Literature DB >> 34094023

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

Farzad Khademi1, Amirhossein Sahebkar2,3,4.   

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.

Entities:  

Keywords:  Antibiotic; Iran; Meta-analysis; Mycobacterium tuberculosis; Resistance

Year:  2021        PMID： 34094023      PMCID： PMC8143714          DOI： 10.22038/IJBMS.2021.48628.11161

Source DB:  PubMed          Journal:  Iran J Basic Med Sci        ISSN： 2008-3866            Impact factor:   2.699


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

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)PublisheddateProvinceEnrollment dateStrain(n)DST Antibiotic resistance (n)
First-line drugsSecond-line drugs
INHRIFEMBPZASTRPASCAPCYCETOOFXKANAMKMDRXDR
Moradi et al (11)2017Ardabil2014-20159Agar proportional10ND1NDNDNDNDNDNDNDNDNDND
Atashi et al (12)2017Ardabil201414Agar proportional20NDNDNDNDNDNDNDNDNDNDNDND
Sahebi et al (13)2016Ardabil20149Molecular31NDNDNDNDNDNDNDNDNDNDNDND
Sahebi et al (14)2015Ardabil2011-201326Molecular34NDNDNDNDNDNDNDNDNDNDNDND
Velayati et al (15)2014Ardabil2010-201165Molecular24NDNDNDNDNDNDNDNDNDND4ND
Moradi et al (11)2017East Azerbaijan2014-201521Agar proportional22ND6NDNDNDNDNDNDNDNDNDND
Atashi et al (12)2017East Azerbaijan201428Agar proportional01NDNDNDNDNDNDNDNDNDNDNDND
Sahebi et al (13)2016East Azerbaijan201428Molecular14NDNDNDNDNDNDNDNDNDNDNDND
Rashedi et al (16)2015East Azerbaijan2012-201448Agar proportional242NDNDNDNDNDNDNDNDND1ND
Sahebi et al (14)2015East Azerbaijan2011-201387Molecular315NDNDNDNDNDNDNDNDNDNDNDND
Moaddab et al (17)2015East Azerbaijan2009-2012100Agar proportional4511821NDNDNDNDNDNDND21ND
Amini et al (18)2019Fars2015-201719Agar proportional310NDNDNDNDNDNDNDNDND1ND
Zarei et al (19)2017Fars2012-2014199Agar proportional383016ND21NDNDNDNDNDNDND22ND
Honarvar et al (20)2015Fars2012-201392Agar proportional1619NDNDNDNDNDNDNDNDNDND24ND
Motamedifar et al (21)2015Fars2004-201359Agar proportionalNDNDNDNDNDNDNDNDNDNDNDND6ND
Velayati et al (15)2014Fars2010-201140Molecular25NDNDNDNDNDNDNDNDNDND5ND
Mansoori et al (22)2018Golestan2014-2015164Agar proportional300ND12NDNDNDNDNDNDNDNDND
Velayati et al (15)2014Golestan2010-201147Molecular32NDNDNDNDNDNDNDNDNDND2ND
Velayati et al (15)2014Guilan2010-201139Molecular12NDNDNDNDNDNDNDNDNDND3ND
Moradi et al (11)2017Hamadan2014-20155Agar proportional00ND2NDNDNDNDNDNDNDNDNDND
Atashi et al (12)2017Hamadan201411Agar proportional10NDNDNDNDNDNDNDNDNDNDNDND
Velayati et al (15)2014Hamadan2010-201121Molecular12NDNDNDNDNDNDNDNDNDND0ND
Zamani et al (23)2016Hormozgan2012-201338Agar proportional4NDNDND2NDNDNDNDNDNDND3ND
Nasiri et al (24)2014Hormozgan2010-201248Agar proportional322ND4NDNDNDNDNDNDND2ND
Velayati et al (15)2014Hormozgan2010-201138Molecular33NDNDNDNDNDNDNDNDNDND3ND
Moradi et al (11)2017Ilam2014-20154Agar proportional00ND1NDNDNDNDNDNDNDNDNDND
Atashi et al (12)2017Ilam20146Agar proportional10NDNDNDNDNDNDNDNDNDNDNDND
Amini et al (18)2019Isfahan2015-201719Agar proportional211NDNDNDNDNDNDNDNDND1ND
Karimi et al (25)2017Isfahan2014-2015205Agar proportional643ND10NDNDNDNDNDNDND4ND
Nasr Esfahani et al (26)2016Isfahan201332Agar proportionalNDND2NDNDNDNDNDNDNDNDNDNDND
Nasiri et al (24)2014Isfahan2010-201245Agar proportional220ND1NDNDNDNDNDNDND2ND
Velayati et al (15)2014Isfahan2010-201142Molecular53NDNDNDNDNDNDNDNDNDND2ND
Velayati et al (15)2014Kerman2010-201124Molecular13NDNDNDNDNDNDNDNDNDND3ND
Mohammadi et al (27)2018Kermanshah2014-201550Agar proportionalNDND7NDNDNDNDNDNDNDNDND8ND
Moradi et al (11)2017Kermanshah2014-201517Agar proportional12ND2NDNDNDNDNDNDNDNDNDND
Atashi et al (12)2017Kermanshah201431Agar proportional12NDNDNDNDNDNDNDNDNDNDNDND
Sahebi et al (13)2016Kermanshah201416Molecular14NDNDNDNDNDNDNDNDNDNDNDND
Sahebi et al (14)2015Kermanshah2011-201351Molecular15NDNDNDNDNDNDNDNDNDNDNDND
Mohajeri et al (28)2014Kermanshah2011-2012112Agar proportional181615272519ND414NDNDND16ND
Nasiri et al (24)2014Kermanshah2010-201215Agar proportional433ND3NDNDNDNDNDNDND3ND
Velayati et al (15)2014Kermanshah2010-201116Molecular12NDNDNDNDNDNDNDNDNDND1ND
Khosravi et al (29)2019Khuzestan2016-2017307Agar proportional61010NDNDNDNDNDNDNDNDND4ND
Khosravi et al (30)2019Khuzestan2015-201737Agar proportional316NDNDNDNDNDNDNDNDNDND5ND
Amini et al (18)2019Khuzestan2015-201720Agar proportional111NDNDNDNDNDNDNDNDND1ND
Badie et al (31)2016Khuzestan201564Agar proportionalNDNDNDNDNDNDNDNDNDNDNDND2ND
Khosravi et al (32)2017Khuzestan2013-201488Agar proportional41355ND32NDNDNDNDNDNDND22ND
Velayati et al (15)2014Khuzestan2010-2011119Molecular73NDNDNDNDNDNDNDNDNDND6ND
Khosravi et al (33)2014Khuzestan2010-2011160Molecular1820NDNDNDNDNDNDNDNDNDND8ND
Moradi et al (11)2017Kurdistan2014-201527Agar proportional00ND3NDNDNDNDNDNDNDNDNDND
Atashi et al (12)2017Kurdistan201423Agar proportional02NDNDNDNDNDNDNDNDNDNDNDND
Sahebi et al (13)2016Kurdistan201412Molecular31NDNDNDNDNDNDNDNDNDNDNDND
Sahebi et al (14)2015Kurdistan2011-201350Molecular33NDNDNDNDNDNDNDNDNDNDNDND
Velayati et al (15)2014Kurdistan2010-201116Molecular20NDNDNDNDNDNDNDNDNDND0ND
Heidary et al (34)2020Lorestan2014-2017106Agar proportional11NDNDNDNDNDNDNDNDNDND4ND
Moradi et al (11)2017Lorestan2014-201519Agar proportional00ND4NDNDNDNDNDNDNDNDNDND
Atashi et al (12)2017Lorestan201427Agar proportional01NDNDNDNDNDNDNDNDNDNDNDND
Velayati et al (15)2014Lorestan2010-201124Molecular05NDNDNDNDNDNDNDNDNDND0ND
Farazi et al (35)2013Markazi2011-2012115Agar proportional328ND3NDNDNDNDNDNDND9 ND
Velayati et al (15)2014Markazi2010-201115Molecular33NDNDNDNDNDNDNDNDNDND2ND
Babamahmoodi et al (36)2014Mazandaran201354Molecular23NDND4NDNDNDNDND33NDND
Velayati et al (15)2014Mazandaran2010-201126Molecular11NDNDNDNDNDNDNDNDNDND1ND
Atashi et al (12)2017Qazvin20145Agar proportional00NDNDNDNDNDNDNDNDNDNDNDND
Velayati et al (15)2014Qazvin2010-201110Molecular10NDNDNDNDNDNDNDNDNDND2ND
Velayati et al (15)2014Qom2010-201161Molecular33NDNDNDNDNDNDNDNDNDND4ND
Amini et al (18)2019Razavi Khorasan2015-201756Agar proportional458NDNDNDNDNDNDNDNDND4ND
Sani et al (37)2015Razavi Khorasan2012-2013100Agar proportional773ND9NDNDNDNDNDNDND4ND
Danesh et al (38)2014Razavi Khorasan2011-201248Agar proportional00000NDNDNDNDNDNDNDNDND
Velayati et al (15)2014Razavi Khorasan2010-2011117Molecular109NDNDNDNDNDNDNDNDNDND2ND
Velayati et al (15)2014Semnan2010-201121Molecular00NDNDNDNDNDNDNDNDNDND0ND
Hashemi Shahri et al (39)2019Sistan and Balouchastan2013-2016100Agar proportional2NDNDNDNDNDNDNDNDNDNDND2ND
Shirazinia et al (40)2017Sistan and Balouchastan2010-2013525Agar proportional15160ND0NDNDNDNDNDNDND7ND
Nasiri et al (24)2014Sistan and Balouchastan2010-201259Agar proportional533ND8NDNDNDNDNDNDND3ND
Velayati et al (15)2014Sistan and Balouchastan2010-2011165Molecular810NDNDNDNDNDNDNDNDNDND1ND
Vaziri et al (41)2019Tehran2014-2018606Agar proportional335ND2NDNDNDNDNDNDND313
Habibnia et al (42)2019Tehran2012-2018100Agar proportional156NDNDNDNDNDNDNDNDNDND17ND
Aghajani et al (43)2019Tehran2011-20186937Molecular16171326NDNDNDNDNDNDNDNDNDND956ND
Amini et al (18)2019Tehran2015-2017220Agar proportional1142NDNDNDNDNDNDNDNDND11ND
Sakhaee et al (44)2017Tehran2013-2016395Agar proportional242440ND60ND12NDND 127ND224
Khanipour et al (45)2016Tehran2010-2015723Agar proportionalNDNDNDNDNDNDNDNDNDNDNDND158
Imani Fooladi et al (46)2014Tehran2009-2011103Agar proportional129NDNDNDNDNDNDNDNDNDND9ND
Tasbiti et al (47)2017Tehran2006-20141442Agar proportional168176169ND33016131513101215333
Sharifipour (48)2014Tehran2011-2012190Agar proportional1258NDNDNDNDNDNDNDNDND30ND
Nasiri et al (24)2014Tehran2010-201285Agar proportional676ND14NDNDNDNDNDNDND6ND
Bahrami et al (49)2013Tehran2010-2012176Agar proportional121948NDNDNDNDNDNDNDNDND10ND
Pooideh et al (50)2015Tehran2010-2011100Agar proportional132326ND37NDNDND61ND21ND4ND
Velayati et al (15)2014Tehran2010-2011324Molecular2026NDNDNDNDNDNDNDNDNDND32ND
Varahram et al (51)2014Tehran2003-20114825Agar proportional Molecular296NDNDNDNDNDNDNDNDNDNDNDNDND
Moradi et al (11)2017West Azerbaijan2014-201510Agar proportional00ND3NDNDNDNDNDNDNDNDNDND
Atashi et al (12)2017West Azerbaijan201412Agar proportional01NDNDNDNDNDNDNDNDNDNDNDND
Sahebi et al (13)2016West Azerbaijan201425Molecular14NDNDNDNDNDNDNDNDNDNDNDND
Sahebi et al (14)2015West Azerbaijan2011-201343Molecular13NDNDNDNDNDNDNDNDNDNDNDND
Velayati et al (15)2014Yazd2010-201112Molecular01NDNDNDNDNDNDNDNDNDND0ND
Atashi et al (12)2017Zanjan20145Agar proportional00NDNDNDNDNDNDNDNDNDNDNDND

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

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

ProvinceAntibiotic resistance (%)
First-line drugsSecond-line drugs
INHRIFEMBPZASTRPASCAPCYCETOOFXKANAMKMDRXDR
Ardabil11.98.9ND11.1NDNDNDNDNDNDNDND6.1ND
East Azerbaijan4.39.92.420.121NDNDNDNDNDNDND8.3ND
Fars16.716.17.8ND10.5NDNDNDNDNDNDND13.6ND
Golestan3.41.50ND7.3NDNDNDNDNDNDND4.2ND
Guilan2.55.1NDNDNDNDNDNDNDNDNDND7.6ND
Hamadan6.98.1ND40NDNDNDNDNDNDNDND0ND
Hormozgan8.26.14.1ND7.1NDNDNDNDNDNDND6.7ND
Ilam148.4ND25NDNDNDNDNDNDNDNDNDND
Isfahan6.23.72.7ND4.5NDNDNDNDNDNDND3.2ND
Kerman4.112.5NDNDNDNDNDNDNDNDNDND12.5ND
Kermanshah9.413.814.222.922.116.9ND3.512.5NDNDND14.2ND
Khuzestan8.911.74ND36.3NDNDNDNDNDNDND6.1ND
Kurdistan8.76.1ND11.1NDNDNDNDNDNDNDND0ND
Lorestan1.54.5ND21NDNDNDNDNDNDNDND3.5ND
Markazi7.46.36.9ND2.6NDNDNDNDNDNDND8.6ND
Mazandaran3.85.1NDND7.4NDNDNDNDND5.55.53.8ND
Qazvin9.46.1NDNDNDNDNDNDNDNDNDND20ND
Qom4.94.9NDNDNDNDNDNDNDNDNDND6.5ND
Razavi Khorasan7.47.4504.6NDNDNDNDNDNDND4.1ND
Semnan00NDNDNDNDNDNDNDNDNDND0ND
Sistan and Balouchastan4.14.30.9ND1.4NDNDNDNDNDNDND1.9ND
Tehran7.67.47.6ND14.71.11.7110.71.53.315.80.9
West Azerbaijan3.410.2ND30NDNDNDNDNDNDNDNDNDND
Yazd08.3NDNDNDNDNDNDNDNDNDND0ND
Zanjan00NDNDNDNDNDNDNDNDNDNDNDND

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

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

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%). Summary of the literature search and study selection in the meta-analysis Extracted information from eligible studies included in the meta-analysis during 2013-2020 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 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 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 Mycobacterium tuberculosis antibiotic resistance profiles in different provinces of Iran during 2013-2020 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

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.
  38 in total

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1.  Genetic diversity of drug-resistant Mycobacterium tuberculosis clinical isolates from Khuzestan province, Iran.

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