PNSP among Iranian children (46.9%) which could be due to the common use of antibiotics in these patients [39]. Therefore, the prescription of penicillin as the first-choice antibiotic in the treatment of S. pneumoniae infections such as meningitis and pneumonia should be avoided. The prevalence of PNSP isolates in Iran has shown a rising trend from 1998 to 2020 (Figure 2). While there was high pneumococcal resistance to amoxicillin in Iran, resistance to other beta-lactam antibiotics such as cephalosporins and carbapenems was rather low. Thus, the extended-spectrum cephalosporins are suitable alternative drugs in the treatment of penicillin-resistant infections including pneumococcal meningitis in Iran. Modification of penicillin-binding proteins (PBPs) particularly PBP1a, PBP2x, and PBP2b as well as mutations in cpoA, ciaH, murM, and murN genes has been described as the main mechanisms of resistance in S. pneumoniae to beta-lactam antibiotics [3]. Pneumococcal resistance to macrolides, fluoroquinolones, and tetracyclines has also been reported [1]. The prevalence of macrolide-resistant S. pneumoniae is geographically variable as it ranges from 25 to 50% in France, Italy, and Greece, 10 to 25% in Spain, Portugal, the UK, Germany, Poland, Norway, and Finland, and 1 to 5% in Latvia and Sweden [68]. In Iran, 41.1% and 53.2% of S. pneumoniae isolates were resistant to erythromycin and azithromycin, respectively. Ribosomal modification, efflux system, and point mutations are involved in the emergence of macrolide-resistant S. pneumoniae [3]. An important mechanism of S. pneumoniae resistance to clindamycin is the alteration of the ribosomal target through erm(B) gene which encodes a 23S RNA methylase [71]. Clindamycin has shown a strong activity against community-acquired infections of S. pneumoniae [71]. However, the rates of clindamycin-resistant pneumococcal strains in the current study were high (31.7%) and included 25% in Egypt, 35.1% in Turkey, and 21.8% in the United States [3,71]. Penicillins and macrolides have been largely applied in the treatment of community-acquired pneumonia and other respiratory tract infections by S. pneumoniae [72]. However, a high resistance rate to these antibiotics has led to the use of quinolones against important bacterial respiratory tract pathogens [72]. Hence, a combination of vancomycin and gentamicin is proposed for treating infections caused by penicillin- and cephalosporin-resistant S. pneumoniae strains [3]. The findings of the present study on the prevalence of fluoroquinolone-resistant strains of S. pneumoniae indicated a low resistance rate to levofloxacin (1.7%) and ciprofloxacin (8.3%) in Iran. The prevalence of fluoroquinolone-resistant pneumococcal strains in other countries was as follows: 4% in Egypt, 1.8% in Turkey, 1-2% in the USA, and <10% in Belgium [3, 71, 72]. A low incidence of vancomycin-resistant S. pneumoniae was found in Iran (1.7%), and no resistance has been reported in many other countries [3]. Factors associated with resistance to fluoroquinolones in clinical pneumococcal isolates include mutations in the quinolone-resistance-determining regions (QRDRs) of gyrA, gyrB, parC, and parE genes as well as the overexpression of pmrA gene (codes for an efflux pump) and patA and patB genes (code for an ABC transporter) [3, 71]. Point mutation in a histidine kinase gene (vncS) is associated with the emergence of vancomycin-tolerant pneumococcal strains [3]. The highest drug resistance rate among pneumococcal isolates in Iran was observed to folate pathway inhibitors (i.e., trimethoprim/sulfamethoxazole (63.9%)). Cotrimoxazole-resistant S. pneumoniae were isolated in 25–45% of strains in the USA, 55% in Egypt, 100% in Saudi Arabia, and 67.2% in Turkey [3, 71]. Mutations in dihydrofolate reductase (DHFR) and in dihydropteroate synthase (DHPS) are the mechanisms of resistance to folate inhibitors [3, 71]. Studies from the Middle East and the USA have reported a high rate of S. pneumoniae resistance to tetracycline which could be attributed to extensive use of this antimicrobial agent [3, 71]. A similar result was observed in the current study (39.9%). Resistance to chloramphenicol (a bacterial protein inhibitor) was high whereas there was no resistance to linezolid. Two other important findings of the study included a high prevalence of MDR pneumococci in Iranian people (45.3%), especially children (57.4%) with a rising trend from 2010 to 2020 (Figure 2), and also the isolation of S. pneumoniae resistant to many drugs (such as erythromycin, azithromycin, tetracycline, trimethoprim/sulfamethoxazole, and amoxicillin) in Iranian children. Available data from CDC showed that MDR S. pneumoniae is responsible for more than 30% of invasive pneumococcal disease throughout the United States [73, 74]. Therefore, timely vaccination in Iranian children and ongoing surveillance on drug resistance trend along with the use of combination therapy or the use of newer antibiotics are needed to improve microorganism susceptibility.


## 5. Conclusion

The current study indicated a high prevalence of PNSP and MDR strains in Iran among all age groups. Similar results were also observed in the frequency of erythromycin-, azithromycin-, tetracycline-, clindamycin-, trimethoprim/sulfamethoxazole-, chloramphenicol-, and amoxicillin-resistantS. pneumoniae strains. These findings could be due to the high consumption of nonprescribed antibiotics in Iran. Hence, strategies to prevent emerging drug-resistant pneumococcal infections and treatment failure in Iran include (1) continuous regional monitoring of nasopharyngeal carriers of antibiotic-resistant S. pneumoniae in children, (2) controlled administration of antibiotics to improve microorganism susceptibility, (3) use of combination therapies or drugs with low resistance rate in accordance with local resistance patterns, and (4) identification of the most common pneumococcal serotypes and their drug resistance rates in Iranian population to produce effective pneumococcal vaccines. The most effective antibiotics for the treatment of pneumococcal infections in Iran based on the current study are levofloxacin, rifampin, vancomycin, ceftriaxone, ciprofloxacin, imipenem, linezolid, and cefotaxime.



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*Source: 5573345-2021-05-27.xml*