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Iranian Journal of Basic Medical Sciences logoLink to Iranian Journal of Basic Medical Sciences
. 2021 Apr;24(4):428–436. doi: 10.22038/IJBMS.2021.48628.11161

An updated systematic review and meta-analysis on Mycobacterium tuberculosis antibiotic resistance in Iran (2013-2020)

Farzad Khademi 1,*, Amirhossein Sahebkar 2,3,4
PMCID: PMC8143714  PMID: 34094023

Abstract

This updated systematic review and meta-analysis follows two aims: 1) to assess Mycobacterium tuberculosis (M. tuberculosis) antibiotic resistance in Iran from 2013 to 2020 and, 2) to assess the trend of resistance from 1999 to 2020. Several national and international databases were systematically searched through MeSH extracted keywords to identify 41 published studies addressing drug-resistant M. tuberculosis in Iran. Meta-analysis was done based on the PRISMA protocols using Comprehensive Meta-Analysis software. The average prevalence of resistance to first- and second-line anti-TB drugs, multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) in new and previously treated tuberculosis (TB) cases in Iran during 2013–2020 were as follows: isoniazid 6.9%, rifampin 7.9%, ethambutol 5.7%, pyrazinamide 20.4%, para-aminosalicylic acid 4.6%, capreomycin 1.7%, cycloserine 1.8%, ethionamide 11.3%, ofloxacin 1.5%, kanamycin 3.8%, amikacin 2.2%, MDR-TB 6.3% and XDR-TB 0.9%. Based on the presented data, M. tuberculosis resistance to first- and second-line anti-TB drugs, as well as MDR-TB, was low during 2013–2020 in Iran. Furthermore, there was a declining trend in TB drug resistance from 1999 to 2020. Hence, to maintain the current decreasing trend and to control and eliminate TB infection in Iran, continuous monitoring of resistance patterns is recommended.

Key Words: Antibiotic, Iran, Meta-analysis, Mycobacterium tuberculosis, Resistance

Introduction

On 24 March 1882, Dr Robert Koch discovered a rod-shaped, aerobic bacterium called Mycobacterium tuberculosis (M. tuberculosis). It is the causative agent for tuberculosis (TB) which is one of the ten most common causes of death worldwide. The latent form of tubercle bacilli has been detected in 1.7 billion people around the world (1-3). Between 5 and 10% of these people will eventually develop the active form of the disease (pulmonary or extrapulmonary) in their lifetime (4, 5). TB is an air-borne and communicable disease and humans are the only natural reservoir of the infection (6). According to the latest report of the World Health Organization (WHO) in 2018, TB remained a global health problem with 10 million infected people (57% adult men, 32% adult women, and 11% children), 1.2 million deaths in HIV-negative and 251,000 deaths in HIV-positive patients (1). In 2014, WHO announced “the End TB Strategy” which aimed to reduce TB-associated deaths (by 90%) and incidence rate (by 80%) and to end the global TB epidemic between 2016 and 2035 (1). To achieve these purposes, developing novel diagnostic tests for rapid detection, use of effective drugs or new treatments, and appropriate vaccination are needed (1). Since 1921, the bacilli Calmette-Guérin (BCG) live attenuated vaccine has been the only approved vaccine for TB prevention in newborns and children. It has variable protection against adult pulmonary TB (0–80%) while it is unable to prevent the reactivation of latent TB (7, 8). Treatment with first-line drugs i. e., isoniazid, rifampin, ethambutol, and pyrazinamide is recommended for a six-month period in drug-susceptible TB as the mortality rate is high without treatment (1). The success rate for first-line drugs is >85%, however, the emergence of drug-resistant M. tuberculosis, particularly multidrug-resistant TB (MDR-TB defined as resistance to isoniazid and rifampin) has led to a decrease in treatment success to 56%, an increase in treatment duration and costs, and administration of more toxic second-line drugs (1). TB incidence in 2018 in Iran, a country with a population of 82 million located in the Middle East, showed a decreasing trend (11, 000; 14 cases per 100,000 population), however, it has shared geographical borders with high incidence countries such as Pakistan (6% in 2018) (1). Hence, continuous surveillance on TB epidemiology especially drug resistance status is of high necessity for disease control. M. tuberculosis antibiotic resistance pattern has previously been studied between March 1999 and May 2013 in Iran (9). Nevertheless, as the prevalence of TB antibiotic resistance is changing over time, we have performed the current systematic review and meta-analysis from 2013 to 2020 to update the evidence in Iran.

Methods

Search strategies and data sources

The current systematic review and meta-analysis was conducted based on the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines (10). The computer-assisted systematic search was done in national and international databases including Scientific Information Database (SID) (www.sid.ir), Magiran (www.Magiran.com), ISI Web of Knowledge, PubMed, and Scopus. Each cross-sectional study published between May 2013 and March 30, 2020, in English or Persian languages on M. tuberculosis antibiotic resistance in Iran was investigated. M. tuberculosis, antibiotic resistance, and Iran were the main medical subject heading (MeSH) extracted keywords used for searching. The reference lists of all included articles were further assessed to find any missed relevant studies.

Data selection criteria and quality assessment

The titles, abstracts, and full texts of collected articles were further evaluated in detail to select eligible studies based on our inclusion and exclusion criteria. In addition, the Joanna Briggs Institute (JBI) critical appraisal checklist was selected to assess the quality of each included article. Eligible studies showed high quality (>5 scores), medium quality (4-5 scores), or low quality (<4 scores) (11). Original articles assessing the prevalence of M. tuberculosis antibiotic resistance with the following features were included in the study: (1) published in English or Persian, 2) limited to Iran, 3) clinical strains of M. tuberculosis isolated from new or previously treated cases, 4) studies evaluating monoresistance (which is defined as resistance to only 1 first- or second-line anti-TB drugs), MDR and XDR (extensively drug-resistant) status and 5) full-text availability. The following studies were excluded from analysis: 1) studies reporting drug resistance patterns in nontuberculous mycobacteria (NTM), 2) studies that only focused on drug resistance mechanisms, 3) studies that solely evaluated any drug resistance status (which is defined as resistance to any drug regardless of monoresistance), 4) non-original studies, 5) duplicate publications including same studies published in both English and Persian languages and two or more relevant studies conducted by the first or corresponding author in the same year and also several multicenter studies with identical information such as same authors’ name, same enrollment time and previously determined antibiotic resistance profiles, 6) studies available only in abstract form and dissertations, 7) studies without sufficient data such as study date or ambiguous information, 8) studies performed merely to evaluate the sensitivity and specificity of different antimicrobial susceptibility testing methods using previous banks of bacterial isolates or clinical isolates of M. tuberculosis with known drug resistance profiles, 9) studies on M. tuberculosis other than antibiotic resistance such as epidemiological patterns or treatment of the disease, and 10) multicenter studies without sufficient and separate data for each province.

Data extraction

Extracted information from eligible studies included in the meta-analysis is shown in Table 1. Important data were as follows: first author’s surname, publication date, region of study, study enrollment date, number of tested isolates, methods used for assessing bacterial antibiotic susceptibility, and prevalence of M. tuberculosis resistance to first- and second-line drugs.

Table 1.

Extracted information from eligible studies included in the meta-analysis during 2013-2020

Author
(Ref)		 Published
date		 Province Enrollment date Strain
(n)		 DST Antibiotic resistance (n)
First-line drugs Second-line drugs
INH RIF EMB PZA STR PAS CAP CYC ETO OFX KAN AMK MDR XDR
Moradi et al (11) 2017 Ardabil 2014-2015 9 Agar proportional 1 0 ND 1 ND ND ND ND ND ND ND ND ND ND
Atashi et al (12) 2017 Ardabil 2014 14 Agar proportional 2 0 ND ND ND ND ND ND ND ND ND ND ND ND
Sahebi et al (13) 2016 Ardabil 2014 9 Molecular 3 1 ND ND ND ND ND ND ND ND ND ND ND ND
Sahebi et al (14) 2015 Ardabil 2011-2013 26 Molecular 3 4 ND ND ND ND ND ND ND ND ND ND ND ND
Velayati et al (15) 2014 Ardabil 2010-2011 65 Molecular 2 4 ND ND ND ND ND ND ND ND ND ND 4 ND
Moradi et al (11) 2017 East Azerbaijan 2014-2015 21 Agar proportional 2 2 ND 6 ND ND ND ND ND ND ND ND ND ND
Atashi et al (12) 2017 East Azerbaijan 2014 28 Agar proportional 0 1 ND ND ND ND ND ND ND ND ND ND ND ND
Sahebi et al (13) 2016 East Azerbaijan 2014 28 Molecular 1 4 ND ND ND ND ND ND ND ND ND ND ND ND
Rashedi et al (16) 2015 East Azerbaijan 2012-2014 48 Agar proportional 2 4 2 ND ND ND ND ND ND ND ND ND 1 ND
Sahebi et al (14) 2015 East Azerbaijan 2011-2013 87 Molecular 3 15 ND ND ND ND ND ND ND ND ND ND ND ND
Moaddab et al (17) 2015 East Azerbaijan 2009-2012 100 Agar proportional 4 5 1 18 21 ND ND ND ND ND ND ND 21 ND
Amini et al (18) 2019 Fars 2015-2017 19 Agar proportional 3 1 0 ND ND ND ND ND ND ND ND ND 1 ND
Zarei et al (19) 2017 Fars 2012-2014 199 Agar proportional 38 30 16 ND 21 ND ND ND ND ND ND ND 22 ND
Honarvar et al (20) 2015 Fars 2012-2013 92 Agar proportional 16 19 ND ND ND ND ND ND ND ND ND ND 24 ND
Motamedifar et al (21) 2015 Fars 2004-2013 59 Agar proportional ND ND ND ND ND ND ND ND ND ND ND ND 6 ND
Velayati et al (15) 2014 Fars 2010-2011 40 Molecular 2 5 ND ND ND ND ND ND ND ND ND ND 5 ND
Mansoori et al (22) 2018 Golestan 2014-2015 164 Agar proportional 3 0 0 ND 12 ND ND ND ND ND ND ND ND ND
Velayati et al (15) 2014 Golestan 2010-2011 47 Molecular 3 2 ND ND ND ND ND ND ND ND ND ND 2 ND
Velayati et al (15) 2014 Guilan 2010-2011 39 Molecular 1 2 ND ND ND ND ND ND ND ND ND ND 3 ND
Moradi et al (11) 2017 Hamadan 2014-2015 5 Agar proportional 0 0 ND 2 ND ND ND ND ND ND ND ND ND ND
Atashi et al (12) 2017 Hamadan 2014 11 Agar proportional 1 0 ND ND ND ND ND ND ND ND ND ND ND ND
Velayati et al (15) 2014 Hamadan 2010-2011 21 Molecular 1 2 ND ND ND ND ND ND ND ND ND ND 0 ND
Zamani et al (23) 2016 Hormozgan 2012-2013 38 Agar proportional 4 ND ND ND 2 ND ND ND ND ND ND ND 3 ND
Nasiri et al (24) 2014 Hormozgan 2010-2012 48 Agar proportional 3 2 2 ND 4 ND ND ND ND ND ND ND 2 ND
Velayati et al (15) 2014 Hormozgan 2010-2011 38 Molecular 3 3 ND ND ND ND ND ND ND ND ND ND 3 ND
Moradi et al (11) 2017 Ilam 2014-2015 4 Agar proportional 0 0 ND 1 ND ND ND ND ND ND ND ND ND ND
Atashi et al (12) 2017 Ilam 2014 6 Agar proportional 1 0 ND ND ND ND ND ND ND ND ND ND ND ND
Amini et al (18) 2019 Isfahan 2015-2017 19 Agar proportional 2 1 1 ND ND ND ND ND ND ND ND ND 1 ND
Karimi et al (25) 2017 Isfahan 2014-2015 205 Agar proportional 6 4 3 ND 10 ND ND ND ND ND ND ND 4 ND
Nasr Esfahani et al (26) 2016 Isfahan 2013 32 Agar proportional ND ND 2 ND ND ND ND ND ND ND ND ND ND ND
Nasiri et al (24) 2014 Isfahan 2010-2012 45 Agar proportional 2 2 0 ND 1 ND ND ND ND ND ND ND 2 ND
Velayati et al (15) 2014 Isfahan 2010-2011 42 Molecular 5 3 ND ND ND ND ND ND ND ND ND ND 2 ND
Velayati et al (15) 2014 Kerman 2010-2011 24 Molecular 1 3 ND ND ND ND ND ND ND ND ND ND 3 ND
Mohammadi et al (27) 2018 Kermanshah 2014-2015 50 Agar proportional ND ND 7 ND ND ND ND ND ND ND ND ND 8 ND
Moradi et al (11) 2017 Kermanshah 2014-2015 17 Agar proportional 1 2 ND 2 ND ND ND ND ND ND ND ND ND ND
Atashi et al (12) 2017 Kermanshah 2014 31 Agar proportional 1 2 ND ND ND ND ND ND ND ND ND ND ND ND
Sahebi et al (13) 2016 Kermanshah 2014 16 Molecular 1 4 ND ND ND ND ND ND ND ND ND ND ND ND
Sahebi et al (14) 2015 Kermanshah 2011-2013 51 Molecular 1 5 ND ND ND ND ND ND ND ND ND ND ND ND
Mohajeri et al (28) 2014 Kermanshah 2011-2012 112 Agar proportional 18 16 15 27 25 19 ND 4 14 ND ND ND 16 ND
Nasiri et al (24) 2014 Kermanshah 2010-2012 15 Agar proportional 4 3 3 ND 3 ND ND ND ND ND ND ND 3 ND
Velayati et al (15) 2014 Kermanshah 2010-2011 16 Molecular 1 2 ND ND ND ND ND ND ND ND ND ND 1 ND
Khosravi et al (29) 2019 Khuzestan 2016-2017 307 Agar proportional 6 10 10 ND ND ND ND ND ND ND ND ND 4 ND
Khosravi et al (30) 2019 Khuzestan 2015-2017 37 Agar proportional 3 16 ND ND ND ND ND ND ND ND ND ND 5 ND
Amini et al (18) 2019 Khuzestan 2015-2017 20 Agar proportional 1 1 1 ND ND ND ND ND ND ND ND ND 1 ND
Badie et al (31) 2016 Khuzestan 2015 64 Agar proportional ND ND ND ND ND ND ND ND ND ND ND ND 2 ND
Khosravi et al (32) 2017 Khuzestan 2013-2014 88 Agar proportional 41 35 5 ND 32 ND ND ND ND ND ND ND 22 ND
Velayati et al (15) 2014 Khuzestan 2010-2011 119 Molecular 7 3 ND ND ND ND ND ND ND ND ND ND 6 ND
Khosravi et al (33) 2014 Khuzestan 2010-2011 160 Molecular 18 20 ND ND ND ND ND ND ND ND ND ND 8 ND
Moradi et al (11) 2017 Kurdistan 2014-2015 27 Agar proportional 0 0 ND 3 ND ND ND ND ND ND ND ND ND ND
Atashi et al (12) 2017 Kurdistan 2014 23 Agar proportional 0 2 ND ND ND ND ND ND ND ND ND ND ND ND
Sahebi et al (13) 2016 Kurdistan 2014 12 Molecular 3 1 ND ND ND ND ND ND ND ND ND ND ND ND
Sahebi et al (14) 2015 Kurdistan 2011-2013 50 Molecular 3 3 ND ND ND ND ND ND ND ND ND ND ND ND
Velayati et al (15) 2014 Kurdistan 2010-2011 16 Molecular 2 0 ND ND ND ND ND ND ND ND ND ND 0 ND
Heidary et al (34) 2020 Lorestan 2014-2017 106 Agar proportional 1 1 ND ND ND ND ND ND ND ND ND ND 4 ND
Moradi et al (11) 2017 Lorestan 2014-2015 19 Agar proportional 0 0 ND 4 ND ND ND ND ND ND ND ND ND ND
Atashi et al (12) 2017 Lorestan 2014 27 Agar proportional 0 1 ND ND ND ND ND ND ND ND ND ND ND ND
Velayati et al (15) 2014 Lorestan 2010-2011 24 Molecular 0 5 ND ND ND ND ND ND ND ND ND ND 0 ND
Farazi et al (35) 2013 Markazi 2011-2012 115 Agar proportional 3 2 8 ND 3 ND ND ND ND ND ND ND 9 ND
Velayati et al (15) 2014 Markazi 2010-2011 15 Molecular 3 3 ND ND ND ND ND ND ND ND ND ND 2 ND
Babamahmoodi et al (36) 2014 Mazandaran 2013 54 Molecular 2 3 ND ND 4 ND ND ND ND ND 3 3 ND ND
Velayati et al (15) 2014 Mazandaran 2010-2011 26 Molecular 1 1 ND ND ND ND ND ND ND ND ND ND 1 ND
Atashi et al (12) 2017 Qazvin 2014 5 Agar proportional 0 0 ND ND ND ND ND ND ND ND ND ND ND ND
Velayati et al (15) 2014 Qazvin 2010-2011 10 Molecular 1 0 ND ND ND ND ND ND ND ND ND ND 2 ND
Velayati et al (15) 2014 Qom 2010-2011 61 Molecular 3 3 ND ND ND ND ND ND ND ND ND ND 4 ND
Amini et al (18) 2019 Razavi Khorasan 2015-2017 56 Agar proportional 4 5 8 ND ND ND ND ND ND ND ND ND 4 ND
Sani et al (37) 2015 Razavi Khorasan 2012-2013 100 Agar proportional 7 7 3 ND 9 ND ND ND ND ND ND ND 4 ND
Danesh et al (38) 2014 Razavi Khorasan 2011-2012 48 Agar proportional 0 0 0 0 0 ND ND ND ND ND ND ND ND ND
Velayati et al (15) 2014 Razavi Khorasan 2010-2011 117 Molecular 10 9 ND ND ND ND ND ND ND ND ND ND 2 ND
Velayati et al (15) 2014 Semnan 2010-2011 21 Molecular 0 0 ND ND ND ND ND ND ND ND ND ND 0 ND
Hashemi Shahri et al (39) 2019 Sistan and Balouchastan 2013-2016 100 Agar proportional 2 ND ND ND ND ND ND ND ND ND ND ND 2 ND
Shirazinia et al (40) 2017 Sistan and Balouchastan 2010-2013 525 Agar proportional 15 16 0 ND 0 ND ND ND ND ND ND ND 7 ND
Nasiri et al (24) 2014 Sistan and Balouchastan 2010-2012 59 Agar proportional 5 3 3 ND 8 ND ND ND ND ND ND ND 3 ND
Velayati et al (15) 2014 Sistan and Balouchastan 2010-2011 165 Molecular 8 10 ND ND ND ND ND ND ND ND ND ND 1 ND
Vaziri et al (41) 2019 Tehran 2014-2018 606 Agar proportional 3 3 5 ND 2 ND ND ND ND ND ND ND 3 13
Habibnia et al (42) 2019 Tehran 2012-2018 100 Agar proportional 15 6 ND ND ND ND ND ND ND ND ND ND 17 ND
Aghajani et al (43) 2019 Tehran 2011-2018 6937 Molecular 1617 1326 ND ND ND ND ND ND ND ND ND ND 956 ND
Amini et al (18) 2019 Tehran 2015-2017 220 Agar proportional 11 4 2 ND ND ND ND ND ND ND ND ND 11 ND
Sakhaee et al (44) 2017 Tehran 2013-2016 395 Agar proportional 24 24 40 ND 60 ND 12 ND ND 12 7 ND 22 4
Khanipour et al (45) 2016 Tehran 2010-2015 723 Agar proportional ND ND ND ND ND ND ND ND ND ND ND ND 15 8
Imani Fooladi et al (46) 2014 Tehran 2009-2011 103 Agar proportional 12 9 ND ND ND ND ND ND ND ND ND ND 9 ND
Tasbiti et al (47) 2017 Tehran 2006-2014 1442 Agar proportional 168 176 169 ND 330 16 13 15 13 10 12 15 33 3
Sharifipour (48) 2014 Tehran 2011-2012 190 Agar proportional 12 5 8 ND ND ND ND ND ND ND ND ND 30 ND
Nasiri et al (24) 2014 Tehran 2010-2012 85 Agar proportional 6 7 6 ND 14 ND ND ND ND ND ND ND 6 ND
Bahrami et al (49) 2013 Tehran 2010-2012 176 Agar proportional 12 19 48 ND ND ND ND ND ND ND ND ND 10 ND
Pooideh et al (50) 2015 Tehran 2010-2011 100 Agar proportional 13 23 26 ND 37 ND ND ND 61 ND 21 ND 4 ND
Velayati et al (15) 2014 Tehran 2010-2011 324 Molecular 20 26 ND ND ND ND ND ND ND ND ND ND 32 ND
Varahram et al (51) 2014 Tehran 2003-2011 4825 Agar proportional Molecular 296 ND ND ND ND ND ND ND ND ND ND ND ND ND
Moradi et al (11) 2017 West Azerbaijan 2014-2015 10 Agar proportional 0 0 ND 3 ND ND ND ND ND ND ND ND ND ND
Atashi et al (12) 2017 West Azerbaijan 2014 12 Agar proportional 0 1 ND ND ND ND ND ND ND ND ND ND ND ND
Sahebi et al (13) 2016 West Azerbaijan 2014 25 Molecular 1 4 ND ND ND ND ND ND ND ND ND ND ND ND
Sahebi et al (14) 2015 West Azerbaijan 2011-2013 43 Molecular 1 3 ND ND ND ND ND ND ND ND ND ND ND ND
Velayati et al (15) 2014 Yazd 2010-2011 12 Molecular 0 1 ND ND ND ND ND ND ND ND ND ND 0 ND
Atashi et al (12) 2017 Zanjan 2014 5 Agar proportional 0 0 ND ND ND ND ND ND ND ND ND ND ND ND
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INH-isoniazid; RIF-rifampin; EMB-ethambutol; PZA-pyrazinamide; STR-streptomycin; PAS-para-aminosalicylic acid; CAP-capreomycin; CYC-cycloserine; ETO-ethionamide; OFX-ofloxacin; KAN-kanamycin; AMK-amikacin; MDR-multiple drug-resistant; XDR-extensively drug-resistant; DST-drug susceptibility testing; ND-not determined

Data analysis

Meta-analyses were conducted using the Comprehensive Meta-Analysis (CMA) (Biostat, Englewood, NJ) software package, and antimicrobial resistance trends were determined by the Graphpad Prism software package. Important analyzed parameters included the rates of M. tuberculosis antibiotic resistance and heterogeneity and publication bias among studies. The pooled estimates of the resistance prevalence for each drug were reported as a percentage and 95% confidence intervals (CIs) using a random-effects model (heterogeneity ≥25%;) or fixed-effects model (heterogeneity <25%;). The possibility of heterogeneity was evaluated by I² statistic and the Chi-square test with the Cochrane Q statistic. The existence of publication bias was assessed by Funnel plots.

Results

As shown in Figure 1, a total of 1,354 articles in Persian and English languages were collected during early literature search. At the end of the screening, 41 eligible articles were included in the meta-analysis based on the predefined inclusion and exclusion criteria. Forty-one included studies describing the prevalence of drug-resistant M. tuberculosis were selected from different provinces of Iran (Table 1). The most common laboratory methods that were used for assessing M. tuberculosis antibiotic susceptibility were agar proportion and molecular techniques such as line probe assay (LPA), real-time polymerase chain reaction (PCR), multiplex allele-specific polymerase chain reaction (MAS-PCR), and multiplex PCR.

Figure 1.

Figure 1

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Summary of the literature search and study selection in the meta-analysis

The total prevalence of isoniazid-resistant M. tuberculosis among new and previously treated cases in Iran was 6.9% (95% CI: 5.5-8.6) between 2013 and 2020, which was estimated using a random-effects model due to existence of significant heterogeneity (I2 = 92.1%; Q = 1101.5; P = 0.00). As shown in Table 2, the highest prevalence of isoniazid-resistant M. tuberculosis strains in different provinces of Iran was found in Fars (16.7%) and the lowest rates were seen in Semnan (0%), Yazd (0%), and Zanjan (0%). Additionally, Figure 2 demonstrates a decreasing trend in the incidence of isoniazid-resistant strains from 2013 to 2020 (6.9%) in comparison with 1999-2013 (19.7%) in Iran. According to the random-effects model (I2=83.7%; Q=516.4; P=0.00), the prevalence of rifampin-resistant M. tuberculosis strains among new and previously treated cases in Iran was 7.9% (95% CI: 6.6-9.5) between 2013 and 2020 which was lower than the previous report from 1999 to 2013 (15%). M. tuberculosis strains isolated from Fars (16.1%), Semnan (0%), and Zanjan (0%) showed the highest and lowest rates of resistance to rifampin, respectively. Among new and previously treated cases between 2013 and 2020, the mean resistance to ethambutol in Iran was 5.7% (95% CI: 4-8). The rate of resistance was highest in Kermanshah (14.2%) and lowest in Golestan (0%). The overall prevalence of ethambutol-resistant M. tuberculosis strains in Iran was calculated using the random-effects model (I2 = 86%; Q = 208.3; P = 0.00). As presented in Figure 2, ethambutol-resistant strains also showed a decreasing pattern in Iran from 1999 to 2020 (9.7% to 5.7%). Frequency of M. tuberculosis resistance to pyrazinamide calculated using the fixed-effects model was 20.4% (95% CI: 15.7-26.2; I2 = 13.2%; Q = 11.5; P = 0.31). The highest resistance rate was found in Hamadan (40%) and the lowest rate was seen in Razavi Khorasan (0%).

Table 2.

Mycobacterium tuberculosis antibiotic resistance profiles in different provinces of Iran during 2013-2020

Province Antibiotic resistance (%)
First-line drugs Second-line drugs
INH RIF EMB PZA STR PAS CAP CYC ETO OFX KAN AMK MDR XDR
Ardabil 11.9 8.9 ND 11.1 ND ND ND ND ND ND ND ND 6.1 ND
East Azerbaijan 4.3 9.9 2.4 20.1 21 ND ND ND ND ND ND ND 8.3 ND
Fars 16.7 16.1 7.8 ND 10.5 ND ND ND ND ND ND ND 13.6 ND
Golestan 3.4 1.5 0 ND 7.3 ND ND ND ND ND ND ND 4.2 ND
Guilan 2.5 5.1 ND ND ND ND ND ND ND ND ND ND 7.6 ND
Hamadan 6.9 8.1 ND 40 ND ND ND ND ND ND ND ND 0 ND
Hormozgan 8.2 6.1 4.1 ND 7.1 ND ND ND ND ND ND ND 6.7 ND
Ilam 14 8.4 ND 25 ND ND ND ND ND ND ND ND ND ND
Isfahan 6.2 3.7 2.7 ND 4.5 ND ND ND ND ND ND ND 3.2 ND
Kerman 4.1 12.5 ND ND ND ND ND ND ND ND ND ND 12.5 ND
Kermanshah 9.4 13.8 14.2 22.9 22.1 16.9 ND 3.5 12.5 ND ND ND 14.2 ND
Khuzestan 8.9 11.7 4 ND 36.3 ND ND ND ND ND ND ND 6.1 ND
Kurdistan 8.7 6.1 ND 11.1 ND ND ND ND ND ND ND ND 0 ND
Lorestan 1.5 4.5 ND 21 ND ND ND ND ND ND ND ND 3.5 ND
Markazi 7.4 6.3 6.9 ND 2.6 ND ND ND ND ND ND ND 8.6 ND
Mazandaran 3.8 5.1 ND ND 7.4 ND ND ND ND ND 5.5 5.5 3.8 ND
Qazvin 9.4 6.1 ND ND ND ND ND ND ND ND ND ND 20 ND
Qom 4.9 4.9 ND ND ND ND ND ND ND ND ND ND 6.5 ND
Razavi Khorasan 7.4 7.4 5 0 4.6 ND ND ND ND ND ND ND 4.1 ND
Semnan 0 0 ND ND ND ND ND ND ND ND ND ND 0 ND
Sistan and Balouchastan 4.1 4.3 0.9 ND 1.4 ND ND ND ND ND ND ND 1.9 ND
Tehran 7.6 7.4 7.6 ND 14.7 1.1 1.7 1 10.7 1.5 3.3 1 5.8 0.9
West Azerbaijan 3.4 10.2 ND 30 ND ND ND ND ND ND ND ND ND ND
Yazd 0 8.3 ND ND ND ND ND ND ND ND ND ND 0 ND
Zanjan 0 0 ND ND ND ND ND ND ND ND ND ND ND ND
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INH-isoniazid; RIF-rifampin; EMB-ethambutol; PZA-pyrazinamide; STR-streptomycin; PAS-para-aminosalicylic acid; CAP-capreomycin; CYC-cycloserine; ETO-ethionamide; OFX-ofloxacin; KAN-kanamycin; AMK-amikacin; MDR-multiple drug-resistant; XDR-extensively drug-resistant; ND-not determined

Figure 2.

Figure 2

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Antimicrobial resistance trends of Mycobacterium tuberculosis strains to isoniazid, rifampin, ethambutol, streptomycin, as well as MDR-TB, among new and previously treated cases in Iran from 1999 to 2020

Second-line anti-TB drugs (groups A-D) used for MDR treatment include 1) group A: fluoroquinolones (ofloxacin, levofloxacin, moxifloxacin, and ciprofloxacin), 2) group B: injectable drugs (aminoglycosides (kanamycin, amikacin, and streptomycin) and cyclic peptides (capreomycin)), 3) group C: ethionamide/prothionamide, cycloserine/terizidone, linezolid and clofazimine, and 4) group D: D2 (bedaquiline and delamanid) and D3 ( para-aminosalicylic acid, imipenem-cilastatin, meropenem, amoxicillin/clavulanate and thioacetazone). The prevalence of M. tuberculosis resistance to these drugs which are mainly used in treatment of MDR-TB was not completely evaluated in the previous study conducted from 1999 to 2013 in Iran. Figure 3 shows the forest plot and funnel plot of streptomycin-resistant M. tuberculosis strains for new and previously treated cases between 2013 and 2020 in Iran. The prevalence of M. tuberculosis resistance to streptomycin was estimated at 10.6% (95% CI: 7.5-14.6; I2 = 89.6%; Q = 192.8; P = 0.00). The maximum and minimum resistance rates were observed in Khuzestan (36.3%) and Sistan and Balouchastan (1.4%), respectively. Similar to first-line anti-TB drugs, the trend of M. tuberculosis resistance to streptomycin decreased between 1999 and 2020 (23.9% to 10.6%) (Figure 2). Frequency of M. tuberculosis resistance to other drugs during 2013 to 2020 were as follows: para-aminosalicylic acid 4.6% (95% CI: 0.3-45.1; I2 = 98.4%; Q = 66.5; P = 0.00), capreomycin 1.7% (95% CI: 0.5-5.4; I2 = 89.3%; Q = 9.3; P = 0.00), cycloserine 1.8% (95% CI: 0.5-5.9; I2 = 79.4%; Q = 4.8; P = 0.02), ethionamide 11.3% (95% CI: 0.6-72.9; I2 = 99.1%; Q = 224.5; P = 0.00), ofloxacin 1.5% (95% CI: 0.3-6.1; I2 = 91.7%; Q = 12.0; P = 0.00), kanamycin 3.8% (95% CI: 0.6-20; I2 = 96.7%; Q = 91.4; P = 0.00), and amikacin 2.2% (95% CI: 0.4-10.9; I2 = 85.8%; Q = 7.0; P = 0.00).

Figure 3.

Figure 3

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Forest plot (a) and funnel plot (b) showing streptomycin-resistant Mycobacterium tuberculosis prevalence among new and previously treated cases between 2013 and 2020 in Iran

Additionally, the pooled estimate of MDR- and XDR-TB in Iran were 6.3% (95% CI: 5-8; I2 = 86.7%; Q = 446.3; P = 0.00) and 0.9% (95% CI: 0.4-2.2; I2 = 78.3%; Q = 13.8; P = 0.00), respectively. Similar to first-line anti-TB drugs, the rate of MDR M. tuberculosis in Iran between 1999 and 2020 showed a downward trend (10.3% to 6.3%). The prevalence of MDR strains was highest in Qazvin (20%) and lowest in Hamadan, Kurdistan, Semnan, and Yazd (0%).

Discussion

Despite the strategies initiated by the National Tuberculosis Control Program (NTP) in 1996, TB continues to be a major health concern in Iran. One of the main reasons is the emergence of drug-resistant M. tuberculosis strains (53). The WHO implemented a general project back in 1994 in which data on anti-TB drug resistance are collected from numerous countries; the results indicate that the prevalence of drug-resistant M. tuberculosis strains is still a major public health concern around the world (1). The current meta-analysis is the newest report on the M. tuberculosis antibiotic resistance in Iran. We believe it provides such overviews of the available data to estimate the total antibiotic resistance. Also, it helps to increase our knowledge on drug-resistant TB trends during the years to prevent further rise in drug resistance and treatment failures. Among the first-line anti-TB drugs recommended by NTP to treat new sputum-positive TB cases in Iran, isoniazid and rifampin are the most effective agents (16). Isoniazid has also been recommended as a preventive therapy in latent TB infections (54). Therefore, isoniazid- and rifampin-resistant cases can increase the risk of treatment failure due to development of MDR-TB. Our analysis showed that 6.9% and 7.9% of both new and previously treated cases between 2013 and 2020 in Iran were resistant to isoniazid and rifampin, respectively. Based on the WHO report in 2018, the global average of isoniazid resistance varies between 7.2% among new TB cases and 11.6% in previously treated TB cases (1). Additionally, findings of the present study on the prevalence of rifampin-resistant strains of M. tuberculosis (7.9%) is comparable with international data from the Western Pacific Region (24%), European Region (10%), South-East Asian Region (6%), African Region (3%) and Region of America (1%) (55). In 2018, WHO announced that the incidence of MDR-TB and rifampicin-resistant TB in new and previously treated TB cases were 3.4% and 18% in the world, respectively (1). The rate of MDR-TB in Iran was low (6.3%). Patients with rifampicin-resistant TB and MDR-TB must be treated with second-line drugs (1). Only a few studies have investigated M. tuberculosis resistance to the second-line anti-TB drugs. This could be due to a low resistance rate to first-line anti-TB drugs in Iran. In addition to MDR-TB and rifampicin-resistant TB, global surveillance and treatment of XDR-TB (defined as MDR-TB plus resistance to at least one of the fluoroquinolones and one of the injectable agents) is completely urgent (1). A total of 28 XDR-TB cases were identified in Iran and 13,068 XDR-TB cases were reported in 2018 by WHO globally (1).

Among first-line anti-TB agents, the highest and lowest resistance rates between 2013 and 2020 in Iran were seen for pyrazinamide (20.4%) and ethambutol (5.7%). It has been suggested that chromosomal mutations are associated with development of drug resistance in clinical M. tuberculosis strains including rifampicin resistance-associated mutations in rpoB gene, mutations in katG or inhA genes in isoniazid-resistant strains, embB or ubiA genes mutations in ethambutol-resistant isolates, and mutations in pncA, rpsA, panD and clpC1 genes among pyrazinamide-resistant isolates (56). Similar resistance mechanisms were seen in M. tuberculosis isolated in Iran (data not shown).

Furthermore, the prevalence of resistant strains to isoniazid, rifampin, ethambutol, and streptomycin as well as MDR-TB in Iran showed a downward trend from 1999 to 2020 (Figure 2). This could be attributed to differences in the methods used for assessing drug susceptibility/antibiotic resistance due to possible heterogeneity among studies (fixed- or random-effects models) or the number of included studies among two reviews. Also, decreased incidence of TB cases in Iran (21 per 100,000 population in 2011 compared with 14 cases in 2018) and fewer Afghan refugees due to sanctions, are other contributory factors. The limitations that need to be acknowledged in this study include: 1) small number of studies reporting resistance to second-line drugs and XDR-TB, 2) lack of studies reporting M. tuberculosis drug resistance in some provinces, 3) lack of individual separation of drug-resistant TB in many studies according to new or previously treated patients, age, ethnicity, nationality (Iranian versus Afghans), and 4) existence of heterogeneity and publication bias among included studies.

Conclusion

The current updated systematic review and meta-analysis summarized the total prevalence of drug-resistant M. tuberculosis strains in new and previously treated TB cases (2013–2020) and drug-resistant TB trend (1999–2020) in Iran. Based on our results, the mean resistance to first- and second-line anti-TB drugs was low in Iran during 2013–2020 as were the cases of MDR-TB and XDR-T. There was also a decreasing trend in resistance of M. tuberculosis from 1999 to 2020. Hence, to continue the current downward trend and control and eliminate TB infections in Iran, continuous monitoring of resistance patterns through optimized and rapid diagnostic tests such as molecular techniques in all provinces of Iran is recommended.

Conflicts of Interest

The author declares that there are no conflicts of interest.

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