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. 2021 May 27;2021:5573345. doi: 10.1155/2021/5573345

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

Farzad Khademi 1, Amirhossein Sahebkar 2,3,4,✉
PMCID: PMC8175142  PMID: 34136307

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.

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 of Streptococcus 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 Table 1 [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) Province Published time Enrollment time Age group Strain (n) AST Antibiotic resistance (n)
PNSP ERY AZM TET LVX RIF CLI VAN SXT CHL CRO AMX CIP IPM LZD CTX MDR
Gharibani et al. [8] Ardabil 2019 2015 Children 43 Disk diffusion 41 32 31 18 0 0 12 0 35 7 ND ND ND ND ND ND 32
Khoshdel et al. [9] Chaharmahal and Bakhtiari 2009 2007 Children 38 Disk diffusion 11 ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND
Imani et al. [10] Chaharmahal and Bakhtiari 2007 2005 ND 17 Broth microdilution 16 10 ND ND ND ND ND ND ND ND 1 ND 2 ND ND ND ND
Abdinia et al. [11] East Azerbaijan 2014 2003–2013 Children 37 Disk diffusion 14 6 ND ND ND 1 ND 0 12 2 4 ND 3 ND ND 3 ND
Hadi and Bagheri [12] Fars 2019 2011–2016 Children 10 Disk diffusion 7 3 ND ND ND ND 3 0 9 1 4 ND ND ND ND ND ND
Kargar et al. [13] Fars 2015 2011–2012 Children/adult 45 Disk diffusion ND ND ND ND 31 ND ND ND ND ND ND ND 40 ND ND ND ND
Kargar et al. [14] Fars 2012 2010–2011 Children/adult 50 Disk diffusion 30 28 22 5 2 ND ND ND 24 0 ND ND ND ND ND 25 30
Shishegar et al. [15] Fars 2011 2007–2008 Children 10 Disk diffusion ND 1 ND ND ND ND ND ND 10 ND 2 4 0 ND ND 2 ND
Japoni et al. [16] Fars 2010 2005–2006 ND 13 Disk diffusion 5 3 ND ND ND ND 1 0 6 1 ND ND 1 ND ND ND ND
Kohanteb and Sadeghi [17] Fars 2007 ND Children/adult 115 Broth microdilution 39 21 15 28 ND ND ND 0 ND 9 7 ND 9 ND ND 5 ND
Ghaemi et al. [18] Golestan 2002 1998–1999 Children 63 Disk diffusion 35 5 ND 23 ND ND 13 ND ND ND ND ND ND ND ND ND ND
Khademi et al. [19] Hamadan 2016 2013–2014 Children/adult 6 Disk diffusion ND ND ND ND ND ND ND 0 3 ND 0 ND 1 ND ND 0 ND
Yousefi Mashouf et al. [20] Hamadan 2014 2009–2013 Children 35 Disk diffusion ND ND ND ND ND ND ND ND 9 12 ND 19 ND ND ND ND ND
Yousefi Mashouf et al. [21] Hamadan 2003 1998–2000 Children 11 Disk diffusion ND ND ND ND ND ND ND ND 3 4 ND 6 ND ND ND ND ND
Mosleh et al. [22, 23] Hamadan 2014 ND ND 55 E-test 52 14 10 ND ND ND ND 0 ND ND ND ND 6 55 ND ND 12
Yeganeh-Moghadam et al. [24] Isfahan 2014 2011–2013 Children 15 Disk diffusion ND 5 9 ND ND ND ND ND 15 ND 9 9 0 ND ND 9 ND
Ghazikalayeh et al. [25] Isfahan 2014 2011–2012 Children 291 Disk diffusion 47 10 ND 74 0 0 5 0 ND ND ND ND ND ND 0 ND ND
Sabory et al. [26] Kermanshah 2015 2012 Children 83 Disk diffusion ND ND 53 ND ND 34 ND ND 31 ND 3 47 ND ND ND ND 34
Khosravi et al. [27] Khuzestan 2007 2005–2006 Adult 6 Disk diffusion ND ND ND 3 ND ND ND ND 0 ND 3 ND ND ND ND ND ND
Moafi and Issazadeh [28] Qazvin 2016 2013–2014 Children 6 Disk diffusion ND ND ND ND ND ND ND ND 4 4 ND ND ND ND ND ND ND
Mamishi et al. [29] Tehran 2019 2017–2018 Children 4 Disk diffusion 1 4 ND ND ND ND 2 0 1 ND ND ND ND ND ND ND ND
Ghahfarokhi et al. [30] Tehran 2020 2015–2019 Children/adult 80 Disk diffusion 29 49 ND 31 ND ND 47 0 57 15 13 ND ND ND ND ND 41
Azarsa et al. [31] Tehran 2019 2015 Children/adult 46 Disk diffusion 12 ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND
Mousavi et al. [32] Tehran 2017 2014–2015 Children 76 Disk diffusion 76 65 65 4 ND 0 ND ND ND ND ND ND ND ND ND ND 76
Ahmadi et al. [33] Tehran 2019 2013–2016 Children/adult 100 Disk diffusion 22 59 ND 57 ND ND 49 ND 92 23 ND ND 3 ND ND ND 54
Houri et al. [34] Tehran 2017 2013–2016 Children 53 Broth microdilution 11 15 ND 13 0 ND ND 0 12 ND 4 ND ND ND 0 3 9
Talebi et al. [35] Tehran 2019 2013–2015 ND 161 Disk diffusion 93 96 ND 121 ND ND 84 ND 151 95 ND ND ND ND ND ND 69
Moghadam et al. [36] Tehran 2017 2013–2015 Children/adult 100 Disk diffusion 26 64 ND 77 0 ND 56 0 96 44 0 ND ND 0 0 ND 71
Farshad et al. [37] Tehran 2016 2013 Adult 48 Disk diffusion 40 ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND
Rahbar et al. [38] Tehran 2019 2012–2016 Children/adult 50 E-test 15 36 35 28 1 ND 26 0 32 13 ND ND ND ND ND ND ND
Tabatabaei et al. [39] Tehran 2017 2012–2015 Children/adult 73 Broth microdilution 16 61 ND ND ND ND ND 0 11 ND 23 ND ND ND ND 31 ND
Talebi et al. [40] Tehran 2016 2011–2013 Children/adult 100 Disk diffusion 28 60 ND 85 ND ND 78 0 93 48 0 0 ND 0 0 0 50
Azadegan et al. [41] Tehran 2015 2011–2013 Children/adult 186 Disk diffusion ND 88 ND 186 ND ND ND ND ND ND ND ND ND ND ND ND ND
Abdollahi et al. [42] Tehran 2018 2011–2012 Children 102 Disk diffusion 61 24 ND 11 0 ND ND 0 70 23 ND ND ND ND ND 0 ND
Ahmadi et al. [43] Tehran 2013 2011 Children/adult 88 Disk diffusion ND 47 ND 55 ND ND ND ND ND ND ND ND ND ND ND ND ND
Soltan Dallal et al. [44] Tehran 2013 2011 Children/adult 15 Disk diffusion 12 10 ND 0 ND ND ND 8 ND 8 ND 12 ND ND ND ND ND
Sadeghi et al. [45] Tehran 2015 2010–2012 Children/adult 80 E-test 36 ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND
Ahmadi et al. [46] Tehran 2015 2010–2012 Children/adult 70 Disk diffusion 60 ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND
Mahmoudi et al. [47] Tehran 2013 2009–2011 Children 7 Disk diffusion 5 ND ND ND ND ND ND ND 7 ND 4 ND ND ND ND ND ND
Khoramrooz et al. [48] Tehran 2012 2009–2010 Children 23 Disk diffusion 6 11 13 ND 0 ND 8 0 23 ND 3 ND 0 ND 0 ND ND
Rahimi et al. [49] Tehran 2015 2008–2012 Children/adult 38 NA 3 2 ND 8 ND ND ND 2 29 4 ND ND 6 ND ND ND ND
Habibian et al. [50] Tehran 2013 2008–2012 ND 50 Broth microdilution 9 ND ND ND ND ND ND 4 ND ND ND ND 2 ND ND ND ND
Dashti et al. [51] Tehran 2012 2008–2009 Children 573 Disk diffusion 53 ND 315 377 ND 0 ND 9 68 34 26 23 9 ND ND 17 ND
Ashtiani et al. [52] Tehran 2014 2001–2011 Children 194 Disk diffusion 89 99 ND ND ND ND ND 0 139 58 23 ND ND ND ND 25 ND
Pourakbari et al. [53] Tehran 2012 2001–2005 Children 46 Disk diffusion 14 29 ND ND ND ND 3 ND 38 8 ND ND ND ND ND ND ND
Aligholi et al. [54] Tehran 2009 2001–2005 Children 50 Agar dilution 15 29 ND ND ND 0 ND 0 ND ND 0 ND 15 ND ND ND ND
Oskoui et al. [55] Tehran 2010 2000–2008 ND 54 Disk diffusion 38 9 ND 10 ND ND ND ND 28 ND ND ND ND ND ND 2 9
Jahanmehr et al. [56] Tehran 2004 1999–2001 ND 66 Disk diffusion 12 ND ND ND ND ND ND 0 ND ND ND 12 ND ND ND ND ND
Oskoui et al. [57] Tehran 2003 1998–2000 ND 130 Disk diffusion 114 10 ND 47 ND ND ND 0 57 28 ND ND ND ND ND ND ND
Rezaeizadeh et al. [58] Tehran 2012 1998–2008 Children 30 Disk diffusion 17 6 ND ND ND ND ND 0 19 6 ND ND ND ND ND ND ND
Modarres et al. [59] Tehran 1998 1993–1995 Children 51 Disk diffusion 1 1 ND ND ND ND ND 29 34 2 ND ND ND ND ND ND ND
Gharailoo et al. [60] Sistan and Balouchastan 2016 2013–2014 Children 42 Disk diffusion 42 23 ND 26 0 ND ND 0 39 6 ND 7 ND ND ND 0 ND
Bokaeian et al. [61] Sistan and Balouchastan 2012 2008–2010 Children 75 Disk diffusion 62 66 ND 43 0 ND ND 0 47 12 0 ND ND 0 ND ND 43
Bokaeian et al. [62] Sistan and Balouchastan 2011 2007–2008 Children/adult 136 Broth microdilution 43 25 ND 13 ND ND ND 0 ND 11 5 ND 2 ND ND 3 18
Rahbar et al. [63] West Azerbaijan 2005 1999–2001 ND 24 Disk diffusion 8 ND ND ND ND ND 0 0 0 ND ND ND 0 ND ND ND ND
Behnaz et al. [64] Yazd 2004 2002 Children 72 Disk diffusion 36 45 ND 22 ND ND ND ND 45 ND ND ND ND ND ND ND ND
Karami et al. [65] Zanjan 2009 2006–2007 Children/adult 57 Broth macrodilution 33 ND ND ND ND ND ND 0 ND ND ND ND ND ND ND ND ND
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PNSP: penicillin-nonsusceptible S. 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 the S. 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.

Figure 1

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Flow diagram of literature search and study selection.

3.2. Total S. pneumoniae Drug Resistance in Iran

The pooled prevalence of S. 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.

Figure 2

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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 of S. 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.

Province Antibiotic resistance (%)
PNSP ERY AZM TET LVX RIF CLI VAN SXT CHL CRO AMX CIP IPM LZD CTX MDR
Ardabil 95.3 74.4 72.1 41.9 1.1 1.1 27.9 1.1 81.4 16.3 ND ND ND ND ND ND 74.4
Chaharmahal and Bakhtiari 69.2 58.8 ND ND ND ND ND ND ND ND 5.9 ND 11.8 ND ND ND ND
East Azerbaijan 37.8 16.2 ND ND ND 2.7 ND 1.3 32.4 5.4 10.8 ND 8.1 ND ND 8.1 ND
Fars 48.6 27.4 25.5 17 24.2 ND 18.5 1.9 66.2 7.3 17.1 40 20.1 ND ND 18.6 60
Golestan 55.6 7.9 ND 36.5 ND ND 20.6 ND ND ND ND ND ND ND ND ND ND
Hamadan 94.5 25.5 18.2 ND ND ND ND 2.5 29.1 34.8 7.1 54.3 11.6 99.1 ND 7.1 21.8
Isfahan 16.2 11.4 60 25.4 0.2 0.2 1.7 0.2 96.9 ND 60 60 3.1 ND 0 60 ND
Kermanshah ND ND 63.9 ND ND 41 ND ND 37.3 ND 3.6 56.6 ND ND ND ND 41
Khuzestan ND ND ND 50 ND ND ND ND 7.1 ND 50 ND ND ND ND ND ND
Qazvin ND ND ND ND ND ND ND ND 66.7 66.7 ND ND ND ND ND ND ND
Tehran 40.2 47.3 68.1 45.7 1.1 0.4 50.1 2.2 69.5 24.1 9.8 12.8 5.9 0.5 0 5.4 47
Sistan and Balouchastan 79.3 55.4 ND 38.1 0.9 ND ND 0.7 81.3 12.1 2.6 16.7 1.5 0.7 ND 2 31.2
West Azerbaijan 33.3 ND ND ND ND ND 2 0.2 2 ND ND ND 2 ND ND ND ND
Yazd 50 62.5 ND 30.6 ND ND ND ND 62.5 ND ND ND ND ND ND ND ND
Zanjan 57.8 ND ND ND ND ND ND 0.9 ND ND ND ND ND ND ND ND ND
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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 of S. 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-Nonsusceptible S. 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.

Figure 3

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Forest plot (a) and funnel plot (b) showing the prevalence of penicillin-nonsusceptible S. pneumoniae in Iranian children.

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-resistant S. 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.

Data Availability

There are no raw data associated with this systematic review and meta-analysis.

Conflicts of Interest

The authors declare that there are no conflicts of interest.

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Data Availability Statement

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