Prevalence and Mechanisms of Carbapenem Resistance in Acinetobacter baumannii : A Comprehensive Systematic Review of Cross-Sectional Studies from Iran

Abstract

Introduction:

Carbapenem-resistant Acinetobacter baumannii (CRAB) is recognized to be among the most difficult antimicrobial-resistant gram-negative bacilli to control and treat. An understanding of the epidemiology of CRAB and the mechanisms of resistance to carbapenems is necessary to develop strategies to curtail their spread.

Methods:

Electronic databases were searched from January 1995 to December 2017 for all studies, which: (1) provide data on the frequency and antibiotic resistance profile of the isolated A. baumannii and (2) describe the mechanisms of carbapenem resistance in detail.

Results:

Sixty-eight studies were found referring to mechanisms of carbapenem resistance in clinical isolates of A. baumannii, and 56 studies were found referring to the frequency of CRAB. The pooled frequency of carbapenem resistance was 85.1% (95% confidence interval [CI]: 82.2–88.1) in 8,067 clinical isolates of A. baumannii. Resistances due to bla_OXA23 (55.3%), bla_OXA24 (41.4%), and bla_OXA58 (5.2%) genes were the most prevalent reported mechanisms of resistance to carbapenem, respectively.

Conclusions:

Our data warn that CRAB will rise if the current situation remains uncontrolled. Better control infection strategies and antibiotic managements, particularly in the health care systems, are needed to limit the spread of this pathogen.

Introduction

A cinetobacter baumannii has now emerged as an important opportunistic pathogen in the hospitals, particularly in intensive care units (ICUs).^1–3 This organism is responsible for a wide variety of nosocomial infections, such as pneumonia, blood infection, endocarditis, meningitis, urinary tract infection, and skin infection.^1,2 High mortality rates associated with A. baumannii infections have been reported, ranging from 8% to 23% in hospitals and from 10% to 43% in ICUs.⁴ This organism has a remarkable ability to quickly develop resistance to multiple antibiotics such as quinolones, aminoglycosides, and carbapenems.^5,6 Carbapenems (imipenem, meropenem, or doripenem) have been considered as extremely potent agents in the treatment of serious infections caused by A. baumannii.^4,7 However, the prevalence of carbapenem-resistant A. baumannii (CRAB) has been increasing rapidly worldwide, leading to treatment failures and prolonging hospitalization.^8,9 Several mechanisms of carbapenem resistance have been identified in A. baumannii (5).

One of the most common mechanisms of carbapenem resistance is the production of carbapenem-hydrolyzing enzymes (carbapenemases).^5,6 These enzymes belong to classes A, B, and D based on molecular Ambler classification.^5,6 Class A carbapenemases consist of six different members (SME, IMI, NMC, GES, SFC, and KPC families) (13). Of these, GES carbapenemases are the most prevalent in A. baumannii, which confer a low level of resistance to carbapenems.^5,6 These carbapenemases are more common in Enterobacteriaceae than A. baumannii.¹⁰ Class B enzymes called metallo-β-lactamases (MBLs) are potent carbapenemases and four types of MBLs have also been reported in A. baumannii, namely IMP, VIM, SIM, and NDM.^5,11 Carbapenem-hydrolyzing class D β-lactamases (CHDLs), also referred to as OXA-type enzymes or oxacillinases, are the most common carbapenemases in A. baumannii.⁵

Currently, six subclasses of OXA related to A. baumannii have been identified (i) OXA-23-like (OXA-23, OXA-27, OXA-49, and OXA-239), (ii) OXA-24-like (OXA-24, OXA-25, OXA-26, OXA-40, and OXA-72), (iii) OXA-51-like, (iv) OXA-58, (v) OXA-143-like (OXA-143 and OXA-231), and (vi) OXA-235-like (OXA-235, OXA-236, and OXA-237).^5,6

The second major mechanism of resistance is loss and/or decrease in outer membrane proteins (OMPs), which leads to a reduction in the permeability of antibiotics.^5,6 Three OMPs (a 29-kDa protein [also known as CarO], a 33- to 36-kDa protein, and OmpW) have been identified in A. baumannii.^5,6 Finally, overexpression of resistance-nodulation-cell division (RND)-type efflux pumps such as AdeABC, AdeFGH, and AdeIJK plays a significant role in carbapenem resistance.^5,6 Iran is a country with the highest rates of CRAB, reaching 92% for imipenem and meropenem.¹²

In Iran, several studies reported the CRAB^13–16; however, a comprehensive study on the prevalence as well as the mechanisms of CRAB has not yet been performed. Therefore, the aims of this study were: to determine the frequency of carbapenem resistance among clinical isolates of A. baumannii and to understand the mechanisms responsible for the emergence of carbapenem resistance in this bacterium.

Methods

Search strategies and study selection

A comprehensive search in PubMed, Web of Science, Scopus, and Iranian databases [i.e., MAGIRAN (www.magiran.com) and SID (www.sid.ir)] was performed from January 1995 to December 2017 for all articles that included the search terms “acinetobacter” AND “Carbapenem*” OR “imipenem” OR “panipenem” OR “Doripenem” OR “Meropenem” OR “Biapenem” OR “Tebipenem” AND “Iran” in their title and/or abstract. Similar strategies and related Persian keywords were used for Iranian databases. The study focused on original articles that were published in English and Persian. Two reviewers (A.F.S. and M.A.) independently performed systematic search, study selection, and data extraction from included studies. Any discrepancies were resolved through consensus discussion.

Inclusion and exclusion criteria

Studies that provided data on the antibiotic resistance in clinical isolates of A. baumannii and/or described the mechanisms of carbapenem resistance in detail were selected. Studies were included if resistance was determined according to Clinical and Laboratory Standards Institute (CLSI) Guideline. Review articles, congress abstracts, studies with languages other than English or Persian, case reports, and editorials were excluded.

Data extraction

For each study, the following information was extracted: author's name, published year, study period, study design, sample size, type of infection, sites of infection, number of A. baumannii tested, proportion of carbapenem resistance, the method of diagnosis of carbapenem resistance, and the mechanisms of carbapenem resistance.

Quantitative data synthesis

The pooled prevalence of CRAB, with 95% confidence intervals (95%CI) was calculated by the random-effects model. The I² test was used to assess between-study heterogeneity, where I² values of 0% indicate no observed heterogeneity whereas larger values indicate increasing heterogeneity. Egger's and Begg's tests were used to check the publication bias (p < 0.05 was considered indicative of statistically significant publication bias). All the analyses were conducted by using Stata 14.0 (StataCorp, College Station, TX).

Quality assessment of studies

The checklist provided by the Joanna Briggs Institute was used to perform the quality assessment.¹⁷

Results

Figure 1 shows the steps that we followed to select the relevant studies. We initially identified 1,000 potentially relevant studies from databases. In the end, there were 88 studies fulfilling the inclusion criteria. Table 1 summarizes the characteristics of each included study. The total number of A. baumannii isolates included in the study was 7,938. All studies exclusively examined the mechanisms of carbapenem resistance in A. baumannii. Disk diffusion, Microbroth dilution, E test, Modified Hodge test, and Multiplex PCR were the methods used in the included studies.

FIG. 1.

Flowchart of study selection for inclusion in the systematic review and meta-analysis.

Table 1.

Characteristics of Included Studies

First author	Published time	City	Study population	Number of A. baumannii	Number of carbapenem-resistant A. baumannii	Genes responsible for carbapenem resistance	Diagnostic methods
Sadeghifard⁴⁶	2006	Tehran	NR	66	66	NR	NR
Feizabadi⁴⁷	2008	Tehran	Hospitalized patient	108	53	bla_OXA-23 like, bla_OXA-24 like and bla_OXA-51 like	Disk diffusion, Multiplex PCR
Morovat⁴⁸	2009	Tehran	NR	80	40	bla_OXA-23 like, bla_OXA-24 like and bla_OXA-58 like	Multiplex PCR
Khaltabadi⁴⁹	2013	Kashan	NR	60	32	NR	Disk diffusion, PCR
Khosroshahi⁵⁰	2010	Ghazvin	Hospitalized patient	15	4	NR	Disk diffusion
Asadollahi1⁵¹	2011	Tehran	Hospitalized patient	100	NR	bla_OXA-23 like, bla_OXA-24 like and bla_OXA-58 like	E test, Multiplex PCR
Shahcheraghi⁵²	2011	Tehran	Hospitalized patient	100	NR	NR	Microbroth dilution, PCR
Ardebili⁵³	2012	Tehran	Hospitalized patient	65	60	NR	NR
Asadollahi⁵⁴	2012	Tehran	Hospitalized patient	23	7	bla_OXA-51 like	E test, Multiplex PCR
Azimi⁵⁵	2012	Tehran	Hospitalized patient	7	6	KPC	Disk diffusion, Modified Hodge test
Dehghani⁵⁶	2012	Tehran	NR	50	39	bla _KPC	Disk diffusion, PCR
Mirnejad⁵⁷	2012	Tehran	NR	50	39	NR
Owlia⁵⁸	2012	Tehran	Outpatient	126	108	NR	Disk diffusion
Peymani⁵⁹	2012	Tabriz	Outpatient	68	68	bla_OXA-23 like	PCR
Sohrabi¹⁴	2012	Tabriz	Hospitalized patient	100	62	bla_OXA-23 like, bla_OXA-40 like and bla_OXA-58 like	PCR
Azimi⁶⁰	2013	Tehran	Hospitalized patient	94	80	bla_OXA-23 like	Disk diffusion, Microbroth dilution, PCR
Japoni⁶¹	2013	Arak	Hospitalized patient	56	47	MBL	Disk diffusion, E test, Modified Hodge test
Japoni⁶²	2014	Arak	Hospitalized patient	56	NR	NR	PCR
Karmostaji⁶³	2013	Tehran	Hospitalized patient	123	103	bla_OXA-23 like, bla_OXA-24 like and bla_OXA-58 like	Disk diffusion, Multiplex PCR
Safari⁶⁴	2013	Hamedan	Hospitalized patient	100	94	MBL producer.	MIC Microbroth dilution
Mohajeri1⁶⁵	2013	Kermanshah	Outpatient	104	104	bla_OXA-23 like, bla_OXA-24 like and bla_OXA-51 like	PCR
Pajand¹⁶	2013	Tehran	Hospitalized patient	75	64	bla_OXA-23 like and bla_OXA-40 like	PCR
Shoja⁶⁶	2013	Ahvaz	Hospitalized patient	206	198	bla_OXA-23 like and bla_OXA-24 like	Multiplex PCR
Vafaei⁶⁷	2013	Tehran	Hospitalized patient	100	76	NR
Fallah⁶⁸	2014	Tehran	Outpatient	108	99	bla_VEB1, bla_IMP1, bla_VIM1 and RER1	Disk diffusion, Microbroth dilution, PCR
Ghajavand⁶⁹	2014	Isfahan	Hospitalized patient	43	40	NR	NR
Hojabri⁷⁰	2014	Tehran/Tabriz	Hospitalized patient	71	60	bla_OXA-23 like, bla_OXA-24 like	E test, PCR
Noori⁷¹	2014	Tehran	Outpatient	108	99	MBL producers	Microbroth dilution, PCR
Norozi⁷²	2014	Kermanshah	Hospitalized patient	84	67	bla_OXA-23 like, bla_OXA-24 like and bla_OXA-58 like	PCR
Peymani¹⁵	2011	Tabriz	Hospitalized patient	100	63	MBL producers	E test, PCR
Tavakol	2014	Tehran	Hospitalized patient	121	NR	bla_OXA-23 like, bla_OXA-24 like, bla_OXA-51 like and bla_OXA-58 like	PCR
Vazirzadeh⁷³	2014	Isfahan	Hospitalized patient	100	96	MBL producers	NR
Aghamiri⁴⁴	2015	Tehran	Hospitalized patient	176	169	bla_IMP and bla_VIM	Disk diffusion, PCR
Azimi⁷⁴	2015	Tehran	Hospitalized patient	65	65	bla_OXA-23 like, bla_OXA-51 like, bla kpc and bla_VIM	Disk diffusion, Multiplex PCR
Azizi⁷⁵	2015	Kerman	Hospitalized patient	65	NR	bla_OXA-23 like, bla_OXA-24 like, bla_OXA-51 like and bla_IMP-55	Disk diffusion, E test, PCR
Bagheri⁷⁶	2015	Kashan	Hospitalized patient	124	110	bla_OXA-23 like, bla_OXA-24 like, bla_OXA-58 like and bla_PER	Disk diffusion, PCR
Bahador⁷⁷	2015	Tehran	Hospitalized patient	62	38	bla_OXA-23 like and bla_VIM-2	Disk diffusion, PCR
Bahador⁷⁸	2015	Tehran	Hospitalized patient	85		bla_OXA-23 like	Modified Hodge test, Multiplex PCR
Bahadori⁷⁹	2015	Bandar Abbas	Hospitalized patient	72	70	bla_OXA-23 like and bla_OXA-24 like	Disk diffusion, Multiplex PCR
Davoodi⁴⁵	2015	Tehran	NR	104	70	bla_VIM-1, bla_VIM-2, bla_IMP1 and bla_IMP2	Disk diffusion, PCR
Farshadzadeh¹³	2015	Tehran	Hospitalized patient	92	NR	bla_OXA-23 like and bla_PER1	E test, PCR
Farsiani⁸⁰	2015	Mashhad		36	32	bla_OXA-23 like, bla_OXA-24 like and bla VIM	E test, PCR
Gholami⁸¹	2015	Tehran	Hospitalized patient	60	60	efflux pump adeA, adeB and adeC	Disk diffusion, Microbroth dilution, PCR
Goudarzi⁸²	2015	Tehran	NR	128	127	bla_IMP and bla_VIM	Disk diffusion, PCR
Kooti⁸³	2015	Shiraz	Hospitalized patient	200	199	bla_OXA-23 like, bla_OXA-24 like and bla_OXA-58 like	Multiplex PCR
Mahdian²¹	2015	Tehran	Hospitalized patient	37	NR	bla_OXA-23 like	PCR
Mohajeri	2015	Kermanshah	Outpatient	42	38	bla_OXA-23 like and bla_OXA-24 like	PCR
Peerayeh⁸⁴	2015	Tehran	NR	123	123	NR	PCR
Rahmani⁸⁵	2015	Shiraz and Tehran	Hospitalized patient	140	129	NR	Microbroth dilution, PCR
Saderi⁸⁶	2015	Tehran	Hospitalized patient	106	102	NR	NR
Safari⁸⁷	2015	Hamedan	Hospitalized patient	100	95	MBL producer	E test, PCR
Salimizand⁸⁸	2015	Mashhad	Hospitalized patient	30	NR	bla_OXA-23 like and bla_OXA-24 like	PCR
Zanganeh⁸⁹	2015	Tehran	Hospitalized patient	58	58	bla_OXA-23 like and bla_OXA-24 like	Microbroth dilution, PCR
Alaei⁹⁰	2016	Shiraz	Hospitalized patient	85	79	bla_OXA-23 like and bla_OXA-24 like	Disk diffusion, Microbroth dilution, PCR
Aliamezani⁹¹	2016	Tehran	Hospitalized patient	8	5	bla_OXA-23 like	Disk diffusion, Microbroth dilution, Multiplex PCR
Azimi⁹²	2016	Tehran	Hospitalized patient	50	NR	bla_KPC, bla_OXA-23 like and bla_VIM	Disk diffusion, Multiplex PCR
Goli⁹³	2017	kashan	Hospitalized patient	124	111	bla_OXA-51 like and VEB1
Goudarzi⁹⁴	2016	Tehran	Hospitalized patient	108	NR	MBL producers	PCR
Khaledi⁹⁵	2016	Tehran	Hospitalized patient	100	NR	Efflux pump	Disk diffusion, Microbroth dilution, Multiplex PCR
Malayeri⁹⁶	2016	Tehran	Outpatient	60	51	bla_OXA-23 like	Microbroth dilution, PCR
Maspi⁹⁷	2016		Hospitalized patient	86	78	MBL producers
Moghadam⁹⁸	2016	Shiraz	Hospitalized patient	98	96	NR	Microbroth dilution, PCR
Pourabbas⁹⁹	2016	Shiraz	Hospitalized patient	61	NR	bla_OXA-23 like, bla_OXA-₄₀ like, bla_OXA-51 like and bla_OXA-58 like	E test, Multiplex PCR
Shoja¹⁰⁰	2016	Ahvaz	Hospitalized patient	124	97	bla_OXA-23 like and bla_OXA-24 like	E test, PCR
Tarashi¹⁰¹	2016	Tehran	Hospitalized patient	189	187	MBL producers	Multiplex PCR
Babapour¹⁰²	2017	Tehran	Hospitalized patient	156	142	NR
Josheghani¹⁰³	2017	Kashan	Hospitalized patient	40	40	bla_OXA-23 like, bla_OXA-40 like and bla_OXA-51 like	Disk diffusion, Multiplex PCR
Bardbari¹⁰⁴	2017	Hamedan	Outpatient	75	73	bla_OXA-23 like and bla_OXA-24 like	Disk diffusion, Microbroth dilution, PCR
Dehbalaei¹⁰⁵	2017	Tehran	Hospitalized patient	48	37	bla_OXA-23 like, bla_OXA-40 like, bla_OXA-58 like, bla_VIM and bla_IMP	Disk diffusion, PCR
Erfani¹⁰⁶	2017	Tehran	Outpatient	107	NR	bla _VIM	Disk diffusion, Microbroth dilution, PCR
Ghalebi¹⁰⁷	2017	Isfahan	Outpatient	40	40	bla_OXA-23 like and bla_OXA-24 like	PCR
Khamesipour¹⁰⁸	2017	Tehran	Outpatient	121	NR	NR	Disk diffusion, PCR
Khodaei¹⁰⁹	2017	Gonbad	Hospitalized patient	50	NR	bla _KPC	Modified Hodge test, PCR
Mirshekar¹¹⁰	2017	Tehran	Hospitalized patient	72	61	bla_OXA-23 like, bla_OXA-24 like and bla_OXA-58 like	PCR
Mohajeri¹¹¹	2017	Kermanshah	Hospitalized patient	75	62	bla_OXA-23 like and bla_OXA-24 like	PCR
Mohammadi¹¹²	2017	Tehran	Hospitalized patient	100	98	bla_OXA-23 like and bla_OXA-24 like	PCR
Mohammadi¹¹³	2017	Tehran	Hospitalized patient	103	96	bla_OXA-23 like, bla_OXA-24 like and bla_OXA-58 like	PCR
Moosavian¹¹⁴	2017	Ahvaz	Hospitalized patient	151	142	NR	Modified Hodge test
Navidinia¹¹⁵	2017	Tehran	Hospitalized patient	37	32	NR	PCR
Owrang¹¹⁶	2017	Tehran	Hospitalized patient	105	103	bla_OXA-23 like and bla_OXA-24 like	PCR
Saffari¹²	2017	Kerman	Hospitalized patient	64	NR	bla_OXA-23 like	Multiplex PCR
Sarhaddi¹¹⁷	2017	Mashhad	Hospitalized patient	54	54	NR	PCR
Sarikhani¹¹⁸	2017	Qom	Hospitalized patient	108	97	bla_OXA-23 like	PCR
Savari¹¹⁹	2017	Tehran	Hospitalized patient	120	NR	NR	PCR
Shamsizadeh¹²⁰	2017	Isfahan	Outpatient	40	34	bla_OXA-23 like	PCR
Shoja¹²¹	2017	Ahvaz	Hospitalized patient	40	36	bla_OXA-23 like and bla_OXA-24 like	E test, PCR
Shokri¹²²	2017	Isfahan	Outpatient	31	28	NR	E test, PCR
Zafari¹²³	2017	Tehran	Hospitalized patient	536	429	NR	Modified Hodge test, PCR

All included studies were cross-sectional studies, among which 10 studies examined patients with burn wounds, three studies examined pneumonia, and the other studies examined all sources of infections. Studies were mostly conducted in the center and capital of Iran (50 in Tehran, 5 in Isfahan, 5 in Kashan, 5 in Shiraz, 3 in Kerman, 2 in Arak, and 1 in Qom).

Prevalence of carbapenem resistance in clinical isolates of A. baumannii

Based on the quality assessment, 56 studies were included for quantitative analysis. In these studies, the reported resistance to carbapenem varied across studies, ranging from 26.6% to 100%. The pooled frequency of carbapenem resistance in clinical isolates of A. baumannii was 85.1% (95%CI: 82.2–88.1; I² = 100%) (Fig. 2). Based on Begg's (p = 0.00) and Egger's (p = 0.01) tests, there was some evidence of publication bias.

FIG. 2.

Forest plot of frequency of carbapenem resistance in clinical isolates of Acinetobacter baumannii.

Mechanisms of carbapenem resistance in clinical isolates of A. baumannii

Sixty-eight studies fulfill the criteria for this section. Resistance due to the bla_OXA23 gene has been reported in 44 papers. Analysis of these studies revealed that 55.39% (2,489/4,493) of resistant A. baumannii strains possessed bla_OXA23 gene. Therefore, bla_OXA23 was the most common gene responsible for resistance to carbapenem among A. baumannii strains. Table 2 showed the other prevalent genes that were responsible for resistance to carbapenem.

Table 2.

Mechanisms of Carbapenem Resistance in Clinical Isolates of Acinetobacter baumannii

Genes responsible for carbapenem resistance	Number of studies	Number of carbapenem-resistant A. baumannii	Number of genes responsible for carbapenem resistance (%)
bla _OXA-23	44	4,493	2,489 (55.3)
bla_OXA-24 like (bla_OXA-24, bla_OXA-₄₀)	31	14,656	1,847 (41.4%)
bla _OXA-58	9	930	46 (5.2)

Discussion

The emergence and spread of CRAB, occurring in the outbreak of health care associated infections, is a concerning public health crisis, especially in the ICU setting. The presence of CRAB could be sufficient to consider this bacteria as highly resistant.^18,19 A. baumannii isolates from different countries have shown resistance to carbapenems in a wide range; especially in developing countries, the occurrence of CRAB infections has become an emergent public health concern in nosocomial infections.²⁰ In Iran, the prevalence of CRAB has been increasing rapidly during the past years, which influences emerging multi-drug resistance.^13,21

According to this analysis, the high rate of resistance to carbapenem (85.1%) was assessed. The CRAB that was reported by different studies ranged from 26.6% to 100%. This level of resistance is higher than previous reports of resistance to imipenem from Iran.^13,21 Increasing the resistance to carbapenems, which were considered the choice of treatment for A. baumannii infections, has created obstacles for the effective treatment of these infections. In addition, rapid expansion of the CRAB infection could be principally because of the dissemination of established resistant clones or the acquisition of resistance elements by susceptible strains. Although the main reason is not obvious, some studies support the second reason.^21–24 The neighboring countries of Iran, including Pakistan, Turkey, Afghanistan, and Iraq, have particularly high rates of CRAB.^25–28 The trends of these countries also were increasing, for example, in Turkey, resistance to carbapenems reached 97.8% in 2015.²⁹ Also, some evidences about community-acquired Multi-Drug Resistant A. baumannii infections have been reported from Afghanistan and Iraq through the past decade.³⁰ Thus, a combination of some factors such as cross-border communication between these countries for travel, work, trade, and medical cure as well as unbounded accessibility of antibiotic drugs such as carbapenems and antibiotic pollution could be the most important cause of this increasing trend.⁶

The main carbapenem resistance mechanism in A. baumannii is frequently related to carbapenemase production, among which the most common ones are CHDLs or OXA-type enzymes and the next ones are MBL enzymes such as VIM, IMP, and NDM. Furthermore, the loss or decrease in OMPs and overexpression of RND-type efflux pumps are the other major mechanisms of resistance.⁵ According to this analysis, in Iran, the production of carbapenemase due to the presence of bla_OXA23 (55.3%) was the most prevalent reported mechanism of carbapenems resistance followed by the existence of bla_OXA-24 like (44.1%) genes. These data indicated that increase in resistance to carbapenems in clinical A. baumannii is principally related to the distribution of OXA-producing strains. Genes encoding OXA carbapenemase such as bla_OXA23 can be allocated in the plasmid elements belonging to the IS4 family. The presence of specific IS such as ISAba1, located upstream of bla_OXA genes, explained that they could often provide promoter sequences for these genes.¹⁹ So an increase in the expression of bla_OXA genes results in diminishing the carbapenems' susceptibility.^31–33 The main issue about OXA carbapenemases is their capability to quickly mutate and develop their range of activity.⁵ OXA-23 belongs to a CHDL subgroup named OXA-23-like, which is the most common acquired resistance mechanism in the different parts of the world.^34–36 In neighboring countries such as Turkey, Afghanistan, and Pakistan they have been frequently presented.^10,37

Twenty five percent and 29.1% of these reported CRAB contained bla_OXA-40 and bla_OXA-24 genes, respectively, that belong to a second subclass of CHDLs termed OXA-24-like comprising OXA-24, OXA-25, OXA-26, OXA-40, and OXA-72. OXA-40 was recognized in CRAB isolates and has been found to be prevalent in France, Spain, and Portugal.^38–40 Moreover, OXA 24 and OXA40 indicate that OXA-72 is the most common mechanism of carbapenem resistance in some countries in the Southern part of Europe such as Croatia, Bosnia and Hecegovina, Serbia.^20,22

The other subclass of CHDLs consists of OXA-58, which was originally known in a CRAB isolate in France,⁴¹ responsible for about 5% of reported CRAB in Iran. Several investigations have identified the bla_OXA-58 gene in A. baumannii isolates from different countries such as Iraq, Kuwait, Turkey, Romania, Greece, Austria, the United Kingdom, and Spain.^33,42,43 The bla_OXA-58 and bla_OXA-23 genes have also been identified in A. baumannii isolated from damaged U.S. military personnel in Iraq and Afghanistan.¹⁰

In addition, in most of the studies conducted in Iran and other countries, VIM- and IMP-type genes were the most predominant genes in MBL producer A. baumannii.^42–45 Besides, the highest rate of resistance caused by NDM carbapenemases has been found to be in Pakistan, whereas in other regions of the Middle East they have been reported sporadically.¹⁰

Diversity of carbapenemase enzymes may be influenced by historical and social dealings and may also be due to wars and travels. Thus, proper management is desirable to control these infections. The remarkable therapeutic choices for CRAB infections are tigecycline and colistin; if resistance to them develops in recent years, the drug resistance crisis may cause high morbidity and mortality.

There were some limitations to this study that should be considered. First, there were limited data regarding non-carbapenemase-resistant mechanisms such as porin loss and specific efflux pump systems in A. baumannii isolates. Increased information about these mechanisms, in addition to the production of carbapenemase, can fortify the real judgment about CRAB in Iran. Second, it cannot fully represent the prevalence of CRAB, because the extent of this bacterium has not yet been assessed in some regions of Iran. Third, we were unable to determine the risk factors for CRAB infection due to the limited information obtained from the studies. Forth, heterogeneity exists among the included studies. Finally, as with any systematic review, the existence of potential publication bias should be considered.

In conclusion, this article warns that antimicrobial resistance will rise every year if the current situation remains uncontrolled. We also propose that the bla_OXA-23 gene may be one of the most widespread reported mechanisms for the development of CRAB in Iran. Better control infection and antibiotic management, particularly in the health care systems, should be obligate to decrease the dissemination and emergence of antimicrobial resistance. It is suggested that a susceptibility test for carbapenems could be predominantly needed if the patient had been cured with carbapenem and glycopetides earlier. Further, to achieve the goal, to decrease the development of CRAB, the regional collaboration has been highlighted by Iran and its bordering countries.

Footnotes

Acknowledgment

The authors thank the reviewers of the Microbial Drug Resistance Journal for their helpful and thoughtful comments.

Authors' Contributions

M.J.N. and P.T.: Designed the protocol.

M.J.N., S.Z., F.F., M.A., R.B., and B.H.: Performed the search, data extraction, and statistical analysis.

M.J.N. and S.Z.: Wrote the first draft of the article.

M.J.N., S.Z., H.G., H.D., M.M.F., and P.T.: Revised the article.

Disclosure Statement

No competing financial interests exist.

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