Prevalence and Mechanisms of Carbapenem Resistance in Klebsiella pneumoniae and Escherichia coli : A Systematic Review and Meta-Analysis of Cross-Sectional Studies from Iran

Abstract

Introduction:

Carbapenem-resistant Enterobacteriaceae (CRE) represents an urgent threat worldwide. We aimed to investigate the frequency of carbapenem-resistant Klebsiella pneumoniae and Escherichia coli in Iran.

Materials and Methods:

PubMed/Medline, Embase, Scopus, Web of Sciences, and Iranian databases were searched to find potentially relevant articles. Statistical analyses were performed using STATA version 14.

Results:

Forty-nine studies fulfilled the inclusion criteria. The pooled rates of resistance to carbapenem in K. pneumoniae and E. coli were 24.0% (95% confidence interval [CI] 18.0–31.0) and 5.0% (95% CI 2.0–8.0), respectively. bla_OXA-48 gene was the most common cause of carbapenem resistance in K. pneumoniae and E. coli.

Conclusions:

CRE is prevalent in Iran, which confers the importance of strength prevention and control measures.

Introduction

The multidrug-resistant gram-negative bacteria (MDR-GNB) are an important threat to public health. Carbapenems, a class of β-lactam antimicrobials, are considered last-line agents against MDR-GNB. This is due, in part, to their broad-spectrum antibacterial activity.^1–4 The increasing prevalence of carbapenem-resistant Enterobacteriaceae (CRE) strains is related to high mortality and it is increasing around the world.¹ In the USA, there were an estimated 140,000 cases per year of health care-associated CRE infections.⁵ Among the Enterobacteriaceae family, Klebsiella pneumoniae and Escherichia coli are among the most common agents of community- and hospital-acquired infections.^6–8 They are also among the most common agents reported for CRE infections around the world.⁵

There are various types of mechanisms that lead to carbapenem-resistant GNB. One of the main mechanisms is acquiring plasmid-encoding carbapenemase.⁹ According to the Ambler classification, there are three classes of carbapenemase: (1) class A containing serine carbapenemases such as non-metallocarbapenemase/imipenemase (NMC/IMI), KPC (K. pneumoniae carbapenemase), Guiana extended-spectrum β-lactamase, and Serratia marcescens enzyme (SME); (2) class B containing metallo-β-lactamases (MBLs) such as VIM (Verona integrin-encoded metallo-β-lactamase), NDM (New Delhi metallo-β-lactamase), and imipenemase (IMP); and (3) class D containing enzymes such as OXA-48 (oxacillinase-48), OXA-232, OXA-181, and OXA-204.^10–14 In the study by Grundmann et al., the most common carbapenemases in E. coli and K. pneumoniae were OXA-48-like enzymes and KPC enzymes, respectively.^15,16 Another mechanism that leads to carbapenem resistance is overexpression of ESBL and/or AmpC β-lactamases combined with a reduction of membrane permeability due to porin modification. Modification of two major porins, OmpK35 or OmpK36, in K. pneumoniae or complete loss of porins, OmpF and OmpC, as in E. coli can lead to carbapenem resistance.^6,17,18

There are many original reports from Iran about the prevalence of CRE in recent years,^19,20 but, a comprehensive systematic review and meta-analysis have not been conducted. Thus, the purposes of this work were to estimate the frequency of carbapenem-resistant K. pneumoniae and E. coli in Iran and to define the mechanisms that lead to carbapenem resistance in these two bacterial species.

Materials and Methods

Search strategy and study selection

PubMed/Medline, Embase, Scopus, Web of Sciences, and Iranian databases from January 2010 to June 2019 were searched to identify potentially relevant studies. The search terms were as follows: “Klebsiella pneumoniae” OR “Escherichia coli” AND (“carbapenem” or ‘imipenem” or “meropenem”) AND Iran. Similar strategies were used for Iranian databases.

Two authors (M.A. and F.F.) independently reviewed the potentially relevant studies and disagreements were resolved by consensus discussion.

Articles were included if they reported the carbapenem resistance in clinical isolates of K. pneumoniae and/or E. coli and/or described the mechanisms of carbapenem resistance in these bacteria. Only studies written in English or Persian were included. Case reports and reviews were excluded. Our study was according to the PRISMA guideline.²¹

Data extraction

The following data were extracted by two independent reviewers: first authors, published year, city, sample size, mean age, sites of infection, proportion of resistance, diagnostic methods, and the mechanisms of carbapenem resistance.

Quality assessment

We assessed the quality of the references according to the checklist provided by JBI (Joanna Briggs Institute).²²

Data analysis

The combined rates of carbapenem-resistant K. pneumoniae and E. coli, with 95% confidence intervals (95% CIs), were analyzed by the random-effects model. Q- and I² statistics were used to assess the between-study heterogeneity.²³ To assess the possibility of publication bias, we performed the Begg's test.²⁴ STATA version 14 was used to analyze the data.

Results

From the databases, 1,066 publications were retrieved. After the evaluation of the titles, abstracts, and full texts, 49 studies were included in this systematic review and meta-analysis (Fig. 1). These 49 studies were divided into 2 groups comprising 39 datasets (35 investigations the mechanisms of carbapenem resistance and 33 investigating the frequency of carbapenem resistance) for K. pneumoniae and 18 datasets (10 investigating the mechanisms of carbapenem resistance and 14 investigating the frequency of carbapenem resistance) for E. coli. Characteristics of the included articles are described in Tables 1 and 2.

FIG. 1.

Flowchart for selection of the study.

Table 1.

Characteristics of Included Studies for Klebsiella pneumoniae

First author	Published time	City	Population	No. of K. pneumoniae	No. of carbapenem-resistant K. pneumoniae	Mechanisms of carbapenem resistance	Diagnostic test
Bahramian⁴⁸	2019	Tehran	Hospitalized patients	120	12	Bla _NDM-6	Disk diffusion, PCR, Sequencing
Zare⁴⁹	2019	Multicenter	Hospitalized patients with cancer	23	5	Carbapenemase genes were not detected	Disk diffusion, PCR
Kiaei⁵⁰	2019	Kerman	Hospitalized patients	175	37	Bla _NDM-1	Disk diffusion, PCR
Hojabri⁵¹	2019	Semnan	Hospitalized patients	NR	43	Bla _NDM-1	Disk diffusion, PCR
Jafari²⁶	2019	Tehran	Hospitalized patients	992	100	bla_OXA-48, bla_NDM	Disk diffusion, modified Hodge test, PCR
Vaez⁵²	2019	Zabol	Outpatients	70	3	bla _NDM	Disk diffusion, modified Hodge test, PCR
Badamchi⁵³	2018	Tehran	Hospitalized patients	93	28	bla_KPC, bla_GES	Disk diffusion, modified Hodge test, PCR
Ghasemnejad⁵⁴	2018	Isfahan	Hospitalized patients and outpatients	96	54	bla _KPC	Disk diffusion, modified Hodge test, PCR
Tabrizi⁵⁵	2018	Tehran	Hospitalized patients	53	5	bla _VIM-2	Disk diffusion, PCR
Solgi²⁰	2018	Isfahan	Hospitalized patients	NR	96	bla_OXa-48, bla_NDM-1	Disk diffusion, modified Hodge test, PCR
Gheitani⁵⁶	2018	Multicenter	NR	183	134	bla_VIM, bla_IMP	Disk diffusion, modified Hodge test, PCR
Koraei⁵⁷	2018	Ahvaz	Hospitalized patients	79	19	Carbapenemase genes were not detected	Disk diffusion, PCR
Moghadampour⁵⁸	2018	Isfahan	Hospitalized patients	80	51	bla_OXA-48, bla_NDM-1	Disk diffusion, modified Hodge test, PCR
Khodadadian⁵⁹	2018	Qom	Hospitalized patients and outpatients	457	117	bla_VIM-1, bla_IMP-1	Disk diffusion, PCR
Armin⁶⁰	2018	Multicenter	NR	145	12	bla _NDM-1	Disk diffusion, PCR
Shoja⁶¹	2018	Bandar Abbas	NR	170	11	bla _NDM-1	Disk diffusion, modified Hodge test, PCR
Hosseinzadeh⁶²	2018	Shiraz	Hospitalized patients	211	29	bla_NDM-1, bla_OXA-48like	Disk diffusion, modified Hodge test, PCR
Shokri⁶³	2017	Isfahan	NR	120	81	bla _NDM-1	Disk diffusion, PCR
Firoozeh⁶⁴	2017	Kashan	Hospitalized patients	181	48	bla_KPC, bla_GES	Disk diffusion, PCR, sequencing
Khorvash⁶⁵	2017	Isfahan	Hospitalized patients	NR	29	bla_VIM, bla_IMP, bla_OXA	Disk diffusion, PCR
Shahcheraghi¹⁹	2017	Hamadan	Hospitalized patients and outpatients	65	8	bla_IMP, bla_NDM-1, bla_OXA-48	Disk diffusion, modified Hodge test, PCR
Solgi⁶⁶	2017	NR	Hospitalized patients	NR	33	bla_NDM-1, bla_NDM-7, bla_OXA-48	Disk diffusion, PCR
Navidinia⁶⁷	2017	Tehran	NR	98	12	bla _KPC	Disk diffusion, PCR
Sadeghi⁶⁸	2017	Tehran	Hospitalized patients	100	8	bla_VIM, bla_OXA, bla_KPC, bla_GES	Disk diffusion, PCR
Solgi⁶⁹	2016	Tehran	Hospitalized patients and outpatients	35	NR	bla _IMP	Disk diffusion, modified Hodge test, PCR
Firoozeh⁷⁰	2016	Kashan	Hospitalized patients	181	48	bla_KPC, bla_GES	Disk diffusion, PCR
Eftekhar⁷¹	2015	Tehran	Hospitalized patients	55	5	Carbapenemase genes were not detected	Disk diffusion, modified Hodge test, PCR
Fazeli⁷²	2015	Isfahan	Hospitalized patients	112	49	bla _NDM-1	Disk diffusion, modified Hodge test, PCR
Zeighami⁷³	2015	Zanjan	NR	149	12	bla_VIM, bla_IMP	Disk diffusion, PCR
Rajabnia⁷⁴	2015	Babol	Hospitalized patients	50	15	bla _VIM	Disk diffusion, PCR
Rodbari⁷⁵	2015	Mashhad	Hospitalized patients and outpatients	280	70	NR	Disk diffusion, modified Hodge test
Farajzadeh⁷⁶	2015	Abadan	Hospitalized patients and outpatients	144	27	bla _KPC	Disk diffusion, PCR
Japoni-Nejad⁷⁷	2014	Arak	Hospitalized patients	100	12	bla_VIM, bla_GES	Disk diffusion, PCR
Azimi⁷⁸	2014	Tehran	Hospitalized patients	NR	28	bla_OXA-48, bla_VIM-4	Disk diffusion, modified Hodge test, PCR
Kamali⁷⁹	2014	Hamedan	Hospitalized patients	65	3	NR	Disk diffusion, modified Hodge test, PCR
Nobari⁸⁰	2014	Tehran	NR	180	25	bla_NDM, bla_VIM, bla_KPC	Disk diffusion, modified Hodge test, PCR
Rastegar-Lari⁸¹	2013	Tehran	Hospitalized patients	29	19	NR	Disk diffusion, modified Hodge test
Shokri⁸²	2013	Isfahan	NR	75	65	NR	Disk diffusion, modified Hodge test
Shahcheraghi⁸³	2013	Tehran	NR	45	7	bla _NDM-1	Disk diffusion, modified Hodge test, PCR

NR, not reported.

Table 2.

Characteristics of Included Studies for Escherichia coli

First author	Published time	City	Population	No. of E. coli	No. of carbapenem-resistant E. coli	Mechanisms of carbapenem resistance	Diagnostic test
Zare⁴⁹	2019	Multicenter	Hospitalized patients with cancer	74	5	Carbapenemase genes were not detected	Disk diffusion, PCR
Koraei⁵⁷	2018	Ahvaz	Hospitalized patients	376	28	Carbapenemase genes were not detected	Disk diffusion, PCR
Fatemi⁸⁴	2018	Isfahan	NR	466	9	bla _NDM-1	Disk diffusion, PCR
Shahbazi⁸⁵	2018	Tehran	Hospitalized patients and outpatients	120	0	Carbapenemase genes were not detected	Disk diffusion, modified Hodge test, PCR
Shams⁸⁶	2018	Qom	NR	160	5	Carbapenemase genes were not detected	Disk diffusion, PCR
Shahcheraghi¹⁹	2017	Hamadan	Hospitalized patients and outpatients	207	18	Carbapenemase genes were not detected	Disk diffusion, modified Hodge test, PCR
Solgi⁸⁷	2017	NR	NR	NR	28	bla_NDM-1, bla_NDM-7, bla_OXA-48like	Disk diffusion, modified Hodge test, PCR
Nojoomi⁸⁸	2017	Tehran	Hospitalized patients	NR	50	bla_OXA-48, bla_IMP	Disk diffusion, PCR
Solgi⁶⁹	2016	Tehran	Hospitalized patients and outpatients	52	NR	bla _IMP	Disk diffusion, modified Hodge test, PCR
Damavandi⁸⁹	2016	Shahrekord	Hospitalized patients and outpatients	200	NR	bla_OXA-23, bla_OXA-24, bla_OXA-48	Disk diffusion, PCR
Shokri⁹⁰	2015	Isfahan	NR	191	5	NR	Disk diffusion, modified Hodge test
Zeighami⁷³	2015	Zanjan	NR	200	0	NR	Disk diffusion, PCR
Ghadiri⁹¹	2014	Tehran	Outpatients	300	30	NR	Disk diffusion
Kamali⁷⁹	2014	Hamedan	Hospitalized patients	205	14	NR	Disk diffusion, modified Hodge test, PCR
Shokri⁸²	2013	Isfahan	NR	285	14	NR	Disk diffusion, modified Hodge test
Shahcheraghi⁸³	2013	Tehran	NR	244	9	NR	Disk diffusion, modified Hodge test
Masaeli⁹²	2012	Tehran	Hospitalized patients	288	90	NR	Disk diffusion
Kalantar⁹³	2010	Kerman	Outpatients	138	0	NR	Disk diffusion, MHT

MHT, modified Hodge test.

All included articles were cross-sectional studies, including from 23 to 992 clinical samples per study. Studies were conducted in different cities; Tehran and Isfahan were the most frequently represented cities. Resistance was determined according to the Clinical and Laboratory Standards Institute (CLSI) guidelines in all included studies. PCR, disk diffusion, and modified Hodge tests were used to determine the CRE. Based on the JBI, the included articles had a low risk of bias.

Frequency and mechanisms of carbapenem resistance in K. pneumoniae

The estimated rate of carbapenem-resistant K. pneumoniae was 24.0% (95% CI 18.0–31.0, I²: 96%) (Fig. 2). Based on Begg's test, publication bias was observed (p = 0.013).

FIG. 2.

The pooled rate of resistance to carbapenem in Klebsiella pneumonia.

Our analysis indicated that 47.1% of carbapenem-resistant K. pneumoniae possessed the bla_OXA-48 gene. Therefore, bla_OXA-48 was responsible for resistance to carbapenem in the majority of clinical isolates of K. pneumoniae (Table 3). The data also indicated that the acquisition of bla_NDM gene is the second cause of resistance to carbapenems in K. pneumoniae.

Table 3.

Mechanisms of Carbapenem Resistance in Klebsiella pneumoniae

Genes responsible for carbapenem resistance	Number of studies	Number of carbapenem-resistant K. pneumoniae	Number of genes responsible for carbapenem resistance, n (%)
bla_OXA-48	9	484	228 (47.1)
bla_NDM	17	684	206 (30.1)
bla_GES	7	366	102 (27.8)
bla_KPC	15	815	99 (12.1)
bla_VIM	14	880	94 (10.6)
bla_IMP	9	523	24 (4.5)

Frequency and mechanisms of carbapenem resistance in E. coli

The estimated rate of carbapenem-resistant E. coli was 5.0% (95% CI 2.0–8.0) (Fig. 3). No evidence of publication bias was observed (Begg's tests p-value was 0.139).

FIG. 3.

The pooled rate of resistance to carbapenem in Escherichia coli.

As shown in Table 4, bla_OXA-48 (37.1%), bla_NDM (21.9%), and bla_IMP (9.6%) genes were responsible for carbapenem resistance in E. coli.

Table 4.

Mechanisms of Carbapenem Resistance in Escherichia coli

Genes responsible for carbapenem resistance	Number of studies	Number of carbapenem-resistant E. coli	Number of genes responsible for carbapenem resistance, n (%)
bla_OXA-48	2	78	29 (37.1)
bla_NDM	4	114	25 (21.9)
bla_IMP	3	83	8 (9.6)

Discussion

The emergence and distribution of CRE are classified as one of the highest risks for public health. There is a high risk of infection with CRE in patients with prior antibiotic exposure and suppressed immune systems, recipients of organ transplant, invasive devices like central venous catheters, or those mechanically ventilated for more than 72 hours.^5,25 In Iran, there is an increasing prevalence of CRE, which is similar with neighboring countries, including Turkey, Iraq, and Pakistan with relatively high rates of CRE.^26–29 Unfortunately, there are no surveillance programs for the prevalence of CRE in Afghanistan, but there are some reports of detecting CRE strains.²⁷

Carbapenems are important for the treatment of health care-associated infections and are used when bacteria have high antibiotic resistance.^30,31 Therefore, the increased prevalence of CRE may lead to increased mortality, prolonged hospital course, as well as increased health care spending and utilization.^31,32

As mentioned, one of the main mechanisms of resistance to carbapenem in E. coli and K. pneumoniae is the production of carbapenemase (i.e., NDM, KPC, VIM, IMP, and OXA).^9,33 Other mechanisms of resistance are the modification of porins combined with the overproduction of AmpC β-lactamases.¹⁷ The current meta-analysis indicated that bla_OXA-48 gene (47.1%) and bla_NDM gene (30.11%) were responsible for resistance to carbapenem in K. pneumoniae. Likewise, the most commonly reported mechanisms of resistance to carbapenem in E. coli were due to the existence of bla_OXA-48 (37.17%) and bla_NDM (21.92%) genes, respectively.

These bacterial strains can receive the plasmid carrying the bla_OXA-48 gene and therefore can produce OXA-48 carbapenemase.^34,35

The OXA-48 is a β-lactamase in class D Ambler classification and can hydrolyze penicillins and imipenem, and has trivial activity against broad-spectrum cephalosporins.³⁶ However, in one study, about 25% of OXA-48 carbapenemase producers showed susceptibility to extended-spectrum cephalosporins.³⁵ Initially, OXA-48 carbapenemase was first reported from Turkey, by isolating from a K. pneumoniae clinical strain, in 2001.³⁷ Dissemination of bla_OXA-48 gene is frequently by insertion of Tn1999-like transposons in pOXA-48a plasmid, and becomes a major concern in antimicrobial drug resistance.^37,38

The data also indicated that the acquisition of bla_NDM gene is the second most common cause of carbapenem resistance in E. coli and K. pneumoniae. The bla_NDM gene can be found in different types of plasmids (i.e., IncHI1, IncX, and IncL/M).³² The bla_NDM is an MBL that is not inhibited by β-lactam inhibitors and hydrolyzes most of β-lactams, including carbapenems, penicillins, and cephalosporins; however, this does not have an effect on aztreonam.^39,40 The bla_NDM gene has been spread worldwide and bacterial strains producing bla_NDM are endemic in India, Balkan, and Middle Eastern countries. There are new concerns about South Africa becoming endemic as well.^41,42

The CRE is spreading around the world may be due to the travel of patients to other countries.⁴³ Also, there are limited treatment options for CRE, because these strains are resistant to many antimicrobial drugs, so it is necessary to follow appropriate control and treatment for patients infected with CRE. The available therapeutic options are divided into two categories of mono-therapies and combination therapies. Currently, the active drugs for the treatment of CRE include the polymyxins, tigecycline, fosfomycin, and aminoglycosides.⁴⁴ Several studies reported combination therapies due to synergistic effects of antibiotics and persistence against the emergence of drug monoresistance lead to better clinical outcomes and a decrease in mortality.^45,46

Delayed antibiotic treatment for severe infections with CRE, such as severe sepsis, could increase the mortality, so a proper empirical therapy based on suspected bacterial agents, epidemiology of local drug resistance, and patient risk factors should be performed.⁴⁷ Therefore, for severe infections with CRE, an empirical therapy, including the combination of carbapenems, colistin, or aminoglycosides, according to the epidemiology of local drug resistance should be prescribed.⁴⁷

Some limitations to this study need to be presented. Data about noncarbapenemase carbapenem-resistant mechanisms, including modification of porins in K. pneumoniae and E. coli, were limited and needed more investigations for better comparing the mechanisms of CRE. Another limitation was due to the lack of data about CRE in some of the regions of Iran; the reported prevalence of this study does not fully represent the situation of CRE in Iran. Likewise, there were limited data about risk factors for CRE infections that needed further studies. In addition, not all included studies tested the same carbapenemase genes. Thus, the frequency of each carbapenemase gene in this study may be biased. Finally, there was heterogeneity between the included studies.

In conclusion, these results indicated that CRE is prevalent in Iran, which confers the importance of strength prevention and control strategies.

Footnotes

Authors' Contributions

M.J.N. and P.T.: designed the study. M.J.N., M.A., F.F., B.D., S.D., S.Z., and B.H.: performed the search, study selection, and statistical analysis. M.J.N. and S.M.J.M.: wrote the first draft of the article. M.J.N., M.M., M.G., H.G., Z.S.S., H.D, and P.T.: revised the article.

Disclosure Statement

No competing financial interests exist.

Funding Information

This study was supported by Shahid Beheshti University of Medical Sciences, Tehran, Iran.

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